scholarly journals Regulating quantal size of neurotransmitter release through a GPCR voltage sensor

2020 ◽  
Vol 117 (43) ◽  
pp. 26985-26995 ◽  
Author(s):  
Quanfeng Zhang ◽  
Bing Liu ◽  
Yinglin Li ◽  
Lili Yin ◽  
Muhammad Younus ◽  
...  
Keyword(s):  
G Protein ◽  
Direct Interaction ◽  
Membrane Voltage ◽  
Dense Core Vesicle ◽  
Cell Functions ◽  
Quantal Size ◽  
Per Se ◽  
Adrenal Chromaffin ◽  
Myocyte Contractility ◽  
G Protein Coupled

Current models emphasize that membrane voltage (Vm) depolarization-induced Ca2+ influx triggers the fusion of vesicles to the plasma membrane. In sympathetic adrenal chromaffin cells, activation of a variety of G protein coupled receptors (GPCRs) can inhibit quantal size (QS) through the direct interaction of G protein Giβγ subunits with exocytosis fusion proteins. Here we report that, independently from Ca2+, Vm (action potential) per se regulates the amount of catecholamine released from each vesicle, the QS. The Vm regulation of QS was through ATP-activated GPCR-P2Y12 receptors. D76 and D127 in P2Y12 were the voltage-sensing sites. Finally, we revealed the relevance of the Vm dependence of QS for tuning autoinhibition and target cell functions. Together, membrane voltage per se increases the quantal size of dense-core vesicle release of catecholamine via Vm → P2Y12(D76/D127) → Giβγ → QS → myocyte contractility, offering a universal Vm-GPCR signaling pathway for its functions in the nervous system and other systems containing GPCRs.

Lysophosphatidylinositol: a novel link between ABC transporters and G-protein-coupled receptors

2014 ◽  
Vol 42 (5) ◽  
pp. 1372-1377 ◽  
Author(s):  
Emily L. Ruban ◽  
Riccardo Ferro ◽  
Syamsul Ahmad Arifin ◽  
Marco Falasca
Keyword(s):  
Cell Proliferation ◽  
G Protein ◽  
Cancer Progression ◽  
Multidrug Resistance Protein 1 ◽  
Autocrine Loop ◽  
Cell Functions ◽  
Cytosolic Phospholipase ◽  
Signalling Cascades ◽  
Novel Strategy ◽  
G Protein Coupled

Lysophosphatidylinositol (LPI) is a well-known bioactive lipid that is able to activate signalling cascades relevant to cell proliferation, migration, survival and tumorigenesis. Our previous work suggested that LPI is involved in cancer progression since it can be released in the medium of Ras-transformed fibroblasts and can function as an autocrine modulator of cell growth. Different research groups have established that LPI is the specific and functional ligand for G-protein-coupled receptor 55 (GPR55) and that this GPR55–LPI axis is able to activate signalling cascades that are relevant for different cell functions. Work in our laboratory has recently unravelled an autocrine loop, by which LPI synthesized by cytosolic phospholipase A2 (cPLA2) is pumped out of the cell by ATP-binding cassette (ABC) transporter C1 (ABCC1)/multidrug resistance protein 1 (MRP1), initiating a signalling cascade downstream of GPR55. Our current work suggests that blockade of this pathway may represent a novel strategy to inhibit cancer cell proliferation.

Selective Regulation of Gq Signaling by G Protein-Coupled Receptor Kinase 2: Direct Interaction of Kinase N Terminus with Activated Gαq

2000 ◽  
Vol 57 (4) ◽  
pp. 826-831 ◽  
Author(s):  
Michele Sallese ◽  
Stefania Mariggiò ◽  
Etrusca D'Urbano ◽  
Luisa Iacovelli ◽  
Antonio De Blasi
Keyword(s):  
G Protein ◽  
Direct Interaction ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
N Terminus ◽  
G Protein Coupled

scholarly journals G-protein-coupled-receptor kinases mediate TNFα-induced NF-κB signalling via direct interaction with and phosphorylation of IκBα

2009 ◽  
Vol 425 (1) ◽  
pp. 169-180 ◽  
Author(s):  
Sonika Patial ◽  
Jiansong Luo ◽  
Katie J. Porter ◽  
Jeffrey L. Benovic ◽  
Narayanan Parameswaran
Keyword(s):  
G Protein ◽  
Direct Interaction ◽  
Signalling Pathway ◽  
Raw 264.7 ◽  
G Protein Coupled Receptor ◽  
Raw 264.7 Macrophages ◽  
Iκb Kinase ◽  
Receptor Kinases ◽  
G Protein Coupled

TNFα (tumour necrosis factor α) is a multifunctional cytokine involved in the pathophysiology of many chronic inflammatory diseases. TNFα activation of the NF-κB (nuclear factor κB) signalling pathway particularly in macrophages has been implicated in many diseases. We demonstrate in the present study that GRK2 and GRK5 (G-protein-coupled-receptor kinases 2 and 5) regulate TNFα-induced NF-κB signalling in Raw 264.7 macrophages. RNAi (RNA interference) knockdown of GRK2 or GRK5 in macrophages significantly inhibited TNFα-induced IκBα (inhibitory κBα) phosphorylation and degradation, NF-κB activation and expression of the NF-κB-regulated gene MIP1β (macrophage inflammatory protein 1β). Consistent with these results, overexpression of GRK2 or GRK5 enhanced TNFα-induced NF-κB activity. In addition, we show that GRK2 and GRK5 interacted with IκBα via the N-terminal domain of IκBα and that IκBα is a substrate for GRK2 and GRK5 in vitro. Furthermore, we also found that GRK5, but not GRK2, phosphorylated IκBα at the same amino acid residues (Ser32/Ser36) as that of IKKβ (IκB kinase β). Interestingly, associated with these results, knockdown of IKKβ in Raw 264.7 macrophages did not affect TNFα-induced IκBα phosphorylation. Taken together, these results demonstrate that both GRK2 and GRK5 are important and novel mediators of a non-traditional IκBα/NF-κB signalling pathway.

scholarly journals Transduction of Multiple Effects of Sphingosine 1-Phosphate (S1P) on T Cell Functions by the S1P1 G Protein-Coupled Receptor

2003 ◽  
Vol 171 (7) ◽  
pp. 3500-3507 ◽  
Author(s):  
Glenn Dorsam ◽  
Markus H. Graeler ◽  
Christine Seroogy ◽  
Yvonne Kong ◽  
Julia K. Voice ◽  
...  
Keyword(s):  
T Cell ◽  
G Protein ◽  
G Protein Coupled Receptor ◽  
Cell Functions ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

scholarly journals Evidence for Osteocalcin Binding and Activation of GPRC6A in β-Cells

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 1866-1880 ◽  
Author(s):  
Min Pi ◽  
Karan Kapoor ◽  
Ruisong Ye ◽  
Satoru Kenneth Nishimoto ◽  
Jeremy C. Smith ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
G Protein ◽  
Computational Models ◽  
Transmembrane Domain ◽  
Structural Basis ◽  
G Protein Coupled Receptor ◽  
Β Cells ◽  
Β Cell ◽  
Cell Functions ◽  
G Protein Coupled

Abstract The possibility that G protein-coupled receptor family C member A (GPRC6A) is the osteocalcin (Ocn)-sensing G protein-coupled receptor that directly regulates pancreatic β-cell functions is controversial. In the current study, we found that Ocn and an Ocn-derived C-terminal hexapeptide directly activate GPRC6A-dependent ERK signaling in vitro. Computational models probe the structural basis of Ocn binding to GPRC6A and predict that the C-terminal hexapeptide docks to the extracellular side of the transmembrane domain of GPRC6A. Consistent with the modeling, mutations in the computationally identified binding pocket of GPRC6A reduced Ocn and C-terminal hexapeptide activation of this receptor. In addition, selective deletion of Gprc6a in β-cells (Gprc6aβ-cell-cko) by crossing Gprc6aflox/flox mice with Ins2-Cre mice resulted in reduced pancreatic weight, islet number, insulin protein content, and insulin message expression. Both islet size and β-cell proliferation were reduced in Gprc6aβ-cell-cko compared with control mice. Gprc6aβ-cell-cko exhibited abnormal glucose tolerance, but normal insulin sensitivity. Islets isolated from Gprc6aβ-cell-cko mice showed reduced insulin simulation index in response to Ocn. These data establish the structural basis for Ocn direct activation of GPRC6A and confirm a role for GPRC6A in regulating β-cell proliferation and insulin secretion.

G Protein-coupled Receptors in Cancer Stem Cells

2020 ◽  
Vol 26 (17) ◽  
pp. 1952-1963 ◽  
Author(s):  
Yuhong Jiang ◽  
Xin Zhuo ◽  
Canquan Mao
Keyword(s):  
Stem Cells ◽  
Cancer Therapy ◽  
Cancer Stem Cells ◽  
G Protein ◽  
Drug Targets ◽  
Underlying Mechanism ◽  
G Protein Coupled Receptors ◽  
Cell Functions ◽  
Exogenous Ligands ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are highly expressed on a variety of tumour tissues while several GPCR exogenous ligands become marketed pharmaceuticals. In recent decades, cancer stem cells (CSCs) become widely investigated drug targets for cancer therapy but the underlying mechanism is still not fully elucidated. There are vigorous participations of GPCRs in CSCs-related signalling and functions, such as biomarkers for CSCs, activation of Wnt, Hedgehog (HH) and other signalling to facilitate CSCs progressions. This relationship can not only uncover a novel molecular mechanism for GPCR-mediated cancer cell functions but also assist our understanding of maintaining and modulating CSCs. Moreover, GPCR antagonists and monoclonal antibodies could be applied to impair CSCs functions and consequently attenuate tumour growth, some of which have been undergoing clinical studies and are anticipated to turn into marketed anticancer drugs. Therefore, this review summarizes and provides sufficient evidences on the regulation of GPCR signalling in the maintenance, differentiation and pluripotency of CSCs, suggesting that targeting GPCRs on the surface of CSCs could be potential therapeutic strategies for cancer therapy.

scholarly journals Localization of Giα proteins in the centrosomes and at the midbody: implication for their role in cell division

2007 ◽  
Vol 178 (2) ◽  
pp. 245-255 ◽  
Author(s):  
Hyeseon Cho ◽  
John H. Kehrl
Keyword(s):  
Cell Division ◽  
G Protein ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Direct Interaction ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Heterotrimeric G Proteins ◽  
Independent Functions ◽  
G Protein Coupled

At the plasma membrane, heterotrimeric G proteins act as molecular switches to relay signals from G protein–coupled receptors; however, Gα subunits also have receptor-independent functions at intracellular sites. Regulator of G protein signaling (RGS) 14, which enhances the intrinsic GTPase activity of Giα proteins, localizes in centrosomes, which suggests the coexpression of Giα. We show expression of Giα1, Giα2, and Giα3 in the centrosomes and at the midbody. Fluorescence resonance energy transfer analysis confirms a direct interaction between RGS14 and Giα1 in centrosomes. Expression of GTPase-deficient Giα1 results in defective cytokinesis, whereas that of wild-type or GTPase-deficient Giα3 causes prolonged mitosis. Cells treated with pertussis toxin, with reduced expression of Giα1, Giα2, and Giα3 or with decreased expression of RGS14 also exhibit cytokinesis defects. These results suggest that Giα proteins and their regulators at these sites may play essential roles during mammalian cell division.

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