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Molecular Basis of Sensory Transduction in Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 24168

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Prof. Dr. Pere Garriga

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Grup de Biotecnologia Molecular i Industrial, Centre de Biotecnologia Molecular, Departament d’Enginyeria Química, Universitat Politècnica de Catalunya-Barcelona Tech, Edifici Gaia, Rambla de Sant Nebridi 22, 08222 Terrassa, Spain
Interests: G protein-coupled receptors; retinal proteins; rhodopsin; membrane proteins; signal transduction
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Prof. Dr. Daniele Dell’Orco

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Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada le Grazie 8, 37134 Verona, Italy
Interests: phototransduction; calcium sensing; molecular basis of hearing; inherited retinal degeneration; molecular dynamics; computational biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Most animals use five senses (vision, hearing, taste, olfaction, and somatosensation) to experience the abundance of stimuli offered by the surrounding environment. Sensory transduction is the process by which physically and chemically heterogeneous stimuli are efficiently converted into an electrical signal that can be properly conveyed and processed by the nervous system. In spite of the variety of specialized sensory cells in different organisms, the molecular components of sensory transduction systems share many common features. The advent of sophisticated sequencing techniques and the increased attention of clinicians to molecular screening have led the discovery of a growing number of mutations in genes encoding fundamental components of sensory transduction pathways, which are often associated with debilitating genetic diseases that affect the senses.

The aim of this Special Issue of IJMS is to collect reviews and original articles on recent investigations of the molecular basis of sensory transduction with particular emphasis on genetic diseases that affect the senses, like inherited retinal degeneration, nonsyndromic hearing loss, and Usher syndrome, as well as genetic alterations of taste and olfaction. All papers, both experimental and theoretical contributions, should highlight the molecular mechanisms at the level of single genes/proteins or their networks. Contributions that detail innovative therapeutic approaches for the treatment of rare sensory diseases are also welcome.

Prof. Dr. Pere Garriga
Prof. Dr. Daniele Dell’Orco
Guest Editors

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Related Special Issue

Molecular Basis of Sensory Transduction in Health and Disease 2.0 in International Journal of Molecular Sciences (4 articles)

Published Papers (10 papers)

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Research

Jump to: Review

17 pages, 4160 KiB

Open AccessArticle

The Transition of Photoreceptor Guanylate Cyclase Type 1 to the Active State

by Manisha Kumari Shahu, Fabian Schuhmann, Alexander Scholten, Ilia A. Solov’yov and Karl-Wilhelm Koch

Int. J. Mol. Sci. 2022, 23(7), 4030; https://doi.org/10.3390/ijms23074030 - 5 Apr 2022

Cited by 2 | Viewed by 1859

Abstract

Membrane-bound guanylate cyclases (GCs), which synthesize the second messenger guanosine-3′, 5′-cyclic monophosphate, differ in their activation modes to reach the active state. Hormone peptides bind to the extracellular domain in hormone-receptor-type GCs and trigger a conformational change in the intracellular, cytoplasmic part of the enzyme. Sensory GCs that are present in rod and cone photoreceptor cells have intracellular binding sites for regulatory Ca²⁺-sensor proteins, named guanylate-cyclase-activating proteins. A rotation model of activation involving an α-helix rotation was described as a common activation motif among hormone-receptor GCs. We tested whether the photoreceptor GC-E underwent an α-helix rotation when reaching the active state. We experimentally simulated such a transitory switch by integrating alanine residues close to the transmembrane region, and compared the effects of alanine integration with the point mutation V902L in GC-E. The V902L mutation is found in patients suffering from retinal cone–rod dystrophies, and leads to a constitutively active state of GC-E. We analyzed the enzymatic catalytic parameters of wild-type and mutant GC-E. Our data showed no involvement of an α-helix rotation when reaching the active state, indicating a difference in hormone receptor GCs. To characterize the protein conformations that represent the transition to the active state, we investigated the protein dynamics by using a computational approach based on all-atom molecular dynamics simulations. We detected a swinging movement of the dimerization domain in the V902L mutant as the critical conformational switch in the cyclase going from the low to high activity state. Full article

(This article belongs to the Special Issue Molecular Basis of Sensory Transduction in Health and Disease)

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19 pages, 2973 KiB

Open AccessArticle

Cation Permeability of Voltage-Gated Hair Cell Ca²⁺ Channels of the Vertebrate Labyrinth

by Marta Martini and Giorgio Rispoli

Int. J. Mol. Sci. 2022, 23(7), 3786; https://doi.org/10.3390/ijms23073786 - 29 Mar 2022

Viewed by 1704

Abstract

Some hearing, vestibular, and vision disorders are imputable to voltage-gated Ca²⁺ channels of the sensory cells. These channels convey a large Ca²⁺ influx despite extracellular Na⁺ being 70-fold more concentrated than Ca²⁺; such high selectivity is lost in low Ca²⁺, and Na⁺ can permeate. Since the permeation properties and molecular identity of sensory Ca²⁺ channels are debated, in this paper, we examine the Na⁺ current flowing through the L- and R-type Ca²⁺ channels of labyrinth hair cells. Ion currents and cytosolic free Ca²⁺ concentrations were simultaneously monitored in whole-cell recording synchronous to fast fluorescence imaging. L-type and R-type channels were present with different densities at selected sites. In 10 nM Ca²⁺, the activation and deactivation time constants of the L-type Na⁺ current were accelerated and its maximal amplitude increased by 6-fold compared to physiological Ca²⁺. The deactivation of the R-type Na⁺ current was not accelerated, and its current amplitude increased by 2.3-fold in low Ca²⁺; moreover, it was partially blocked by nifedipine in a voltage- and time-dependent manner. In conclusion, L channel gating is affected by the ion species permeating the channel, and its selectivity filter binds Ca²⁺ more strongly than that of R channel; furthermore, external Ca²⁺ prevents nifedipine from perturbing the R selectivity filter. Full article

(This article belongs to the Special Issue Molecular Basis of Sensory Transduction in Health and Disease)

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21 pages, 6937 KiB

Open AccessArticle

Molecular Properties of Human Guanylate Cyclase-Activating Protein 3 (GCAP3) and Its Possible Association with Retinitis Pigmentosa

by Anna Avesani, Laura Bielefeld, Nicole Weisschuh, Valerio Marino, Pascale Mazzola, Katarina Stingl, Tobias B. Haack, Karl-Wilhelm Koch and Daniele Dell’Orco

Int. J. Mol. Sci. 2022, 23(6), 3240; https://doi.org/10.3390/ijms23063240 - 17 Mar 2022

Cited by 3 | Viewed by 1645

Abstract

The cone-specific guanylate cyclase-activating protein 3 (GCAP3), encoded by the GUCA1C gene, has been shown to regulate the enzymatic activity of membrane-bound guanylate cyclases (GCs) in bovine and teleost fish photoreceptors, to an extent comparable to that of the paralog protein GCAP1. To date, the molecular mechanisms underlying GCAP3 function remain largely unexplored. In this work, we report a thorough characterization of the biochemical and biophysical properties of human GCAP3, moreover, we identified an isolated case of retinitis pigmentosa, in which a patient carried the c.301G>C mutation in GUCA1C, resulting in the substitution of a highly conserved aspartate residue by a histidine (p.(D101H)). We found that myristoylated GCAP3 can activate GC1 with a similar Ca²⁺-dependent profile, but significantly less efficiently than GCAP1. The non-myristoylated form did not induce appreciable regulation of GC1, nor did the p.D101H variant. GCAP3 forms dimers under physiological conditions, but at odds with its paralogs, it tends to form temperature-dependent aggregates driven by hydrophobic interactions. The peculiar properties of GCAP3 were confirmed by 2 ms molecular dynamics simulations, which for the p.D101H variant highlighted a very high structural flexibility and a clear tendency to lose the binding of a Ca²⁺ ion to EF3. Overall, our data show that GCAP3 has unusual biochemical properties, which make the protein significantly different from GCAP1 and GCAP2. Moreover, the newly identified point mutation resulting in a substantially unfunctional protein could trigger retinitis pigmentosa through a currently unknown mechanism. Full article

(This article belongs to the Special Issue Molecular Basis of Sensory Transduction in Health and Disease)

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21 pages, 7453 KiB

Open AccessArticle

Phototransduction in Anuran Green Rods: Origins of Extra-Sensitivity

by Luba A. Astakhova, Artem D. Novoselov, Maria E. Ermolaeva, Michael L. Firsov and Alexander Yu. Rotov

Int. J. Mol. Sci. 2021, 22(24), 13400; https://doi.org/10.3390/ijms222413400 - 13 Dec 2021

Cited by 3 | Viewed by 2541

Abstract

Green rods (GRs) represent a unique type of photoreceptor to be found in the retinas of anuran amphibians. These cells harbor a cone-specific blue-sensitive visual pigment but exhibit morphology of the outer segment typical for classic red rods (RRs), which makes them a perspective model object for studying cone–rod transmutation. In the present study, we performed detailed electrophysiological examination of the light sensitivity, response kinetics and parameters of discrete and continuous dark noise in GRs of the two anuran species: cane toad and marsh frog. Our results confirm that anuran GRs are highly specialized nocturnal vision receptors. Moreover, their rate of phototransduction quenching appeared to be about two-times slower than in RRs, which makes them even more efficient single photon detectors. The operating intensity ranges for two rod types widely overlap supposedly allowing amphibians to discriminate colors in the scotopic region. Unexpectedly for typical cone pigments but in line with some previous reports, the spontaneous isomerization rate of the GR visual pigment was found to be the same as for rhodopsin of RRs. Thus, our results expand the knowledge on anuran GRs and show that these are even more specialized single photon catchers than RRs, which allows us to assign them a status of “super-rods”. Full article

(This article belongs to the Special Issue Molecular Basis of Sensory Transduction in Health and Disease)

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28 pages, 6061 KiB

Open AccessArticle

Disulfide Dimerization of Neuronal Calcium Sensor-1: Implications for Zinc and Redox Signaling

by Viktoriia E. Baksheeva, Alexey V. Baldin, Arthur O. Zalevsky, Aliya A. Nazipova, Alexey S. Kazakov, Vasiliy I. Vladimirov, Neonila V. Gorokhovets, François Devred, Pavel P. Philippov, Alexandr V. Bazhin, Andrey V. Golovin, Andrey A. Zamyatnin, Jr., Dmitry V. Zinchenko, Philipp O. Tsvetkov, Sergei E. Permyakov and Evgeni Yu. Zernii

Int. J. Mol. Sci. 2021, 22(22), 12602; https://doi.org/10.3390/ijms222212602 - 22 Nov 2021

Cited by 8 | Viewed by 2942

Abstract

Neuronal calcium sensor-1 (NCS-1) is a four-EF-hand ubiquitous signaling protein modulating neuronal function and survival, which participates in neurodegeneration and carcinogenesis. NCS-1 recognizes specific sites on cellular membranes and regulates numerous targets, including G-protein coupled receptors and their kinases (GRKs). Here, with the use of cellular models and various biophysical and computational techniques, we demonstrate that NCS-1 is a redox-sensitive protein, which responds to oxidizing conditions by the formation of disulfide dimer (dNCS-1), involving its single, highly conservative cysteine C38. The dimer content is unaffected by the elevation of intracellular calcium levels but increases to 10–30% at high free zinc concentrations (characteristic of oxidative stress), which is accompanied by accumulation of the protein in punctual clusters in the perinuclear area. The formation of dNCS-1 represents a specific Zn²⁺-promoted process, requiring proper folding of the protein and occurring at redox potential values approaching apoptotic levels. The dimer binds Ca²⁺ only in one EF-hand per monomer, thereby representing a unique state, with decreased α-helicity and thermal stability, increased surface hydrophobicity, and markedly improved inhibitory activity against GRK1 due to 20-fold higher affinity towards the enzyme. Furthermore, dNCS-1 can coordinate zinc and, according to molecular modeling, has an asymmetrical structure and increased conformational flexibility of the subunits, which may underlie their enhanced target-binding properties. In HEK293 cells, dNCS-1 can be reduced by the thioredoxin system, otherwise accumulating as protein aggregates, which are degraded by the proteasome. Interestingly, NCS-1 silencing diminishes the susceptibility of Y79 cancer cells to oxidative stress-induced apoptosis, suggesting that NCS-1 may mediate redox-regulated pathways governing cell death/survival in response to oxidative conditions. Full article

(This article belongs to the Special Issue Molecular Basis of Sensory Transduction in Health and Disease)

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18 pages, 5359 KiB

Open AccessArticle

A Novel GUCA1A Variant Associated with Cone Dystrophy Alters cGMP Signaling in Photoreceptors by Strongly Interacting with and Hyperactivating Retinal Guanylate Cyclase

by Amedeo Biasi, Valerio Marino, Giuditta Dal Cortivo, Paolo Enrico Maltese, Antonio Mattia Modarelli, Matteo Bertelli, Leonardo Colombo and Daniele Dell’Orco

Int. J. Mol. Sci. 2021, 22(19), 10809; https://doi.org/10.3390/ijms221910809 - 6 Oct 2021

Cited by 4 | Viewed by 2019

Abstract

Guanylate cyclase-activating protein 1 (GCAP1), encoded by the GUCA1A gene, is a neuronal calcium sensor protein involved in shaping the photoresponse kinetics in cones and rods. GCAP1 accelerates or slows the cGMP synthesis operated by retinal guanylate cyclase (GC) based on the light-dependent levels of intracellular Ca²⁺, thereby ensuring a timely regulation of the phototransduction cascade. We found a novel variant of GUCA1A in a patient affected by autosomal dominant cone dystrophy (adCOD), leading to the Asn104His (N104H) amino acid substitution at the protein level. While biochemical analysis of the recombinant protein showed impaired Ca²⁺ sensitivity of the variant, structural properties investigated by circular dichroism and limited proteolysis excluded major structural rearrangements induced by the mutation. Analytical gel filtration profiles and dynamic light scattering were compatible with a dimeric protein both in the presence of Mg²⁺ alone and Mg²⁺ and Ca²⁺. Enzymatic assays showed that N104H-GCAP1 strongly interacts with the GC, with an affinity that doubles that of the WT. The doubled IC₅₀ value of the novel variant (520 nM for N104H vs. 260 nM for the WT) is compatible with a constitutive activity of GC at physiological levels of Ca²⁺. The structural region at the interface with the GC may acquire enhanced flexibility under high Ca²⁺ conditions, as suggested by 2 μs molecular dynamics simulations. The altered interaction with GC would cause hyper-activity of the enzyme at both low and high Ca²⁺ levels, which would ultimately lead to toxic accumulation of cGMP and Ca²⁺ in the photoreceptor outer segment, thus triggering cell death. Full article

(This article belongs to the Special Issue Molecular Basis of Sensory Transduction in Health and Disease)

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17 pages, 2943 KiB

Open AccessArticle

Bitter Taste Receptor T2R14 Modulates Gram-Positive Bacterial Internalization and Survival in Gingival Epithelial Cells

by Manoj Reddy Medapati, Anjali Yadav Bhagirath, Nisha Singh, Robert J. Schroth, Rajinder P. Bhullar, Kangmin Duan and Prashen Chelikani

Int. J. Mol. Sci. 2021, 22(18), 9920; https://doi.org/10.3390/ijms22189920 - 14 Sep 2021

Cited by 12 | Viewed by 2626

Abstract

Bitter-taste receptors (T2Rs) have emerged as key players in host–pathogen interactions and important modulators of oral innate immunity. Previously, we reported that T2R14 is expressed in gingival epithelial cells (GECs) and interacts with competence stimulating peptides (CSPs) secreted by the cariogenic Streptococcus mutans. The underlying mechanisms of the innate immune responses and physiological effects of T2R14 on Gram-positive bacteria are not well characterized. In this study, we examined the role of T2R14 in internalization and growth inhibitory effects on Gram-positive bacteria, namely Staphylococcus aureus and S. mutans. We utilized CRISPR-Cas9 T2R14 knockdown (KD) GECs as the study model to address these key physiological mechanisms. Our data reveal that the internalization of S. aureus is significantly decreased, while the internalization of S. mutans remains unaffected upon knockdown of T2R14 in GECs. Surprisingly, GECs primed with S. mutans CSP-1 resulted in an inhibition of growth for S. aureus, but not for S. mutans. The GECs infected with S. aureus induced T2R14-dependent human β-defensin-2 (hBD-2) secretion; however, S. mutans–infected GECs did not induce hBD-2 secretion, but induced T2R14 dependent IL-8 secretion. Interestingly, our results show that T2R14 KD affects the cytoskeletal reorganization in GECs, thereby inhibiting S. aureus internalization. Our study highlights the distinct mechanisms and a direct role of T2R14 in influencing physiological responses to Gram-positive bacteria in the oral cavity. Full article

(This article belongs to the Special Issue Molecular Basis of Sensory Transduction in Health and Disease)

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19 pages, 12965 KiB

Open AccessArticle

Comparative Molecular Dynamics Investigation of the Electromotile Hearing Protein Prestin

by Gianfranco Abrusci, Thomas Tarenzi, Mattia Sturlese, Gabriele Giachin, Roberto Battistutta and Gianluca Lattanzi

Int. J. Mol. Sci. 2021, 22(15), 8318; https://doi.org/10.3390/ijms22158318 - 2 Aug 2021

Cited by 2 | Viewed by 2715

Abstract

The mammalian protein prestin is expressed in the lateral membrane wall of the cochlear hair outer cells and is responsible for the electromotile response of the basolateral membrane, following hyperpolarisation or depolarisation of the cells. Its impairment marks the onset of severe diseases, like non-syndromic deafness. Several studies have pointed out possible key roles of residues located in the Transmembrane Domain (TMD) that differentiate mammalian prestins as incomplete transporters from the other proteins belonging to the same solute-carrier (SLC) superfamily, which are classified as complete transporters. Here, we exploit the homology of a prototypical incomplete transporter (rat prestin, rPres) and a complete transporter (zebrafish prestin, zPres) with target structures in the outward open and inward open conformations. The resulting models are then embedded in a model membrane and investigated via a rigorous molecular dynamics simulation protocol. The resulting trajectories are analyzed to obtain quantitative descriptors of the equilibration phase and to assess a structural comparison between proteins in different states, and between different proteins in the same state. Our study clearly identifies a network of key residues at the interface between the gate and the core domains of prestin that might be responsible for the conformational change observed in complete transporters and hindered in incomplete transporters. In addition, we study the pathway of Cl

^{-}

ions in the presence of an applied electric field towards their putative binding site in the gate domain. Based on our simulations, we propose a tilt and shift mechanism of the helices surrounding the ion binding cavity as the working principle of the reported conformational changes in complete transporters. Full article

(This article belongs to the Special Issue Molecular Basis of Sensory Transduction in Health and Disease)

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Review

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19 pages, 2518 KiB

Open AccessReview

Calcium- and Integrin-Binding Protein 2 (CIB2) in Physiology and Disease: Bright and Dark Sides

by Giuditta Dal Cortivo and Daniele Dell’Orco

Int. J. Mol. Sci. 2022, 23(7), 3552; https://doi.org/10.3390/ijms23073552 - 24 Mar 2022

Cited by 2 | Viewed by 2725

Abstract

Calcium- and integrin-binding protein 2 (CIB2) is a small EF-hand protein capable of binding Mg²⁺ and Ca²⁺ ions. While its biological function remains largely unclear, an increasing number of studies have shown that CIB2 is an essential component of the mechano-transduction machinery that operates in cochlear hair cells. Mutations in the gene encoding CIB2 have been associated with non-syndromic deafness. In addition to playing an important role in the physiology of hearing, CIB2 has been implicated in a multitude of very different processes, ranging from integrin signaling in platelets and skeletal muscle to autophagy, suggesting extensive functional plasticity. In this review, we summarize the current understanding of biochemical and biophysical properties of CIB2 and the biological roles that have been proposed for the protein in a variety of processes. We also highlight the many molecular aspects that remain unclarified and deserve further investigation. Full article

(This article belongs to the Special Issue Molecular Basis of Sensory Transduction in Health and Disease)

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13 pages, 4629 KiB

Open AccessReview

Structural Insights into Retinal Guanylate Cyclase Activator Proteins (GCAPs)

by James B. Ames

Int. J. Mol. Sci. 2021, 22(16), 8731; https://doi.org/10.3390/ijms22168731 - 13 Aug 2021

Cited by 9 | Viewed by 2027

Abstract

Retinal guanylate cyclases (RetGCs) promote the Ca²⁺-dependent synthesis of cGMP that coordinates the recovery phase of visual phototransduction in retinal rods and cones. The Ca²⁺-sensitive activation of RetGCs is controlled by a family of photoreceptor Ca²⁺ binding proteins known as guanylate cyclase activator proteins (GCAPs). The Mg²⁺-bound/Ca²⁺-free GCAPs bind to RetGCs and activate cGMP synthesis (cyclase activity) at low cytosolic Ca²⁺ levels in light-activated photoreceptors. By contrast, Ca²⁺-bound GCAPs bind to RetGCs and inactivate cyclase activity at high cytosolic Ca²⁺ levels found in dark-adapted photoreceptors. Mutations in both RetGCs and GCAPs that disrupt the Ca²⁺-dependent cyclase activity are genetically linked to various retinal diseases known as cone-rod dystrophies. In this review, I will provide an overview of the known atomic-level structures of various GCAP proteins to understand how protein dimerization and Ca²⁺-dependent conformational changes in GCAPs control the cyclase activity of RetGCs. This review will also summarize recent structural studies on a GCAP homolog from zebrafish (GCAP5) that binds to Fe²⁺ and may serve as a Fe²⁺ sensor in photoreceptors. The GCAP structures reveal an exposed hydrophobic surface that controls both GCAP1 dimerization and RetGC binding. This exposed site could be targeted by therapeutics designed to inhibit the GCAP1 disease mutants, which may serve to mitigate the onset of retinal cone-rod dystrophies. Full article

(This article belongs to the Special Issue Molecular Basis of Sensory Transduction in Health and Disease)

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