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Review

Phosphoinositides in Retinal Function and Disease

by
Theodore G. Wensel
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Cells 2020, 9(4), 866; https://doi.org/10.3390/cells9040866
Submission received: 1 March 2020 / Revised: 26 March 2020 / Accepted: 30 March 2020 / Published: 2 April 2020
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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Abstract

:
Phosphatidylinositol and its phosphorylated derivatives, the phosphoinositides, play many important roles in all eukaryotic cells. These include modulation of physical properties of membranes, activation or inhibition of membrane-associated proteins, recruitment of peripheral membrane proteins that act as effectors, and control of membrane trafficking. They also serve as precursors for important second messengers, inositol (1,4,5) trisphosphate and diacylglycerol. Animal models and human diseases involving defects in phosphoinositide regulatory pathways have revealed their importance for function in the mammalian retina and retinal pigmented epithelium. New technologies for localizing, measuring and genetically manipulating them are revealing new information about their importance for the function and health of the vertebrate retina.

1. Introduction

Phosphoinositides are membrane phospholipids with the six-member cyclic polyol myo-inositol, (CHOH)6, or O-phosphorylated forms of inositol, as their headgroup (Figure 1). The phosphorylated forms are of low abundance in eukaryotic cells of all types, generally comprising 1% or less of total phospholipid. Nevertheless, they play critical roles in cellular regulation, and defects in their synthesis and regulation lead to devastating diseases [1,2,3,4,5,6]. The retina is clearly no exception to this generality, but surprisingly few details have been worked out in what is arguably one of the most extensively studied tissues in our bodies, about the regulation and regulatory roles of retinal phosphoinositides. Recent technological advances make it possible to make substantial advances in this field in the next few years.

2. Chemical Structures of Phosphoinositides

Phosphoinositides (abbreviated here as “PI”) include phosphatidylinositol (PtdIns), in which the 1′-position of the inositol ring is attached via a phosphodiester bond to the sn-3 position of (1, 2) diacyl glycerol, and derivatives of PtdIns with one, two, or three phosphates attached in various combinations to the 4′, 5′ or 3′ hydroxyls of PtdIns. Including PtdIns, a total of eight different PI head groups are commonly found in eukaryotic cells (Figure 1) [4,5].

3. Phosphatidylinositol Content in the Retina and RPE

PtdIns is a relatively substantial component of the membranes of most cells in metazoans, with mole fractions ranging from ~4%–20% of total phospholipid [4]. Early reports stated that retina phospholipids contained 4.4%–6.4% PtdIns across six different mammalian species [7,8,9]. Interestingly, rod outer segment (ROS) membranes were found to have much lower levels, 1.5% to 2.5% in bovine and 2.1% in frog [10,11,12,13]. Retinal pigment epithelial cells (RPE), in contrast, have higher levels of PtdIns, at 6.5% of total phospholipid [14], while ER membranes isolated from bovine retinas contain 9.6% PtdIns [10]. The general picture that emerges is that total PtdIns content in total retinal membranes outside of outer segments and that of RPE are more or less “normal” as compared to other tissues and cell types, consistent with the notion that widespread roles of PI are likely to be conserved in many retinal cell types. In contrast, ROS have an unusually low PtdIns content, suggesting different roles for this lipid class in that organelle. This idea is consistent with findings discussed below, indicating different lipid compositions in plasma membranes as compared to ciliary membranes.

4. Content of Minor Phosphoinositides in the Retina and RPE

As a negatively charged lipid, which typically contains one polyunsaturated side chain fatty acid, such as arachidonic acid [8], PtdIns has a major impact on the physical properties of the membrane domains containing it. In contrast, the phosphorylated forms are much less abundant, and exert their influence on cell physiology largely through interactions with proteins with high-affinity and high-specificity PI-binding domains [15,16,17]. There have been few measurements of phosphorylated PI in retina or cells isolated from retina, although there have been several papers addressing the turnover of PtdIns and other PI, or activity of enzymes involved in PI metabolism [18,19,20,21]. The likely reason for the absence of information on PI levels is their low abundance and the lack of sensitivity provided by conventional methods for lipid analysis. More sensitive techniques have been developed recently, including one based on recombinant phosphoinositide-binding domains fused to an epitope tag, allowing sensitive detection by enzyme-linked immunosorbent assays (ELISAs) and measurement of chemiluminescence [22]. This technique was used to quantify PI(3)P and PI(3,4,5)P3 in preparations of rod cells that contain both outer segments and fragments of the inner segments and demonstrated levels of PI(3)P at 0.0035 mol% of total phospholipid under illumination conditions that yielded the highest levels of that lipid, and at least 10-fold lower (i.e., undetectable) levels of PI(3,4,5)P3. PI(4)P and PI(4,5)P2 are, in general, found at much higher levels than the 3-phosphorylated PI, but even those appear to be present in rods at very low levels, which are only about 10-fold higher than the levels of PI(3)P, i.e., on the order of 0.04 mol% (He and Wensel, unpublished observations).

Comparison to Other Tissues and Cell Types

These numbers are comparable to those found in other eukaryotic cells, reported as PtdIns3P, 0.002% of phospholipid mass; PtdIns4P, 0.05%; PtdIns5P, 0.002%; PtdIns(4,5)P, 0.05%; PtdIns(3,4)P, 0.0001%; PtdIns(3,5)P, 0.0001% [17], see also references in [23]. A more recent mass spectrometry study reported PI(3,4,5)3 levels as 50-fold or more lower than those of the more common PIs in mammalian U87MG cells [24]. An interesting observation derived from measurements of PI levels in cultured cells is that, generally, they do not change greatly upon activation with extracellular stimuli; for the more common forms, PtdIns, PI(4)P, PI(4,5)P2 and PI(3)P, the change is generally less than 30% [17]. The implication, for PI(4,5)P2, which is rapidly degraded to form InsP3 and diacylglycerol upon activation of phospholipase C isozymes by G-protein-coupled receptors or growth factor receptors [25,26], is that homeostatic mechanisms are in place to regenerate rapidly the pools of both PI(4,5)P2 and its precursor PI(4)P upon PLC activation. In contrast, PI(3,4,5)P3 level changes due to receptor stimulation are generally too low to have a major impact on levels of its precursor, PI(4,5)P2.

5. Importance of PI Generally

Despite their low abundance, phosphoinositides play major roles in regulation of cell signaling and membrane dynamics, and are essential for control of a wide range of processes including development, proliferation and differentiation, membrane excitability, exocytosis, phagocytosis, cell motility, and detection of extracellular signals [4]. These functional roles are primarily mediated by a plethora of enzymes, scaffold proteins and complex-nucleating proteins containing phosphoinositide-binding domains of high affinity and high specificity. Genetic defects in the enzymes responsible for their regulation are, in most cases, lethal at the embryo stage, except for some cases of redundancy (i.e., more than one gene encoding enzymes or PI-binding proteins with similar activities). Cell-type specific deletion of these enzymes leads to more specific pathologies, e.g., neurodegeneration in the case of the type III PI-3 kinase, Vps34 (also known as PIK3C3) [27,28]. Some of these enzymes, such as type I PI-3 kinases, can act as oncogenes when mutations disrupt their regulation, and are considered prime targets for cancer chemotherapy, whereas others, such as the phosphoinositide phosphatase, PTEN, are considered tumor suppressor genes [29]; these therapeutic targets are present in the retina, where their roles in retinal function, and any effects of drugs targeting them are unknown.

Importance of Phosphoinositides for Dynamics and Functions of Membranes in Retina and RPE

Among the most important roles of phosphoinositides and their protein effectors are those mediating intracellular membrane traffic, by directing membrane proteins and lipids from one compartment to another in response to cellular needs and changing environments. For example, PI(3)P is found in early and recycling endosomes, and is important for recruiting key proteins that regulate trafficking to these compartments [30]. It is also important for autophagy, a survival-promoting pathway leading to the lysosomal degradation of organelles [31]. PI(4)P is enriched in the Golgi apparatus, and is thought to be important for membrane trafficking through the Golgi compartments and from the Golgi to the plasma membrane and other subcellular compartments [32], likely including disk membranes. PI(4,5)P2 plays a key role in clathrin-mediated endocytosis, and serves to direct many effector proteins to the plasma membrane where it is primarily found [33].
PI(4,5)P2 and other phosphoinositides directly regulate the activity of ion channels, transporters and enzymes in membranes [34,35]. In addition, PI(4,5)P2 serves as the substrate for phosphoinositide-specific phospholipase C, leading to production of the important second messengers, inositol (1,4,5) trisphosphate (InsP3) and diacylglycerol [25,26,36,37]. Phosphoinositides are also critically important for regulating interactions between membranes and cytoskeletal elements [38,39]. Changes in these interactions are critical for cell growth and mobility, and for remodeling of intracellular structures. They may well play a role in cytoskeleton-dependent disk morphogenesis in rods.

6. Membrane Trafficking in Retina and RPE

Every aspect of retinal biology depends heavily on the correct organization and composition of highly specialized membranes, from the unique disc membranes of the photoreceptor sensory cilia, to the ribbon synapses of rods, cones, and bipolar cells, to the apical processes of RPE (retinal pigmented epithelium) cells, uniquely tuned to the detection and engulfment of shed outer segment fragments. The formation, maintenance, and functions of these membranes rely heavily on the phosphorylated phosphoinositides [2,3,4,40]. Despite the intense interest in phosphoinositide research in recent decades, surprisingly little is known about their regulation and functional roles in the retina, although it is known that disruption of phosphoinositide regulation can lead to blindness in human patients and animal models [41,42,43,44,45,46,47,48]. The membranes and pathways they regulate are known to be essential for the function and health of the retina as well as for disease processes and cellular responses to disease states.
One of the reasons for the dearth of knowledge has been a lack of tools for studying these very low-abundance lipids within the multiple cell types of the retina and the adjacent retinal pigment epithelium. Recently, tools developed by the broader PI field have begun to be applied to the unique challenges and opportunities posed by the retina [22,49]. Doing so will have enormous impact on our understanding of the cell biology of the retina and its disruption in disease. This can help to inform the design and optimization of therapies aimed at treating and preventing retinal dysfunction and degeneration.

7. Features of the Retina that Make It Ideal for Studies of Phosphoinositide Regulation In Vivo

The field of phosphoinositide regulation has long been dominated by studies in cultured immortalized cell lines, giving rise to a critical need for elucidation of their physiological regulation in terminally differentiated neurons. For this reason, in vivo studies have broad significance for this field. There are several features of the retina that make it particularly amenable to studies of phosphoinositide regulation in vivo. These include the ability to assay both structure and function non-invasively, the ease of making cell-type-specific knockouts, the ability to isolate rod cells for either biochemical analysis or ultrastructure determination, an extensive understanding of biochemistry and cell biology, especially of rods, which exceeds that of any of other vertebrate neurons, and a wealth of knowledge of RPE cell biology.

8. Importance of Phosphoinositides for Membrane Trafficking in Retina

Despite years of study, no convincing evidence has accumulated for an important role for phosphoinositides in the phototransduction cascade. In contrast, a steady stream of evidence supports a central role for these lipids in membrane trafficking and sorting in all mammalian cell types, just as a critical role in photoreceptors for membrane sorting and trafficking has long been established [3,50,51]. A review article in 2011 covered advances in understanding the roles of phosphoinositides in photoreceptors [6]. It is highly likely that events such as endocytosis and exocytosis, endosomal sorting, membrane budding, post-Golgi vesicle trafficking, and disk morphogenesis all depend on phosphoinositide dynamics, and published reports support a role for PI(3)P and PI(4,5)P2 in rhodopsin trafficking [52,53]. For example, PI(4,5)P2-binding proteins, ezrin and moesin, were reported to colocalize with Rac1 and Rab8 on rhodopsin transport carrier vesicles at the site of their fusion with the plasma membrane. A recent report suggesting the involvement of actin-nucleating proteins Arp2/Arp3 in basal disc extension [54] potentially implicates local pools or PI(4,5)P2, which are known to be critical for their function [55,56].
In cone photoreceptors, ablation of a type I PI-3 kinase leads to enhanced sensitivity to light damage [57]. Mutations in the phosphoinositide phosphatase, synaptojanin 1 lead to defects in synaptic vesicle trafficking in cone cells [44].

9. Retinal Cilia and Phosphoinositides

Phosphoinositides, and especially PI(4,5)P2 and PI(4)P, have been proposed to play important roles in assembly, disassembly, and regulation of primary cilia [52,58,59,60,61,62]. The lipid content of cilia is different from that of the plasma membrane, and a membrane diffusion barrier surrounding the cilium has been demonstrated (see [63] for a review). Two PI-5-phosphatases, INPP5E and OCRL, essential for cilium function have been reported to be localized to the cilium [41,64,65,66]

Phosphoinositides and the BBSome

The BBSome, a heterooctameric protein complex involved in ciliary trafficking, whose defects lead to the blinding ciliopathy, Bardet–Biedl syndrome, binds to membranes, and shows a preference for acidic lipids, including phosphoinositides [67,68], and isolated BBS5 which contains pleckstrin homology domains, binds to phosphoinositides, especially PI(3)P [68]. More recently, it was shown that a core BBSome complex containing BBS 1, 4, 5, 8, 9 and 18 and a smaller sub-complex lacking BBS1 and BBS5 bind phosphoinositides with similar specificities. A caveat for these studies is that the commercial “PIP strips” used have local surface densities of phosphoinositides that far exceed anything found under physiological conditions, so further investigation of phosphoinositide-binding of the BBSome and its sub-complexes is warranted.

10. Autophagy and other Stress Responses Involving Redirection of Membrane Traffic and Phosphoinositides

It has been reported that light exposure induces elements of the autophagy pathway in rods and that autophagy plays an important role in photoreceptor homeostasis [69,70,71,72,73]. This pathway has been suggested to be a neuroprotective one that forestalls apoptosis under conditions of stress [69,74]. This process may be part of a more general neuroprotective response involving re-direction of membrane traffic and phosphoinositides. As discussed below, Synaptojanin-1 has been implicated in autophagy in zebrafish cones [75].

11. Evidence for Effects of Light on Phosphoinositide Metabolism

A number of early reports in the 1980s suggested that light had measurable impacts on PI metabolism in photoreceptors or the retina generally. Based on measurement of 32Pi incorporated into PtdIns by metabolic labeling, it was reported that exposure of isolated frog retina to light decreased levels of PIP2 by 14% after 5 s and 37% after 15 s, while levels of PI(4)P, PtdIns and other acidic lipids remained essentially constant [76]. Subsequent publications from the same group reported increased levels of 3H inositol and 32P into phosphoinositides upon illumination [77]. They also reported PI(4,5)P2-specific phospholipase C (PLC) activity in frog photoreceptors, and PLC immunoreactivity in bovine rod outer segments [78,79], as well as PI-kinase and PIP-kinase activities in frog ROS [19]. Another group found that exposure of rat retinas to light led to decreased staining of rod outer segments with anti-PI(4,5)P2 antibodies [80,81]. The caveats of those experiments are that it is known that physical properties of outer segment membranes and their protein composition are altered by bright light exposure, and that it is difficult to establish the specificity of such antibody staining. In addition to light, reports on regulation of photoreceptor PLC by Ca2+ [82] or by subunits of the phototransduction G protein, transducin [83], were published, also suggesting a possible influence of light exposure, which is known to control levels of Ca2+ and active and inactive forms of transducin subunits.
In contrast, another group [84] reported that bovine rod outer segments have very little PIP kinase activity as compared to the rest of the retina (consistent with the previously reported low level of PI(4,5)P2 in outer segment membranes), and that light adaptation had no measurable effect on phosphoinositide metabolism as compared to in vivo dark adaptation. Yet another group, using metabolic labeling with [3H]inositol, reported that light led to decreases in PIP2 levels without generation of InsP3, suggesting light-dependent activity of a phosphatase rather than of phospholipase C [85]. In vitro studies demonstrated that the presence of PI(4,5)P2 in membranes could affect the activity of components of the phototransduction cascade [86,87], including the cGMP-gated cation channel and the cGMP phosphodiesterase-transducin complex. The physiological relevance of effects of PI(4,5)P2 on phototransduction or of effects of light on PI(4,5)P2 metabolism remains untested, and it seems to be possible to explain the entire time-course of rod light responses without invoking any participation by phosphoinositide metabolism [88]. Antibodies specific for isoforms of phospholipase C or Gαq/11 PLC-coupled subunits revealed the presence of PLCβ4 and Gαq/11 in rod outer segments, and Gαq and other PKC isoforms elsewhere in the retina [89]. The functional roles of these proteins in outer segments are not known. There have been suggestions that slower effects of prolonged light exposure, such as arrestin translocation from the inner to outer segments of rod cells, may be mediated by a phospholipase C cascade [90].

Light Regulation of PI-3 Kinase

Interest has turned toward Type I PI-3 kinase and PI(3,4,5)P3, with reports of effects of light on the activity of this enzyme in bovine rod outer segments [91,92], which were reported to be mediated by light-stimulated activation and tyrosine phosphorylation of the insulin receptor [93,94,95]. Deletion of the p85α regulatory subunit of Type I PI-3 kinase in cone cells resulted in progressive degeneration of cones, without observable effects on rod survival [57]. Likewise, cone-specific inactivation of the gene encoding the p110α catalytic subunit also resulted in defects in cone survival [96].
In contrast, Type I PI-3 kinase and its product, PI(3,4,5)P3, seem to be much less important for rod function. Rod-specific ablation of the p85α gene using two different rod-specific Cre transgenes yielded no obvious defects in retinal morphology or rod cell survival [22,97], although modest effects on kinetics of light response recovery and arrestin translocation were reported in one case [97]. Quantitative analysis of PI(3,4,5)P3 levels in rods isolated from dark-adapted or light-adapted retinas revealed levels of this phosphoinositide of more than one order magnitude lower than those found for PI(3)P in the light, or at least two orders of magnitude lower than light-stimulated levels of PI(4,5)P2 [22].

12. PI(4,5)P2 and Phospholipase C in Intrinsically Photosensitive Ganglion Cells

In addition to image-forming light detection mediated by rods and cones, the vertebrate retina also contains intrinsically photosensitive retinal ganglion cells. These contain phototransduction cascades reminiscent of that found in invertebrate rhabdomeric photoreceptors [98,99,100,101,102,103,104]. Light activates melanopsin, encoded by the Opn4 gene, a visual pigment which is more closely related to invertebrate opsins than to vertebrate opsin [105]. In M1-type ganglion cells, melanopsin photoisomerization leads to activation of a Gαq/11/14 class G-protein, which activates the phosphoinositide-specific phospholipase C isoform, PLCβ4; the phospholipase presumably acts on PI(4,5)P2 as in other cell types, including Drosophila photoreceptors, which contain a homologous phospholipase, to produce diacylglycerol and InsP3. PI(4,5)P2 hydrolysis, in turn, leads to the activation of the cation channels TRPC6 and TRPC7 [104]. In M4 ganglion cells, a different phototransduction cascade involving cyclic nucleotides and cyclic nucleotide-regulated HCN channels, whereas in M2 ganglion cells, both of these cascades operate [102].

13. Studies of PI Metabolism in the RPE

A variety of extracellular stimuli acting on tyrosine kinase-associated receptors or G protein-coupled-receptors have been reported to stimulate release of inositol phosphates in cultured RPE cells, presumably derived from PLC action of PI(4,5)P2, on a timescale of tens of minutes; effective stimuli included fetal bovine serum, agonists for muscarinic, histamine, and serotonin, peptides, including bradykinin, arginine vasopressin, bombesin and oxytocin, [106,107,108,109]. The physiological relevance of these observations was not explored, but an in vivo study using frogs demonstrated dramatic acceleration of inositol phosphate release, especially of InsP3, following stimulation by light [21]. Acutely isolated rat RPE cells were reported to release InsP3 in response to induction of phagocytosis by addition of isolated rod outer segments [110]; this InsP3 release was not observed in cells from Royal College of Surgeon (RCS) rats, which have a defect in OS phagocytosis due to a deficiency in the receptor tyrosine kinase, MERTK [111]. As in many other cell types, insulin has been reported to stimulate activity of Type I PI-3 kinase to produce PI(3,4,5)P3 [95,112,113]. Responses to hypoxia [112,114,115] and elevated glucose [116,117] are also reported to involve this pathway in RPE.
A number of important processes in RPE are known to rely on phosphoinositides, but how they are regulated in these cells is not well understood. Phagocytosis, autophagy, endocytosis and endosome processing, establishment of epithelial cell polarity and extension of microvilli membranes are all known to critically depend on phosphoinositides. For example, both autophagy and phagocytosis involve the recruitment of the ubiquitin-like protein, LC3 [118,119,120], whose recruitment to membranes depends on PI(3)P. Phagocytosis is also thought to require PI(4,5)P2 and lysosomal fusion may involve other phosphoinositides such as PI(3,5)P2 and PI(5)P [22,121,122,123,124,125].

14. Phosphoinositide Kinases and Phosphatase

In mammals, there are 47 genes encoding 19 PI-kinase and PIP-kinases and 28 PIP phosphatases [126].

14.1. Kinases

The kinase isoforms are divided into three major families: PI 4-kinases (PI4Ks), the PI 3-kinases (PI3Ks), and PIP (PIP) kinases (PIPKs) [127]. The nomenclature for these is a bit confusing, as some enzymes termed “PI-kinases” actually act primarily as PIP kinases. For example, Type I PI-3 kinases primarily use PI(4,5)P2 as their substrate to produce PI(3,4,5)P3, and there is little evidence for a substantial portion of cellular PI(3)P being formed by these enzymes. When the Type III PI-3 kinase, Vps34, was knocked out in mouse rod cells and phosphoinositide levels measured, the results suggested complete ablation of PI(3)P despite the presence of the Type I enzyme [22]. Several of these have been reported to be expressed in retina or RPE at the level of protein, mRNA or enzyme activity and most, if not all, are likely present at some level; however, as far as their functions, only the Type I and Type III PI-3 kinase have been studied using gene knockouts in the retina and RPE [22,49,57,128]. Global knockouts have been produced for the α, β, and γ isoforms of Type I PIP-kinases, which are the major source of PI(4,5)P2 in most cells [16]. Of these, the γ isoform seems to have the highest expression in the retina [129] and in other neurons [130,131] and leads to severe neuronal phenotypes and early postnatal mortality when knocked out [132]. Type II PIP-kinases have been observed in retina and are reported to be regulated by tyrosine phosphorylation [133]. The proteins encoded by the mouse genes, Pip4k2a, Pip4k2b, Pip4k2c, Pip5k1a, and Pip5k1c were all observed in a proteomic study of mouse retina [134].

14.2. Phosphatases

The phosphoinositide phosphatases encoded by Inpp1, Inpp4a, Inpp4b, Inpp5e, Mtmr2 and Synj1 (synaptojanin-1) have also been detected in retina by proteomics [134]. As noted below, defects in synaptojanin-1 and INPP5E are associated with retinal defects, as is the phosphoinositide 5-phosphatase, OCRL (oculocerebrorenal syndrome of Lowe) [135,136]. Among the other enzymes detected, almost none were enriched in the rod outer segment fraction as compared to the rest of the retina, consistent with the relatively low PI content of that organelle. One exception was Pip4k2c, the PI(5)P-4-kinase Type II γ isoform. Inactivation of the mouse Pip4kc2 gene was found to lead to hyperactivation of the immune system, but the retinal phenotype was not examined [137].

15. Retinal Phenotypes of Genetic Defects in Genes Related to Phosphoinositide Metabolism and Signaling

Rods and cones have a very high rate of metabolism and biosynthesis of membrane components, due to the energetic demands of the phototransduction cascade and the daily shedding of ~10% of the disk membranes (based on observation of a rate of 9%–13% in the rhesus monkey [138], which have to be engulfed and recycled by the RPE. As highly polarized cells, their function and health depend critically on efficient and accurate transport of the correct proteins and lipids to the correct compartments. A host of human blinding diseases have been linked to defects in membrane transport and sorting [139,140]. In RPE cells, massive amounts of membrane traffic are associated with their role as professional phagophores. Defects in RPE phagocytosis, as in MERTK deficiency [111,141] and Bestrophin deficiency [142,143,144,145], cause retinal degeneration in humans and animal models and have been proposed to play a role in age-related macular degeneration [146].

15.1. Phosphatases and Inherited Retinopathies

Inherited defects in the phosphoinositide phosphatase, INPP5E, are associated with the multi-syndromic ciliopathies, Joubert syndrome and Bardet–Biedl syndrome [147,148,149,150], and with retinal degeneration. The substrates for this phosphatase are PI(4,5)P2 and PI(3,4,5)P3, and its critical role in the cilia suggests that regulating levels of PI(4,5)P2 may be important in ciliogenesis and cilium stability.
Synaptojanins are phosphoinositide phosphatases associated with synaptic function [151,152,153], including vesicle uncoating and endocytosis. Synaptojanin-1 deficiency causes severe cone defects in zebrafish and has been implicated in the regulation of autophagy in cones [45,46,75].
Defects in another phosphoinositide phosphatase, OCRL, are associated with a severe ciliopathy, oculocerebrorenal syndrome of Lowe [136]. Symptoms of this disease include glaucoma, a disease of the retina.

15.2. PI3NM3

The phosphatidyl inositol transfer protein PIT3NM3 (aka CCL118) is the mammalian homologue of the Drosophila retinal degeneration gene, rdgB, and defects in it are associated with autosomal dominant cone-rod dystrophy CORD5 [154,155,156,157,158,159]. The protein has also been implicated in cancer metastasis [160]. In zebrafish, the Class I phosphatidylinositol transfer protein β isoform, Pitpnb, is essential for biogenesis and maintenance of double cones [161].

15.3. PI Binding Proteins

Proteins with phosphoinositide-binding domains have also been associated with retinal disease. These include the product of the tub/TUB gene [162,163] and a related protein, TULP1 [47,164,165,166]. Tub was discovered as the protein encoded by a gene whose mutation in tubby mice causes obesity, deafness and blindness. The widely expressed members of the tubby family, including TULP1-TULP4, have a characteristic carboxyl-terminal tubby domain consisting of an alpha helix surrounded by a beta barrel which has been shown to bind to specific phosphoinositides [167]. Both Tub and Tulp1 are expressed in the retina, and TULP1 mutations cause retinitis pigmentosa [47,168].

16. Conclusions

While the overall field of phosphoinositide regulation and signaling has made dramatic advances in recent years, our understanding of specific regulatory pathways in specific cell types of the retina remains limited. The emergence of new technologies for cell-type-specific gene manipulation, along with imaging techniques for subcellular localization of phosphoinositides, their regulatory enzymes and their effector proteins, and the development of more sensitive methods for measuring PI levels, bodes well for rapid progress in understanding the roles of retinal phosphoinositides in the coming years.

Funding

The author’s research in this area has been supported by NIH grants R01-EY007981, R01-EY025218 and the Robert A. Welch Foundation, Q0035.

Conflicts of Interest

The author declares no conflicts of interest relevant to this paper.

References

  1. Phan, T.K.; Williams, S.A.; Bindra, G.K.; Lay, F.T.; Poon, I.K.H.; Hulett, M.D. Phosphoinositides: Multipurpose cellular lipids with emerging roles in cell death. Cell Death Differ. 2019, 26, 781–793. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Dickson, E.J.; Hille, B. Understanding phosphoinositides: Rare, dynamic, and essential membrane phospholipids. Biochem. J. 2019, 476, 1–23. [Google Scholar] [CrossRef] [PubMed]
  3. Schink, K.O.; Tan, K.W.; Stenmark, H. Phosphoinositides in Control of Membrane Dynamics. Annu. Rev. Cell Dev. Biol. 2016, 32, 143–171. [Google Scholar] [CrossRef] [PubMed]
  4. Balla, T. Phosphoinositides: Tiny lipids with giant impact on cell regulation. Physiol. Rev. 2013, 93, 1019–1137. [Google Scholar] [CrossRef]
  5. Maffucci, T. An introduction to phosphoinositides. Curr. Top. Microbiol. Immunol. 2012, 362, 1–42. [Google Scholar] [CrossRef]
  6. Brockerhoff, S.E. Phosphoinositides and photoreceptors. Mol. Neurobiol. 2011, 44, 420–425. [Google Scholar] [CrossRef] [Green Version]
  7. Broekhuyse, R.M. Phospholipids in tissues of the eye. I. Isolation, characterization and quantitative analysis by two-dimensional thin-layer chromatography of diacyl and vinyl-ether phospholipids. Biochim. Biophys. Acta 1968, 152, 307–315. [Google Scholar] [CrossRef]
  8. Anderson, R.E.; Feldman, L.S.; Feldman, G.L. Lipids of ocular tissues. II. The phospholipids of mature bovine and rabbit whole retina. Biochim. Biophys. Acta 1970, 202, 367–373. [Google Scholar] [CrossRef]
  9. Anderson, R.E. Lipids of ocular tissues. IV. A comparison of the phospholipids from the retina of six mammalian species. Exp. Eye Res. 1970, 10, 339–344. [Google Scholar] [CrossRef]
  10. Anderson, R.E.; Maude, M.B.; Zimmerman, W. Lipids of ocular tissues--X. Lipid composition of subcellular fractions of bovine retina. Vision Res. 1975, 15, 1087–1090. [Google Scholar] [CrossRef]
  11. Anderson, R.E.; Maude, M.B. Phospholipids of bovine outer segments. Biochemistry 1970, 9, 3624–3628. [Google Scholar] [CrossRef] [PubMed]
  12. Nielsen, N.C.; Fleischer, S.; McConnell, D.G. Lipid composition of bovine retinal outer segment fragments. Biochim. Biophys. Acta 1970, 211, 10–19. [Google Scholar] [CrossRef]
  13. Anderson, R.E.; Risk, M. Lipids of ocular tissues. IX. The phospholipids of frog photoreceptor membranes. Vision Res. 1974, 14, 129–131. [Google Scholar] [CrossRef]
  14. Anderson, R.E.; Lissandrello, P.M.; Maude, M.B.; Matthes, M.T. Lipids of bovine retinal pigment epithelium. Exp. Eye Res. 1976, 23, 149–157. [Google Scholar] [CrossRef]
  15. Balla, T. Inositol-lipid binding motifs: Signal integrators through protein-lipid and protein-protein interactions. J. Cell Sci. 2005, 118, 2093–2104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Choi, S.; Thapa, N.; Tan, X.; Hedman, A.C.; Anderson, R.A. PIP kinases define PI4,5P(2)signaling specificity by association with effectors. Biochim. Biophys. Acta 2015, 1851, 711–723. [Google Scholar] [CrossRef] [Green Version]
  17. Lemmon, M.A. Membrane recognition by phospholipid-binding domains. Nat. Rev. Mol. Cell Biol. 2008, 9, 99–111. [Google Scholar] [CrossRef]
  18. Anderson, R.E.; Maude, M.B.; Kelleher, P.A. Metabolism of phosphatidylinositol in the frog retina. Biochim. Biophys. Acta 1980, 620, 236–246. [Google Scholar] [CrossRef]
  19. Choe, H.G.; Ghalayini, A.J.; Anderson, R.E. Phosphoinositide metabolism in frog rod outer segments. Exp. Eye Res. 1990, 51, 167–176. [Google Scholar] [CrossRef]
  20. Gehm, B.D.; Mc Connell, D.G. Phosphoinositide synthesis in bovine rod outer segments. Biochemistry 1990, 29, 5442–5446. [Google Scholar] [CrossRef]
  21. Rodriguez de Turco, E.B.; Gordon, W.C.; Bazan, N.G. Light stimulates in vivo inositol lipid turnover in frog retinal pigment epithelial cells at the onset of shedding and phagocytosis of photoreceptor membranes. Exp. Eye Res. 1992, 55, 719–725. [Google Scholar] [CrossRef]
  22. He, F.; Agosto, M.A.; Anastassov, I.A.; Tse, D.Y.; Wu, S.M.; Wensel, T.G. Phosphatidylinositol-3-phosphate is light-regulated and essential for survival in retinal rods. Sci. Rep. 2016, 6, 26978. [Google Scholar] [CrossRef]
  23. Stephens, L.R.; Jackson, T.R.; Hawkins, P.T. Agonist-stimulated synthesis of phosphatidylinositol(3,4,5)-trisphosphate: A new intracellular signalling system? Biochim. Biophys. Acta 1993, 1179, 27–75. [Google Scholar] [CrossRef]
  24. Bui, H.H.; Sanders, P.E.; Bodenmiller, D.; Kuo, M.S.; Donoho, G.P.; Fischl, A.S. Direct analysis of PI(3,4,5)P3 using liquid chromatography electrospray ionization tandem mass spectrometry. Anal. Biochem. 2018, 547, 66–76. [Google Scholar] [CrossRef]
  25. Kadamur, G.; Ross, E.M. Mammalian phospholipase C. Annu. Rev. Physiol. 2013, 75, 127–154. [Google Scholar] [CrossRef] [Green Version]
  26. Trebak, M.; Lemonnier, L.; Smyth, J.T.; Vazquez, G.; Putney, J.W., Jr. Phospholipase C-coupled receptors and activation of TRPC channels. Handb Exp. Pharmacol. 2007, 593–614. [Google Scholar]
  27. Wang, L.; Budolfson, K.; Wang, F. Pik3c3 deletion in pyramidal neurons results in loss of synapses, extensive gliosis and progressive neurodegeneration. Neuroscience 2011, 172, 427–442. [Google Scholar] [CrossRef] [Green Version]
  28. Zhou, X.; Wang, L.; Hasegawa, H.; Amin, P.; Han, B.X.; Kaneko, S.; He, Y.; Wang, F. Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway. Proc. Natl. Acad. Sci. USA 2010, 107, 9424–9429. [Google Scholar] [CrossRef] [Green Version]
  29. Carnero, A.; Blanco-Aparicio, C.; Renner, O.; Link, W.; Leal, J.F. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr. Cancer Drug Targets 2008, 8, 187–198. [Google Scholar] [CrossRef]
  30. Carpentier, S.; N’Kuli, F.; Grieco, G.; Van Der Smissen, P.; Janssens, V.; Emonard, H.; Bilanges, B.; Vanhaesebroeck, B.; Gaide Chevronnay, H.P.; Pierreux, C.E.; et al. Class III phosphoinositide 3-kinase/VPS34 and dynamin are critical for apical endocytic recycling. Traffic 2013, 14, 933–948. [Google Scholar] [CrossRef]
  31. Dall’Armi, C.; Devereaux, K.A.; Di Paolo, G. The role of lipids in the control of autophagy. Curr. Biol. 2013, 23, R33–R45. [Google Scholar] [CrossRef] [Green Version]
  32. Lenoir, M.; Overduin, M. PtdIns(4)P signalling and recognition systems. Adv. Exp. Med. Biol. 2013, 991, 59–83. [Google Scholar] [CrossRef]
  33. McLaughlin, S.; Wang, J.; Gambhir, A.; Murray, D. PIP(2) and proteins: Interactions, organization, and information flow. Annu. Rev. Biophys. Biomol. Struct. 2002, 31, 151–175. [Google Scholar] [CrossRef] [Green Version]
  34. Falkenburger, B.H.; Jensen, J.B.; Dickson, E.J.; Suh, B.C.; Hille, B. Phosphoinositides: Lipid regulators of membrane proteins. J. Physiol. 2010, 588, 3179–3185. [Google Scholar] [CrossRef]
  35. Hilgemann, D.W.; Feng, S.; Nasuhoglu, C. The complex and intriguing lives of PIP2 with ion channels and transporters. Sci. STKE 2001, 2001, re19. [Google Scholar] [CrossRef]
  36. Fukami, K.; Inanobe, S.; Kanemaru, K.; Nakamura, Y. Phospholipase C is a key enzyme regulating intracellular calcium and modulating the phosphoinositide balance. Prog. Lipid Res. 2010, 49, 429–437. [Google Scholar] [CrossRef]
  37. Vines, C.M. Phospholipase C. Adv. Exp. Med. Biol. 2012, 740, 235–254. [Google Scholar] [CrossRef]
  38. Shewan, A.; Eastburn, D.J.; Mostov, K. Phosphoinositides in cell architecture. Cold Spring Harb. Perspect. Biol. 2011, 3, a004796. [Google Scholar] [CrossRef] [Green Version]
  39. Yin, H.L.; Janmey, P.A. Phosphoinositide regulation of the actin cytoskeleton. Annu. Rev. Physiol. 2003, 65, 761–789. [Google Scholar] [CrossRef]
  40. Hille, B.; Dickson, E.J.; Kruse, M.; Vivas, O.; Suh, B.C. Phosphoinositides regulate ion channels. Biochim. Biophys. Acta 2015, 1851, 844–856. [Google Scholar] [CrossRef]
  41. Bielas, S.L.; Silhavy, J.L.; Brancati, F.; Kisseleva, M.V.; Al-Gazali, L.; Sztriha, L.; Bayoumi, R.A.; Zaki, M.S.; Abdel-Aleem, A.; Rosti, R.O.; et al. Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat. Genet. 2009, 41, 1032–1036. [Google Scholar] [CrossRef] [Green Version]
  42. Jacoby, M.; Cox, J.J.; Gayral, S.; Hampshire, D.J.; Ayub, M.; Blockmans, M.; Pernot, E.; Kisseleva, M.V.; Compere, P.; Schiffmann, S.N.; et al. INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat. Genet. 2009, 41, 1027–1031. [Google Scholar] [CrossRef] [Green Version]
  43. Saar, K.; Al-Gazali, L.; Sztriha, L.; Rueschendorf, F.; Nur, E.K.M.; Reis, A.; Bayoumi, R. Homozygosity mapping in families with Joubert syndrome identifies a locus on chromosome 9q34.3 and evidence for genetic heterogeneity. Am. J. Hum. Genet. 1999, 65, 1666–1671. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. George, A.A.; Hayden, S.; Holzhausen, L.C.; Ma, E.Y.; Suzuki, S.C.; Brockerhoff, S.E. Synaptojanin 1 is required for endolysosomal trafficking of synaptic proteins in cone photoreceptor inner segments. PLoS ONE 2014, 9, e84394. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Holzhausen, L.C.; Lewis, A.A.; Cheong, K.K.; Brockerhoff, S.E. Differential role for synaptojanin 1 in rod and cone photoreceptors. J. Comp. Neurol. 2009, 517, 633–644. [Google Scholar] [CrossRef] [Green Version]
  46. Van Epps, H.A.; Hayashi, M.; Lucast, L.; Stearns, G.W.; Hurley, J.B.; De Camilli, P.; Brockerhoff, S.E. The zebrafish nrc mutant reveals a role for the polyphosphoinositide phosphatase synaptojanin 1 in cone photoreceptor ribbon anchoring. J. Neurosci. 2004, 24, 8641–8650. [Google Scholar] [CrossRef] [Green Version]
  47. Hagstrom, S.A.; North, M.A.; Nishina, P.L.; Berson, E.L.; Dryja, T.P. Recessive mutations in the gene encoding the tubby-like protein TULP1 in patients with retinitis pigmentosa. Nat. Genet. 1998, 18, 174–176. [Google Scholar] [CrossRef]
  48. Jacobson, S.G.; Cideciyan, A.V.; Huang, W.C.; Sumaroka, A.; Roman, A.J.; Schwartz, S.B.; Luo, X.; Sheplock, R.; Dauber, J.M.; Swider, M.; et al. TULP1 mutations causing early-onset retinal degeneration: Preserved but insensitive macular cones. Invest. Ophthalmol. Vis. Sci. 2014, 55, 5354–5364. [Google Scholar] [CrossRef] [Green Version]
  49. He, F.; Nichols, R.M.; Kailasam, L.; Wensel, T.G.; Agosto, M.A. Critical Role for Phosphatidylinositol-3 Kinase Vps34/PIK3C3 in ON-Bipolar Cells. Invest. Ophthalmol. Vis. Sci. 2019, 60, 2861–2874. [Google Scholar] [CrossRef] [Green Version]
  50. Hammond, G.R.; Hong, Y. Phosphoinositides and Membrane Targeting in Cell Polarity. Cold Spring Harb. Perspect. Biol. 2018, 10. [Google Scholar] [CrossRef]
  51. Mayinger, P. Phosphoinositides and vesicular membrane traffic. Biochim. Biophys. Acta 2012, 1821, 1104–1113. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Chuang, J.Z.; Zhao, Y.; Sung, C.H. SARA-regulated vesicular targeting underlies formation of the light-sensing organelle in mammalian rods. Cell 2007, 130, 535–547. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Deretic, D.; Traverso, V.; Parkins, N.; Jackson, F.; Rodriguez de Turco, E.B.; Ransom, N. Phosphoinositides, ezrin/moesin, and rac1 regulate fusion of rhodopsin transport carriers in retinal photoreceptors. Mol. Biol. Cell 2004, 15, 359–370. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Spencer, W.J.; Lewis, T.R.; Phan, S.; Cady, M.A.; Serebrovskaya, E.O.; Schneider, N.F.; Kim, K.Y.; Cameron, L.A.; Skiba, N.P.; Ellisman, M.H.; et al. Photoreceptor disc membranes are formed through an Arp2/3-dependent lamellipodium-like mechanism. Proc. Natl. Acad. Sci. USA 2019. [Google Scholar] [CrossRef]
  55. Bucki, R.; Wang, Y.H.; Yang, C.; Kandy, S.K.; Fatunmbi, O.; Bradley, R.; Pogoda, K.; Svitkina, T.; Radhakrishnan, R.; Janmey, P.A. Lateral distribution of phosphatidylinositol 4,5-bisphosphate in membranes regulates formin- and ARP2/3-mediated actin nucleation. J. Biol. Chem. 2019, 294, 4704–4722. [Google Scholar] [CrossRef] [Green Version]
  56. Daste, F.; Walrant, A.; Holst, M.R.; Gadsby, J.R.; Mason, J.; Lee, J.E.; Brook, D.; Mettlen, M.; Larsson, E.; Lee, S.F.; et al. Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature. J. Cell Biol. 2017, 216, 3745–3765. [Google Scholar] [CrossRef]
  57. Ivanovic, I.; Anderson, R.E.; Le, Y.Z.; Fliesler, S.J.; Sherry, D.M.; Rajala, R.V. Deletion of the p85alpha regulatory subunit of phosphoinositide 3-kinase in cone photoreceptor cells results in cone photoreceptor degeneration. Invest. Ophthalmol. Vis. Sci. 2011, 52, 3775–3783. [Google Scholar] [CrossRef] [Green Version]
  58. Xu, W.; Jin, M.; Huang, W.; Wang, H.; Hu, R.; Li, J.; Cao, Y. Apical PtdIns(4,5)P2 is required for ciliogenesis and suppression of polycystic kidney disease. FASEB J. 2019, 33, 2848–2857. [Google Scholar] [CrossRef] [Green Version]
  59. Phua, S.C.; Nihongaki, Y.; Inoue, T. Autonomy declared by primary cilia through compartmentalization of membrane phosphoinositides. Curr. Opin. Cell Biol. 2018, 50, 72–78. [Google Scholar] [CrossRef]
  60. Park, J.; Lee, N.; Kavoussi, A.; Seo, J.T.; Kim, C.H.; Moon, S.J. Ciliary Phosphoinositide Regulates Ciliary Protein Trafficking in Drosophila. Cell Rep. 2015, 13, 2808–2816. [Google Scholar] [CrossRef] [Green Version]
  61. Garcia-Gonzalo, F.R.; Phua, S.C.; Roberson, E.C.; Garcia, G., 3rd; Abedin, M.; Schurmans, S.; Inoue, T.; Reiter, J.F. Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling. Dev. Cell 2015, 34, 400–409. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Vieira, O.V.; Gaus, K.; Verkade, P.; Fullekrug, J.; Vaz, W.L.; Simons, K. FAPP2, cilium formation, and compartmentalization of the apical membrane in polarized Madin-Darby canine kidney (MDCK) cells. Proc. Natl. Acad. Sci. USA 2006, 103, 18556–18561. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Nachury, M.V.; Seeley, E.S.; Jin, H. Trafficking to the ciliary membrane: How to get across the periciliary diffusion barrier? Annu. Rev. Cell Dev. Biol. 2010, 26, 59–87. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Luo, N.; West, C.C.; Murga-Zamalloa, C.A.; Sun, L.; Anderson, R.M.; Wells, C.D.; Weinreb, R.N.; Travers, J.B.; Khanna, H.; Sun, Y. OCRL localizes to the primary cilium: A new role for cilia in Lowe syndrome. Hum. Mol. Genet. 2012, 21, 3333–3344. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Coon, B.G.; Hernandez, V.; Madhivanan, K.; Mukherjee, D.; Hanna, C.B.; Barinaga-Rementeria Ramirez, I.; Lowe, M.; Beales, P.L.; Aguilar, R.C. The Lowe syndrome protein OCRL1 is involved in primary cilia assembly. Hum. Mol. Genet. 2012, 21, 1835–1847. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Humbert, M.C.; Weihbrecht, K.; Searby, C.C.; Li, Y.; Pope, R.M.; Sheffield, V.C.; Seo, S. ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting. Proc. Natl. Acad. Sci. USA 2012, 109, 19691–19696. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Jin, H.; White, S.R.; Shida, T.; Schulz, S.; Aguiar, M.; Gygi, S.P.; Bazan, J.F.; Nachury, M.V. The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 2010, 141, 1208–1219. [Google Scholar] [CrossRef] [Green Version]
  68. Nachury, M.V.; Loktev, A.V.; Zhang, Q.; Westlake, C.J.; Peranen, J.; Merdes, A.; Slusarski, D.C.; Scheller, R.H.; Bazan, J.F.; Sheffield, V.C.; et al. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 2007, 129, 1201–1213. [Google Scholar] [CrossRef] [Green Version]
  69. Chinskey, N.D.; Zheng, Q.D.; Zacks, D.N. Control of Photoreceptor Autophagy after Retinal Detachment: The Switch from Survival to Death. Invest. Ophthalmol. Vis. Sci. 2014, 55, 688–695. [Google Scholar] [CrossRef] [Green Version]
  70. Reme, C.; Drinker, C.K.; Aeberhard, B. Modification of autophagic degradation by medium- and illumination conditions in frog visual cells in vitro. Doc. Ophthalmol. 1984, 56, 377–383. [Google Scholar] [CrossRef]
  71. Reme, C. Autophagy in rods and cones of the vertebrate retina. Dev. Ophthalmol. 1981, 4, 101–148. [Google Scholar]
  72. Reme, C.E.; Sulser, M. Diurnal variation of autophagy in rod visual cells in the rat. Albrecht Von Graefes Arch. Klin. Exp. Ophthalmol. 1977, 203, 261–270. [Google Scholar] [CrossRef]
  73. Chen, Y.; Sawada, O.; Kohno, H.; Le, Y.Z.; Subauste, C.; Maeda, T.; Maeda, A. Autophagy protects the retina from light-induced degeneration. J. Biol. Chem. 2013, 288, 7506–7518. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Besirli, C.G.; Chinskey, N.D.; Zheng, Q.D.; Zacks, D.N. Autophagy activation in the injured photoreceptor inhibits fas-mediated apoptosis. Invest. Ophthalmol. Vis. Sci. 2011, 52, 4193–4199. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. George, A.A.; Hayden, S.; Stanton, G.R.; Brockerhoff, S.E. Arf6 and the 5’phosphatase of synaptojanin 1 regulate autophagy in cone photoreceptors. Bioessays 2016, 38 (Suppl. 1), S119–S135. [Google Scholar] [CrossRef]
  76. Ghalayini, A.; Anderson, R.E. Phosphatidylinositol 4,5-bisphosphate: Light-mediated breakdown in the vertebrate retina. Biochem. Biophys. Res. Commun. 1984, 124, 503–506. [Google Scholar] [CrossRef]
  77. Anderson, R.E.; Maude, M.B.; Pu, G.A.; Hollyfield, J.G. Effect of light on the metabolism of lipids in the rat retina. J. Neurochem. 1985, 44, 773–778. [Google Scholar] [CrossRef] [PubMed]
  78. Tarver, A.P.; Anderson, R.E. Phospholipase C activity and substrate specificity in frog photoreceptors. Exp. Eye Res. 1988, 46, 29–35. [Google Scholar] [CrossRef]
  79. Ghalayini, A.J.; Tarver, A.P.; Mackin, W.M.; Koutz, C.A.; Anderson, R.E. Identification and immunolocalization of phospholipase C in bovine rod outer segments. J. Neurochem. 1991, 57, 1405–1412. [Google Scholar] [CrossRef]
  80. Das, N.D.; Yoshioka, T.; Samuelson, D.; Shichi, H. Immunocytochemical localization of phosphatidylinositol-4,5-bisphosphate in dark- and light-adapted rat retinas. Cell Struct. Funct. 1986, 11, 53–63. [Google Scholar] [CrossRef] [Green Version]
  81. Das, N.D.; Yoshioka, T.; Samuelson, D.; Cohen, R.J.; Shichi, H. Immunochemical evidence for the light-regulated modulation of phosphatidylinositol-4,5-bisphosphate in rat photoreceptor cells. Cell Struct. Funct. 1987, 12, 471–481. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Panfoli, I.; Morelli, A.; Pepe, I. Calcium ion-regulated phospholipase C activity in bovine rod outer segments. Biochem. Biophys. Res. Commun. 1990, 173, 283–288. [Google Scholar] [CrossRef]
  83. Grigorjev, I.V.; Grits, A.I.; Artamonov, I.D.; Baranova, L.A.; Volotovski, I.D. betagamma-Transducin stimulates hydrolysis and synthesis of phosphatidylinositol 4,5-bisphosphate in bovine rod outer segment membranes. Biochim. Biophys. Acta 1996, 1310, 131–136. [Google Scholar] [CrossRef] [Green Version]
  84. Van Rooijen, L.A.; Bazan, N.G. The inositide cycle in bovine photoreceptor membranes. Life Sci. 1986, 38, 1685–1693. [Google Scholar] [CrossRef]
  85. Millar, F.A.; Fisher, S.C.; Muir, C.A.; Edwards, E.; Hawthorne, J.N. Polyphosphoinositide hydrolysis in response to light stimulation of rat and chick retina and retinal rod outer segments. Biochim. Biophys. Acta 1988, 970, 205–211. [Google Scholar] [CrossRef]
  86. He, F.; Mao, M.; Wensel, T.G. Enhancement of phototransduction g protein-effector interactions by phosphoinositides. J. Biol. Chem. 2004, 279, 8986–8990. [Google Scholar] [CrossRef] [Green Version]
  87. Womack, K.B.; Gordon, S.E.; He, F.; Wensel, T.G.; Lu, C.C.; Hilgemann, D.W. Do phosphatidylinositides modulate vertebrate phototransduction? J. Neurosci. 2000, 20, 2792–2799. [Google Scholar] [CrossRef]
  88. Gross, O.P.; Pugh, E.N., Jr.; Burns, M.E. Spatiotemporal cGMP dynamics in living mouse rods. Biophys J. 2012, 102, 1775–1784. [Google Scholar] [CrossRef] [Green Version]
  89. Peng, Y.W.; Rhee, S.G.; Yu, W.P.; Ho, Y.K.; Schoen, T.; Chader, G.J.; Yau, K.W. Identification of components of a phosphoinositide signaling pathway in retinal rod outer segments. Proc. Natl. Acad. Sci. USA 1997, 94, 1995–2000. [Google Scholar] [CrossRef] [Green Version]
  90. Orisme, W.; Li, J.; Goldmann, T.; Bolch, S.; Wolfrum, U.; Smith, W.C. Light-dependent translocation of arrestin in rod photoreceptors is signaled through a phospholipase C cascade and requires ATP. Cell Signal. 2010, 22, 447–456. [Google Scholar] [CrossRef] [Green Version]
  91. Guo, X.; Ghalayini, A.J.; Chen, H.; Anderson, R.E. Phosphatidylinositol 3-kinase in bovine photoreceptor rod outer segments. Invest. Ophthalmol. Vis. Sci. 1997, 38, 1873–1882. [Google Scholar] [PubMed]
  92. Guo, X.X.; Huang, Z.; Bell, M.W.; Chen, H.; Anderson, R.E. Tyrosine phosphorylation is involved in phosphatidylinositol 3-kinase activation in bovine rod outer segments. Mol. Vis. 2000, 6, 216–221. [Google Scholar] [PubMed]
  93. Rajala, R.V.; McClellan, M.E.; Chan, M.D.; Tsiokas, L.; Anderson, R.E. Interaction of the retinal insulin receptor beta-subunit with the p85 subunit of phosphoinositide 3-kinase. Biochemistry 2004, 43, 5637–5650. [Google Scholar] [CrossRef] [PubMed]
  94. Rajala, R.V.; Anderson, R.E. Light regulation of the insulin receptor in the retina. Mol. Neurobiol. 2003, 28, 123–138. [Google Scholar] [CrossRef]
  95. Rajala, R.V.; McClellan, M.E.; Ash, J.D.; Anderson, R.E. In vivo regulation of phosphoinositide 3-kinase in retina through light-induced tyrosine phosphorylation of the insulin receptor beta-subunit. J. Biol. Chem. 2002, 277, 43319–43326. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Rajala, R.V.; Ranjo-Bishop, M.; Wang, Y.; Rajala, A.; Anderson, R.E. The p110alpha isoform of phosphoinositide 3-kinase is essential for cone photoreceptor survival. Biochimie 2015, 112, 35–40. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Ivanovic, I.; Allen, D.T.; Dighe, R.; Le, Y.Z.; Anderson, R.E.; Rajala, R.V. Phosphoinositide 3-kinase signaling in retinal rod photoreceptors. Invest. Ophthalmol. Vis. Sci. 2011, 52, 6355–6362. [Google Scholar] [CrossRef]
  98. Detwiler, P.B. Phototransduction in Retinal Ganglion Cells. Yale J. Biol. Med. 2018, 91, 49–52. [Google Scholar]
  99. Graham, D.M.; Wong, K.Y.; Shapiro, P.; Frederick, C.; Pattabiraman, K.; Berson, D.M. Melanopsin ganglion cells use a membrane-associated rhabdomeric phototransduction cascade. J. Neurophysiol. 2008, 99, 2522–2532. [Google Scholar] [CrossRef]
  100. Hardie, R.C. Photosensitive TRPs. Handb. Exp. Pharmacol. 2014, 223, 795–826. [Google Scholar] [CrossRef]
  101. Isoldi, M.C.; Rollag, M.D.; Castrucci, A.M.; Provencio, I. Rhabdomeric phototransduction initiated by the vertebrate photopigment melanopsin. Proc. Natl. Acad. Sci. USA 2005, 102, 1217–1221. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Jiang, Z.; Yue, W.W.S.; Chen, L.; Sheng, Y.; Yau, K.W. Cyclic-Nucleotide- and HCN-Channel-Mediated Phototransduction in Intrinsically Photosensitive Retinal Ganglion Cells. Cell 2018, 175, 652–664 e612. [Google Scholar] [CrossRef] [Green Version]
  103. Montell, C. Drosophila visual transduction. Trends Neurosci. 2012, 35, 356–363. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Xue, T.; Do, M.T.; Riccio, A.; Jiang, Z.; Hsieh, J.; Wang, H.C.; Merbs, S.L.; Welsbie, D.S.; Yoshioka, T.; Weissgerber, P.; et al. Melanopsin signalling in mammalian iris and retina. Nature 2011, 479, 67–73. [Google Scholar] [CrossRef] [PubMed]
  105. Arendt, D. Evolution of eyes and photoreceptor cell types. Int. J. Dev. Biol. 2003, 47, 563–571. [Google Scholar] [PubMed]
  106. Kuriyama, S.; Ohuchi, T.; Yoshimura, N.; Honda, Y. Growth factor-induced cytosolic calcium ion transients in cultured human retinal pigment epithelial cells. Invest. Ophthalmol. Vis. Sci. 1991, 32, 2882–2890. [Google Scholar]
  107. Osborne, N.N.; FitzGibbon, F.; Schwartz, G. Muscarinic acetylcholine receptor-mediated phosphoinositide turnover in cultured human retinal pigment epithelium cells. Vision Res. 1991, 31, 1119–1127. [Google Scholar] [CrossRef]
  108. Feldman, E.L.; Randolph, A.E.; Johnston, G.C.; DelMonte, M.A.; Greene, D.A. Receptor-coupled phosphoinositide hydrolysis in human retinal pigment epithelium. J. Neurochem. 1991, 56, 2094–2100. [Google Scholar] [CrossRef]
  109. York, N.; Halbach, P.; Chiu, M.A.; Bird, I.M.; Pillers, D.M.; Pattnaik, B.R. Oxytocin (OXT)-stimulated inhibition of Kir7.1 activity is through PIP2-dependent Ca(2+) response of the oxytocin receptor in the retinal pigment epithelium in vitro. Cell Signal. 2017, 37, 93–102. [Google Scholar] [CrossRef]
  110. Heth, C.A.; Marescalchi, P.A. Inositol triphosphate generation in cultured rat retinal pigment epithelium. Invest. Ophthalmol. Vis. Sci. 1994, 35, 409–416. [Google Scholar]
  111. D’Cruz, P.M.; Yasumura, D.; Weir, J.; Matthes, M.T.; Abderrahim, H.; LaVail, M.M.; Vollrath, D. Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum. Mol. Genet. 2000, 9, 645–651. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Treins, C.; Giorgetti-Peraldi, S.; Murdaca, J.; Semenza, G.L.; Van Obberghen, E. Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J. Biol. Chem. 2002, 277, 27975–27981. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Geraldes, P.; Yagi, K.; Ohshiro, Y.; He, Z.; Maeno, Y.; Yamamoto-Hiraoka, J.; Rask-Madsen, C.; Chung, S.W.; Perrella, M.A.; King, G.L. Selective regulation of heme oxygenase-1 expression and function by insulin through IRS1/phosphoinositide 3-kinase/Akt-2 pathway. J. Biol. Chem. 2008, 283, 34327–34336. [Google Scholar] [CrossRef] [Green Version]
  114. Mwaikambo, B.R.; Yang, C.; Chemtob, S.; Hardy, P. Hypoxia up-regulates CD36 expression and function via hypoxia-inducible factor-1- and phosphatidylinositol 3-kinase-dependent mechanisms. J. Biol. Chem. 2009, 284, 26695–26707. [Google Scholar] [CrossRef] [Green Version]
  115. Yang, X.M.; Wang, Y.S.; Zhang, J.; Li, Y.; Xu, J.F.; Zhu, J.; Zhao, W.; Chu, D.K.; Wiedemann, P. Role of PI3K/Akt and MEK/ERK in mediating hypoxia-induced expression of HIF-1alpha and VEGF in laser-induced rat choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2009, 50, 1873–1879. [Google Scholar] [CrossRef]
  116. Kim, D.I.; Lim, S.K.; Park, M.J.; Han, H.J.; Kim, G.Y.; Park, S.H. The involvement of phosphatidylinositol 3-kinase/Akt signaling in high glucose-induced downregulation of GLUT-1 expression in ARPE cells. Life Sci. 2007, 80, 626–632. [Google Scholar] [CrossRef]
  117. Qin, D.; Zhang, G.M.; Xu, X.; Wang, L.Y. The PI3K/Akt signaling pathway mediates the high glucose-induced expression of extracellular matrix molecules in human retinal pigment epithelial cells. J. Diabetes Res. 2015, 2015, 920280. [Google Scholar] [CrossRef]
  118. Ferguson, T.A.; Green, D.R. Autophagy and phagocytosis converge for better vision. Autophagy 2014, 10, 165–167. [Google Scholar] [CrossRef] [Green Version]
  119. Kim, J.Y.; Zhao, H.; Martinez, J.; Doggett, T.A.; Kolesnikov, A.V.; Tang, P.H.; Ablonczy, Z.; Chan, C.C.; Zhou, Z.; Green, D.R.; et al. Noncanonical autophagy promotes the visual cycle. Cell 2013, 154, 365–376. [Google Scholar] [CrossRef] [Green Version]
  120. Muniz-Feliciano, L.; Doggett, T.A.; Zhou, Z.; Ferguson, T.A. RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye. Autophagy 2017, 13, 2072–2085. [Google Scholar] [CrossRef] [Green Version]
  121. Shaw, J.D.; Hama, H.; Sohrabi, F.; DeWald, D.B.; Wendland, B. PtdIns(3,5)P2 is required for delivery of endocytic cargo into the multivesicular body. Traffic 2003, 4, 479–490. [Google Scholar] [CrossRef]
  122. Ketel, K.; Krauss, M.; Nicot, A.S.; Puchkov, D.; Wieffer, M.; Muller, R.; Subramanian, D.; Schultz, C.; Laporte, J.; Haucke, V. A phosphoinositide conversion mechanism for exit from endosomes. Nature 2016, 529, 408–412. [Google Scholar] [CrossRef]
  123. Isobe, Y.; Nigorikawa, K.; Tsurumi, G.; Takemasu, S.; Takasuga, S.; Kofuji, S.; Hazeki, K. PIKfyve accelerates phagosome acidification through activation of TRPML1 while arrests aberrant vacuolation independent of the Ca2+ channel. J. Biochem. 2019, 165, 75–84. [Google Scholar] [CrossRef]
  124. Ikonomov, O.C.; Sbrissa, D.; Shisheva, A. Localized PtdIns 3,5-P2 synthesis to regulate early endosome dynamics and fusion. Am. J. Physiol. Cell Physiol. 2006, 291, C393–C404. [Google Scholar] [CrossRef] [Green Version]
  125. Dong, X.P.; Shen, D.; Wang, X.; Dawson, T.; Li, X.; Zhang, Q.; Cheng, X.; Zhang, Y.; Weisman, L.S.; Delling, M.; et al. PI(3,5)P(2) controls membrane trafficking by direct activation of mucolipin Ca(2+) release channels in the endolysosome. Nat. Commun. 2010, 1, 38. [Google Scholar] [CrossRef] [Green Version]
  126. Sasaki, T.; Takasuga, S.; Sasaki, J.; Kofuji, S.; Eguchi, S.; Yamazaki, M.; Suzuki, A. Mammalian phosphoinositide kinases and phosphatases. Prog. Lipid Res. 2009, 48, 307–343. [Google Scholar] [CrossRef]
  127. Brown, J.R.; Auger, K.R. Phylogenomics of phosphoinositide lipid kinases: Perspectives on the evolution of second messenger signaling and drug discovery. BMC Evol. Biol. 2011, 11, 4. [Google Scholar] [CrossRef] [Green Version]
  128. Azadi, S.; Brush, R.S.; Anderson, R.E.; Rajala, R.V. Class I Phosphoinositide 3-Kinase Exerts a Differential Role on Cell Survival and Cell Trafficking in Retina. Adv. Exp. Med. Biol. 2016, 854, 363–369. [Google Scholar] [CrossRef]
  129. Sakagami, H.; Katsumata, O.; Hara, Y.; Tamaki, H.; Fukaya, M. Preferential localization of type I phosphatidylinositol 4-phosphate 5-kinase gamma at the periactive zone of mouse photoreceptor ribbon synapses. Brain Res. 2014, 1586, 23–33. [Google Scholar] [CrossRef]
  130. Wenk, M.R.; Pellegrini, L.; Klenchin, V.A.; Di Paolo, G.; Chang, S.; Daniell, L.; Arioka, M.; Martin, T.F.; De Camilli, P. PIP kinase Igamma is the major PI(4,5)P(2) synthesizing enzyme at the synapse. Neuron 2001, 32, 79–88. [Google Scholar] [CrossRef] [Green Version]
  131. Wright, B.D.; Loo, L.; Street, S.E.; Ma, A.; Taylor-Blake, B.; Stashko, M.A.; Jin, J.; Janzen, W.P.; Frye, S.V.; Zylka, M.J. The lipid kinase PIP5K1C regulates pain signaling and sensitization. Neuron 2014, 82, 836–847. [Google Scholar] [CrossRef] [Green Version]
  132. Di Paolo, G.; Moskowitz, H.S.; Gipson, K.; Wenk, M.R.; Voronov, S.; Obayashi, M.; Flavell, R.; Fitzsimonds, R.M.; Ryan, T.A.; De Camilli, P. Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking. Nature 2004, 431, 415–422. [Google Scholar] [CrossRef]
  133. Huang, Z.; Guo, X.X.; Chen, S.X.; Alvarez, K.M.; Bell, M.W.; Anderson, R.E. Regulation of type II phosphatidylinositol phosphate kinase by tyrosine phosphorylation in bovine rod outer segments. Biochemistry 2001, 40, 4550–4559. [Google Scholar] [CrossRef]
  134. Zhao, L.; Chen, Y.; Bajaj, A.O.; Eblimit, A.; Xu, M.; Soens, Z.T.; Wang, F.; Ge, Z.; Jung, S.Y.; He, F.; et al. Integrative subcellular proteomic analysis allows accurate prediction of human disease-causing genes. Genome Res. 2016, 26, 660–669. [Google Scholar] [CrossRef] [Green Version]
  135. Prosseda, P.P.; Luo, N.; Wang, B.; Alvarado, J.A.; Hu, Y.; Sun, Y. Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome. J. Cell Sci. 2017, 130, 3447–3454. [Google Scholar] [CrossRef] [Green Version]
  136. Attree, O.; Olivos, I.M.; Okabe, I.; Bailey, L.C.; Nelson, D.L.; Lewis, R.A.; McInnes, R.R.; Nussbaum, R.L. The Lowe’s oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature 1992, 358, 239–242. [Google Scholar] [CrossRef]
  137. Shim, H.; Wu, C.; Ramsamooj, S.; Bosch, K.N.; Chen, Z.; Emerling, B.M.; Yun, J.; Liu, H.; Choo-Wing, R.; Yang, Z.; et al. Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system. Proc. Natl. Acad. Sci. USA 2016, 113, 7596–7601. [Google Scholar] [CrossRef] [Green Version]
  138. Young, R.W. The renewal of rod and cone outer segments in the rhesus monkey. J. Cell Biol. 1971, 49, 303–318. [Google Scholar] [CrossRef] [Green Version]
  139. Adams, N.A.; Awadein, A.; Toma, H.S. The retinal ciliopathies. Ophthalmic Genet. 2007, 28, 113–125. [Google Scholar] [CrossRef]
  140. Wheway, G.; Parry, D.A.; Johnson, C.A. The role of primary cilia in the development and disease of the retina. Organogenesis 2013, 10, 69–85. [Google Scholar] [CrossRef] [Green Version]
  141. Gal, A.; Li, Y.; Thompson, D.A.; Weir, J.; Orth, U.; Jacobson, S.G.; Apfelstedt-Sylla, E.; Vollrath, D. Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat. Genet. 2000, 26, 270–271. [Google Scholar] [CrossRef]
  142. Marmorstein, A.D.; Johnson, A.A.; Bachman, L.A.; Andrews-Pfannkoch, C.; Knudsen, T.; Gilles, B.J.; Hill, M.; Gandhi, J.K.; Marmorstein, L.Y.; Pulido, J.S. Mutant Best1 Expression and Impaired Phagocytosis in an iPSC Model of Autosomal Recessive Bestrophinopathy. Sci Rep. 2018, 8, 4487. [Google Scholar] [CrossRef]
  143. Strauss, O.; Reichhart, N.; Gomez, N.M.; Muller, C. Contribution of Ion Channels in Calcium Signaling Regulating Phagocytosis: MaxiK, Cav1.3 and Bestrophin-1. Adv. Exp. Med. Biol. 2016, 854, 739–744. [Google Scholar] [CrossRef]
  144. Muller, C.; Mas Gomez, N.; Ruth, P.; Strauss, O. CaV1.3 L-type channels, maxiK Ca(2+)-dependent K(+) channels and bestrophin-1 regulate rhythmic photoreceptor outer segment phagocytosis by retinal pigment epithelial cells. Cell Signal. 2014, 26, 968–978. [Google Scholar] [CrossRef]
  145. Xiao, Q.; Hartzell, H.C.; Yu, K. Bestrophins and retinopathies. Pflugers Arch. 2010, 460, 559–569. [Google Scholar] [CrossRef] [Green Version]
  146. Strauss, O. The retinal pigment epithelium in visual function. Physiol. Rev. 2005, 85, 845–881. [Google Scholar] [CrossRef] [Green Version]
  147. Luo, N.; Lu, J.; Sun, Y. Evidence of a role of inositol polyphosphate 5-phosphatase INPP5E in cilia formation in zebrafish. Vision Res. 2012, 75, 98–107. [Google Scholar] [CrossRef] [Green Version]
  148. Travaglini, L.; Brancati, F.; Silhavy, J.; Iannicelli, M.; Nickerson, E.; Elkhartoufi, N.; Scott, E.; Spencer, E.; Gabriel, S.; Thomas, S.; et al. Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders. Eur. J. Hum. Genet. 2013, 21, 1074–1078. [Google Scholar] [CrossRef] [Green Version]
  149. Plotnikova, O.V.; Seo, S.; Cottle, D.L.; Conduit, S.; Hakim, S.; Dyson, J.M.; Mitchell, C.A.; Smyth, I.M. INPP5E interacts with AURKA, linking phosphoinositide signaling to primary cilium stability. J. Cell Sci. 2015, 128, 364–372. [Google Scholar] [CrossRef] [Green Version]
  150. Xu, W.; Jin, M.; Hu, R.; Wang, H.; Zhang, F.; Yuan, S.; Cao, Y. The Joubert Syndrome Protein Inpp5e Controls Ciliogenesis by Regulating Phosphoinositides at the Apical Membrane. J. Am. Soc. Nephrol. 2017, 28, 118–129. [Google Scholar] [CrossRef]
  151. Verstreken, P.; Koh, T.W.; Schulze, K.L.; Zhai, R.G.; Hiesinger, P.R.; Zhou, Y.; Mehta, S.Q.; Cao, Y.; Roos, J.; Bellen, H.J. Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating. Neuron 2003, 40, 733–748. [Google Scholar] [CrossRef] [Green Version]
  152. Chi, Y.; Zhou, B.; Wang, W.Q.; Chung, S.K.; Kwon, Y.U.; Ahn, Y.H.; Chang, Y.T.; Tsujishita, Y.; Hurley, J.H.; Zhang, Z.Y. Comparative mechanistic and substrate specificity study of inositol polyphosphate 5-phosphatase Schizosaccharomyces pombe Synaptojanin and SHIP2. J. Biol. Chem. 2004, 279, 44987–44995. [Google Scholar] [CrossRef] [Green Version]
  153. Chang-Ileto, B.; Frere, S.G.; Chan, R.B.; Voronov, S.V.; Roux, A.; Di Paolo, G. Synaptojanin 1-mediated PI(4,5)P2 hydrolysis is modulated by membrane curvature and facilitates membrane fission. Dev. Cell 2011, 20, 206–218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Lev, S.; Hernandez, J.; Martinez, R.; Chen, A.; Plowman, G.; Schlessinger, J. Identification of a novel family of targets of PYK2 related to Drosophila retinal degeneration B (rdgB) protein. Mol. Cell Biol. 1999, 19, 2278–2288. [Google Scholar] [CrossRef] [Green Version]
  155. Tian, D.; Lev, S. Cellular and developmental distribution of human homologues of the Drosophilia rdgB protein in the rat retina. Invest. Ophthalmol. Vis. Sci. 2002, 43, 1946–1953. [Google Scholar]
  156. Kohn, L.; Kadzhaev, K.; Burstedt, M.S.I.; Haraldsson, S.; Hallberg, B.; Sandgren, O.; Golovleva, I. Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families. Eur. J. Hum. Genet. 2007, 15, 664–671. [Google Scholar] [CrossRef]
  157. Kohn, L.; Kadzhaev, K.; Burstedt, M.S.I.; Haraldsson, S.; Sandgren, O.; Golovleva, I. Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families. Rencent Adv. Exp. Med. Biol. 2008, 613, 229–234. [Google Scholar] [CrossRef]
  158. Kohn, L.; Kohl, S.; Bowne, S.J.; Sullivan, L.S.; Kellner, U.; Daiger, S.P.; Sandgren, O.; Golovleva, I. PITPNM3 is an uncommon cause of cone and cone-rod dystrophies. Ophthalmic Genet. 2010, 31, 139–140. [Google Scholar] [CrossRef] [Green Version]
  159. Bakhoum, M.F.; Sengillo, J.D.; Cui, X.; Tsang, S.H. Autoimmune retinopathy in a patient with a missense mutation in PITPNM3. Retin Cases Brief. Rep. 2018, 12 (Suppl. 1), S72–S75. [Google Scholar] [CrossRef]
  160. Lin, Z.; Li, W.; Zhang, H.; Wu, W.; Peng, Y.; Zeng, Y.; Wan, Y.; Wang, J.; Ouyang, N. CCL18/PITPNM3 enhances migration, invasion, and EMT through the NF-kappaB signaling pathway in hepatocellular carcinoma. Tumour Biol. 2016, 37, 3461–3468. [Google Scholar] [CrossRef]
  161. Ile, K.E.; Kassen, S.; Cao, C.; Vihtehlic, T.; Shah, S.D.; Mousley, C.J.; Alb, J.G., Jr.; Huijbregts, R.P.; Stearns, G.W.; Brockerhoff, S.E.; et al. Zebrafish class 1 phosphatidylinositol transfer proteins: PITPbeta and double cone cell outer segment integrity in retina. Traffic 2010, 11, 1151–1167. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  162. Chang, B.; Hawes, N.L.; Hurd, R.E.; Davisson, M.T.; Nusinowitz, S.; Heckenlively, J.R. Retinal degeneration mutants in the mouse. Vision Res. 2002, 42, 517–525. [Google Scholar] [CrossRef] [Green Version]
  163. Borman, A.D.; Pearce, L.R.; Mackay, D.S.; Nagel-Wolfrum, K.; Davidson, A.E.; Henderson, R.; Garg, S.; Waseem, N.H.; Webster, A.R.; Plagnol, V.; et al. A homozygous mutation in the TUB gene associated with retinal dystrophy and obesity. Hum. Mutat. 2014, 35, 289–293. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Hagstrom, S.A.; Watson, R.F.; Pauer, G.J.; Grossman, G.H. Tulp1 is involved in specific photoreceptor protein transport pathways. Adv. Exp. Med. Biol. 2012, 723, 783–789. [Google Scholar] [CrossRef] [PubMed]
  165. Xi, Q.; Pauer, G.J.; Traboulsi, E.I.; Hagstrom, S.A. Mutation screen of the TUB gene in patients with retinitis pigmentosa and Leber congenital amaurosis. Exp. Eye Res. 2006, 83, 569–573. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Xi, Q.; Pauer, G.J.; West, K.A.; Crabb, J.W.; Hagstrom, S.A. Retinal degeneration caused by mutations in TULP1. Adv. Exp. Med. Biol. 2003, 533, 303–308. [Google Scholar] [CrossRef]
  167. Mukhopadhyay, S.; Jackson, P.K. The tubby family proteins. Genome Biol. 2011, 12, 225. [Google Scholar] [CrossRef] [Green Version]
  168. Hagstrom, S.A.; Duyao, M.; North, M.A.; Li, T. Retinal degeneration in tulp1-/- mice: Vesicular accumulation in the interphotoreceptor matrix. Invest. Ophthalmol. Vis. Sci. 1999, 40, 2795–2802. [Google Scholar]
Cells 09 00866 g001 550
Figure 1. Structures of the cellular phosphoinositides and enzymes responsible for their synthesis and interconversion. Phosphoinositides (PI) species are shown with the acyl chains most commonly found on phosphatidylinositol, which is the starting point for all the others, arachidonic acid (20:4) and stearic acid (C18). Relative font sizes correlate with relative abundance.
Figure 1. Structures of the cellular phosphoinositides and enzymes responsible for their synthesis and interconversion. Phosphoinositides (PI) species are shown with the acyl chains most commonly found on phosphatidylinositol, which is the starting point for all the others, arachidonic acid (20:4) and stearic acid (C18). Relative font sizes correlate with relative abundance.
Cells 09 00866 g001

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Wensel, T.G. Phosphoinositides in Retinal Function and Disease. Cells 2020, 9, 866. https://doi.org/10.3390/cells9040866

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Wensel, Theodore G. 2020. "Phosphoinositides in Retinal Function and Disease" Cells 9, no. 4: 866. https://doi.org/10.3390/cells9040866

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Wensel, T. G. (2020). Phosphoinositides in Retinal Function and Disease. Cells, 9(4), 866. https://doi.org/10.3390/cells9040866

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