Role of GPR39 in Neurovascular Homeostasis and Disease
Abstract
:1. Introduction
2. Gene Organization and Isoforms of GPR39
3. GPR39 Expression Patterns
4. Preliminary GWAS Data Suggests Potential Roles for GPR39 in Human Vascular and Neurovascular Disease
5. G-protein Regulation via Post-Translational Modification
6. Constitutive Pathway Acts through Gα12/13 and Rho Kinase to Promote Resistance to Stress and Inflammation
7. Deorphaned Endogenous Ligands Implicate GPR39 in Moderating Neuro-Excitability and Vascular Tone through Gαq and/or Gαs Pathways
7.1. Obestatin Controversy
7.2. Zinc Ligand-Activated Pathway Requires Specific Amino Acid Sites and Interacts with the Constitutive Pathway
7.3. Zinc Induces Gαq and Gαs Cascade with Cross Modulation of the Constitutive Pathway
7.4. Eicosanoid Binding Implicates GPR39 Activity in Regulating Vascular Tone
7.5. Synthetic Ligands, Biased Agonism, and Receptor Desensitization
8. Role of GPR39 in Nervous System Homeostasis
8.1. GPR39 Tempers Neuroexcitability in Neurotransmission
8.2. GPR39 in pH Homeostasis
8.3. GPR39 Regulates Inflammation and Vascular Pathology
9. Targeting GPR39 as a Therapy for Neurological and Neuropsychiatric Disorders
9.1. Epilepsy Treatment
9.2. Chronic Pain
9.3. Alzheimer’s Disease and Vascular Dementia
9.4. Neuropsychiatric Disease: Anxiety, Depression, Addiction
9.4.1. Anxiety
9.4.2. Depression
Depression and Zinc Agonism of GPR39
Neurotransmission Modulation (Monoaminergic and Glutamatergic Systems)
Depression Interplay with Neuroprotection and Inflammatory Pathways
9.4.3. Addiction
9.5. Neuroendocrine Influences on the Nervous System
10. Looking toward Future Research into GPR39’s Role in Neurovascular Pathology
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
14,15-EET | 14,15-epoxyeicosatrienoate, vasodilating eicosonoid |
15-HETE | 15-hydroxyeicosatetraenoate, vasoconstricting eicosonoid |
2-AG | 2-arachidonoyl glycerol, endocannabinoid |
5-HT | serotonin |
Aβ | amyloid beta |
AML | acute myeloid leukemia |
BDNF | brain-derived neurotrophic factor |
cAMP | cyclic adenosine monophosphate |
CAD | coronary artery disease |
Ca levels | calcium levels |
CBR1 | endocannabinoid receptor 1 |
CHO | cell line derived from Chinese hamster ovaries |
COS-7 | cell line derived from kidney of African Green Monkey |
CRE | cAMP response element (CRE) transcription factor |
CREB | cAMP response element-binding protein (CREB) |
DAG | diacylglcerol |
ECL | extracellular domain |
ERK | extracellular signal-regulated kinase |
Gα12/13 | G-protein inositol alpha 12/13, GPR39’s constitutively active signaling cascade |
Gαq | G-protein inositol alpha q, zinc-activated signaling cascade through GPR39 |
Gαs | G-protein inositol alpha s, zinc-activated signaling cascade through GPR39 |
GnR | ghrelin receptor |
GPCR | G-protein coupled receptor |
GPR39 | G protein coupled receptor 39, also known as ZnR (zinc receptor) |
GPR39-C3 | synthetic agonist of GPR39, also known as C3 or TC-G 1008 |
HEK293T | Cell line derived from human kidney |
HT | hypertension |
IL-10 | interleukin 10 |
IP3 | 1,3,4-triphosphate |
KCC2 | K+/Cl-cotransporter |
KO | knock out |
LPS | lipopolysaccharide (LPS), bacteria-derived compound to induce inflammatory sepsis |
Lung Cap | lung capacity |
LYPD1 | LY6/PLAUR domain containing 1 gene, antisense gene overlapping with GPR39’s second exon, overlaps with GPR39-1a but not GPR39-1b |
MAPK | mitogen-activated protein kinase |
MCI | mild cognitive impairment |
mVSMCs | microvascular smooth muscle cells |
NHE-1 | Na+/H+ exchanger |
NTSR1 | Neurotensin receptor 1 |
OE | over expression |
PAM | positive allosteric modulator |
PI3 | phosphoinositide 3 |
PKA | phosphokinase A |
PKB/AKT | protein kinase B/Ak-strain transforming pathways |
PKC | phosphokinase C |
PKIB | Protein kinase A inhibitor beta |
PLC | phospholipase C |
sc-RNAseq | single cell RNA sequencing |
SRE | serum response element, constitutive pathway of GPR39 signaling cascade |
SNRI | serotonin and norepinephrine reuptake inhibitor |
SSRI | selective serotonin reuptake inhibitor |
TM | transmembrane domain |
TrkB | Tropomyosin receptor kinase B |
VCI | vascular cognitive dementia |
VCID | vascular cognitive impairment and dementia |
VSMC | vascular smooth muscle cell |
WT | wild type |
ZnT3 | zinc transporter |
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(A) | |||||
---|---|---|---|---|---|
Organism | Detection Method | Probe Source | GPR39 Variant Detected | Expression Pattern | Publication Source |
Human | Northern blot for RNA, probe using 32P- Labeled DNA fragment with complete open reading frame | Fetal human brain cDNA library, GPR39 isolated by rapid PCR in search for relatives of Growth Hormone Secretagogue Receptor and Neurotensin Receptor Type 1. | 1a, 1b | Amygdala, caudate nucleus, corpus callosum, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, medulla, spinal cord, occipital pole, frontal lobe, temporal lobe | [8] |
Mouse | In situ hybridization, mRNA | Mouse | 1a, 1b. Probe does not overlap with LYPD1/ MGC29643 antisense gene | Amygdala, hippocampus (dentate gyrus, CA1, CA3), auditory cortex, layer 2 piriform cortex, ventral pallidum, inferior olive, NOT in hypothalamus | [10] |
Rat | Quantitative RT-PCR (QPCR), in situ hybridization | Rat | 1a | Very low expression in CNS; high expression in peripheral metabolic organs | [12] |
Rat | Quantitative RT-PCR (QPCR) | Rat | 1b | Widely expressed but low expression in cerebellum, cortex, pons, hippocampus, hypothalamus, striatum, amygdala, septum. 1b overlaps with antisense gene LYPD1, which is expressed strongly in all brain regions. | [12] |
Mouse | Quantitative RT-PCR (QPCR), | Mouse | 1a | Low levels in whole brain, septum, hypothalamus, hippocampus | [24] |
Mouse | GPR39 promoter expressing LacZ instead of GPR39, no functional GPR39 | Mouse | 1a, 1b | Septum, hippocampus (dentate gyrus), amygdala (discrete cells), NO hypothalamic expression. Strong expression in small intestine nerve plexus. | [24] |
Rat | Quantitative RT-PCR (QPCR) | Rat | 1a, 1b | Pituitary, hypothalamus, cerebellum, cerebrum | [11] |
Mouse | RT-PCR in GPR39 KO mice and WT littermates | Mouse | 1a, 1b | Low brain expression | [25] |
Rat | Quantitative RT-PCR (QPCR) | Rat | 1a, 1b | NOT in pituitary or hypothalamus | [26] |
Human | Protein— immunohistochemistry, antibody to GPR39 third extracellular domain | Anti-human antibody | 1a | Staining in microglia and peri- capillary cells (pericytes), higher density of GPR39 expressing microglia in mild cognitive impairment brains | [7] |
(B) | |||||
In vitro System | Intervention | GPR39 Variant | Result | Publication Source | |
CHO cells (hamster ovary), HEK293T cells (human kidney) | GPR39 cDNA expression | 1a, 1b | Increased obestatin stimulation with cAMP production; GPR39 constitutively activates serum response element (SRE) | [11] | |
COS-7 cells (monkey kidney) | GPR39 expression from human stomach cDNA library | 1a, 1b | Zn2+ stimulated Gs pathway and cAMP increase; high constitutive activity | [26] | |
HEK293T cells (human kidney) | GPR39 overexpression from human cDNA | 1a, 1b | GPR39 constitutively active through SRE- mediated transcriptional activity | [25] | |
CHO-K1 cells (hamster ovary) | Human and mouse GPR39 cDNA (1a) from genomic DNA, rat GPR39 obtained by RT-PCR from cDNA of rat liver. | 1a, 1b | Zn2+ identified as GPR39 agonist in fetal bovine serum peptide extraction, showed Zn mobilizes calcium through Gαq-PLC pathway for human, mouse, and rat GPR39. | [27] |
Knockout Strain Name | Targeting Strategy | Phenotype Observed | Reference |
---|---|---|---|
Gpr39tm1Lex | Exon 1 replacement with selection cassette | Increeased body weight and fat composition, increased cholestrol levels, reduced hyperphagia after fasting. | [24] |
loss of hippocampal Zn-enhanced KCC2 activity and surface expression | [22] | ||
increased sensitivity to dextran sodium sulfate ulcerative colitis model and reduced rate of recovery | [33] | ||
Increase in Cholera-toxin induced intestinal fluid secretion | [32] | ||
Increased numbers of active osteoblasts, disorganized bone matrix deposition, down-regulation of collagen processing enzymes | [31] | ||
Gpr39tm1Dgen | Exon 1 selection cassette knock-in | No effect on body weight or food intake | [25] |
Impaired glucose tolerance, decreased plasma insulin response | [35] | ||
Impaired insulin secretion | [36] | ||
Increased fat accumulation with high-fat diet, elimination of diet-induced thermogenesis | [37] | ||
Decreased TMEM16A current in small intestine fibroblast-like cells | [30] | ||
Resistance to monoamine-based antidepressants | [38] | ||
depressive-like behavior, reduced thymus weight; reduced splenocytes viability, reduced splenocytes proliferative response, increased IL-6 production | [39] | ||
Delayed wound healing | [34] | ||
lower hippocampal CREB and BDNF levels, depressive-like behavior and anxiety-like phenotype | [40] | ||
Gpr39em1(IMPC)Bay | CRISPR Exon 1 Deletion | decreased bone mineral density | International Mouse Phenotyping Consortium (IMPC) |
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Xu, Y.; Barnes, A.P.; Alkayed, N.J. Role of GPR39 in Neurovascular Homeostasis and Disease. Int. J. Mol. Sci. 2021, 22, 8200. https://doi.org/10.3390/ijms22158200
Xu Y, Barnes AP, Alkayed NJ. Role of GPR39 in Neurovascular Homeostasis and Disease. International Journal of Molecular Sciences. 2021; 22(15):8200. https://doi.org/10.3390/ijms22158200
Chicago/Turabian StyleXu, Yifan, Anthony P. Barnes, and Nabil J. Alkayed. 2021. "Role of GPR39 in Neurovascular Homeostasis and Disease" International Journal of Molecular Sciences 22, no. 15: 8200. https://doi.org/10.3390/ijms22158200