HomeProtein ExpressionOverview of G Protein-coupled Receptors (GPCRs)

Overview of G Protein-coupled Receptors (GPCRs)

The superfamily of G protein-coupled receptors (GPCRs) contains upwards of 1000 distinct members that mediate the vast majority of responses to hormones, neurotransmitters, sensory stimuli, and various autocrine and paracrine factors. These integral membrane proteins have a conserved primary structure that contains seven hydrophobic regions that span the plasma membrane. Upon binding agonist, GPCRs undergo a conformational change that promotes coupling to heterotrimeric guanine nucleotide binding proteins (G proteins) that consist of α, β and γ subunits. The agonist-occupied GPCR acts as a guanine nucleotide exchange factor and activates the G protein by promoting the dissociation of GDP from the Gα subunit. The nucleotide-free Gα then binds GTP and the Gα-GTP and Gβγ subunits dissociate and interact with various effector proteins.

In order to ensure that extracellular stimuli are translated into intracellular signals of appropriate magnitude and specificity, GPCR signaling cascades are tightly regulated. GPCRs are subject to three principle modes of regulation: (i) desensitization, the process whereby a receptor becomes refractory to continued stimuli; (ii) internalization, where receptors are physically removed from the cell surface by endocytosis; and (iii) down-regulation, where total cellular receptor levels are decreased. GPCR desensitization is primarily mediated by second messenger dependent kinases, such as protein kinase A (PKA) and protein kinase C (PKC), and by GPCR kinases (GRKs). GRKs specifically phosphorylate activated GPCRs and initiate the recruitment of arrestins, which mediate receptor desensitization and internalization.

GRKs are found in metazoans and, in mammals, the seven GRKs can be divided into three subfamilies based on overall structural organization and homology: GRK1 (rhodopsin kinase) and GRK7; GRK2 (βARK1) and GRK3 (βARK2); and GRK4, GRK5 and GRK6. GRKs are serine/threonine kinases with a tripartite modular structure. A central ~330 amino acid catalytic domain is flanked by an ~180 residue N-terminal region that contains a regulator of G protein signaling (RGS) domain and an ~60-160 amino acid C-terminal lipid-binding domain. Interestingly, the X-ray crystal structure of GRK2 suggests that it can simultaneously bind to receptor, Gαq (through the RGS domain), and Gβγ (through a C-terminal pleckstrin homology domain), thus providing an effective mechanism to terminate signaling.

A critical component in modulating GRK function involves regulating the activity and cellular localization of GRKs. Phosphorylation appears to play an important role in regulating GRK activity. GRK2 phosphorylation by ERK1/2 inhibits GRK2 activity while phosphorylation by PKA, Src, and PKC results in increased activity. In contrast, GRK5 activity is attenuated by PKC phosphorylation but stimulated by autophosphorylation. GRK function is also regulated by interaction with a large number of additional proteins including G protein subunits, the GRK-interacting protein GIT1, caveolin-1, phosphoinositide 3-kinase, cytoskeletal proteins such as tubulin and actin, and various calcium binding proteins. Phospholipids also play an important role in regulating GRK function since Gβγ-mediated GRK2 activation is dependent on negatively charged phospholipids. Interestingly, while GRK4 subfamily members do not bind Gβγ subunits, these kinases share an amino-terminal lipid-binding domain that may facilitate receptor phosphorylation. These kinases also have the ability to associate with phospholipids via a carboxyl-terminal domain that is either palmitoylated (GRK4 and 6) or can directly bind phospholipids (GRK5). Thus, the immediate phospholipid environment may have a general and critical role in modulating GRK function.

While in vitro studies have provided important insight into GRK/receptor interaction, other studies have focused on manipulating GRKs in intact cell systems and model organisms. For example, transfection of antisense GRK constructs has revealed subtype-specific regulation of H2 histamine receptors (by GRK2), pituitary adenylate cyclase activating peptide (PACAP) type 1 and corticotrophin releasing factor (CRF1) receptors (by GRK3), metabotropic glutamate type 1 receptors (by GRK4), thyrotropin receptors (by GRK5), and calcitonin gene-related peptide (CGRP) receptors (by GRK6). Insight into GRK specificity/function has also been gained from transgenic mice where cardiac-specific overexpression of GRK2 or a carboxyl-terminal GRK2 mini-gene demonstrates specific in vivo effects on cardiac function. Functional knockouts of GRKs have also provided important physiological insight. Disruption of the mouse GRK2 gene results in embryonic lethality while a mutation that disrupts expression of Gprk2 (a Drosophila GRK4 homolog) leads to specific defects in embryogenesis. Disruption of the mouse GRK3 gene results in attenuated desensitization of olfactory and cholinergic responses while mutation of a GRK2/3 homolog in C. elegans results in defective chemosensation. A mouse GRK5 knockout leads to muscarinic supersensitivity and impaired receptor desensitization, while disruption of the GRK6 gene results in supersensitivity to the locomoter-stimulating effects of cocaine and amphetamine. These findings suggest that GRKs are involved not only in regulating signaling but may also have critical roles in regulating growth and development.

The Table below contains accepted modulators and additional information.


βARK-1: β-Adrenergic receptor kinase-1
βARK-2: β-Adrenergic receptor kinase-2
mGluR1: Metabotropic glutamate receptor type 1
NCS-1: Neuronal calcium sensor
ND: Not determined
PIP2: Phosphatidylinositol 4,5-bisphosphate
Ro 32-0432: 2-{1-[3-(Amidinothio)propyl]-1H-indol-3-yl}-3-(1-methylindol-3-yl)-maleimide methanesulfonate
Ro 31-8220: 2-(8-[(Dimethylamino)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl)-3-(1-methylindol-3-yl)maleimide hydrochloride
ESCS: Enhanced S cone syndrome


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