Regulator of G-protein signaling 2 is a protein that in humans is encoded by the RGS2 gene. [5] [6] It is part of a larger family of RGS proteins that control signalling through G-protein coupled receptors (GPCR).
Regulator of G-protein signaling 2 is a protein that in humans is encoded by the RGS2 gene. [5] [6] It is part of a larger family of RGS proteins that control signalling through G-protein coupled receptors (GPCR).
RGS2 is thought to have protective effects against myocardial hypertrophy as well as atrial arrhythmias. [7] [8] Increased stimulation of Gs coupled β1-adrenergic receptors and Gq coupled α1-adrenergic receptors in the heart can result in cardiac hypertrophy. [7] In the case of Gq protein coupled receptor (GqPCR) mediated hypertrophy, Gαq will activate the intracellular affectors phospholipase Cβ and rho guanine nucleotide exchange factor to stimulate cell processes which lead to cardiomyocyte hypertrophy. [7] [9] RGS2 functions as a GTPase Activating Protein (GAP) which acts to increase the natural GTPase activity of the Gα subunit. [7] [9] By increasing the GTPase activity of the Gα subunit, RGS2 promotes GTP hydrolysis back to GDP, thus converting the Gα subunit back to its inactive state and reducing its signalling ability. [9] Both GsPCR and GqPCR activation can contribute to cardiac hypertrophy via activation of MAP Kinases as well. RGS2 has been shown to decrease phosphorylation of those MAP kinases and therefore decrease their activation in response to Gαs signalling. [7]
In the case of GsPCR mediated hypertrophy, the main mechanism by which signalling contributes to hypertrophy is through the Gβγ subunit; Gαs signalling by itself is not sufficient. [10] Nevertheless, RGS2 has been shown to inhibit Gs mediated hypertrophy. The mechanism of how RGS2 regulates increased Gβγ signalling is not well understood, apart from the fact that it is unrelated to RGS2's GAP function. [10] A deficiency in RGS2 has been linked with increased cardiac hypertrophy in mice. [7] RGS2 deficient hearts appear normal until confronted with an increased workload, to which they respond readily with increased Gαq signalling and hypertrophy. [7] [10]
Gαs subunits increase adenyl cyclase activity, which in turn leads to cAMP accumulation in the myocyte nucleus to trigger hypertrophy. RGS2 regulates the effects of increased Gαs signalling through its GAP function. [7] Stimulation of GsPCRs not only leads to hypertrophy but it has also been shown to selectively induce higher expression levels of RGS2 which in turn, protects against hypertrophy, providing a mechanism for maintaining homeostatic conditions. [7]
There has also been some evidence of a role of RGS2 in atrial arrhythmias where RGS2 deficient mice exhibited prolonged and greater susceptibility to electrically induced atrial fibrillation. [8] This was attributed to a decrease in RGS2's inhibitory effects on Gq coupled M3 muscarinic receptor signalling, resulting in increased Gαq activity. [8] The M3 muscarinic receptor normally activates delayed rectifier potassium channels in the atria, thus increased Gαq activity is thought to result in an altered potassium flux, a decreased refractory period, increased chance of current re-entry and inappropriate contraction. [8]
RGS2 has been shown to interact with PRKG1 [13] and ADCY5. [14]
GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a protein domain common to many GTPases.
GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are also known as RGS protein, or RGS proteins, and these proteins are crucial in controlling the activity of G proteins. Regulation of G proteins is important because these proteins are involved in a variety of important cellular processes. The large G proteins, for example, are involved in transduction of signaling from the G protein-coupled receptor for a variety of signaling processes like hormonal signaling, and small G proteins are involved in processes like cellular trafficking and cell cycling. GAP's role in this function is to turn the G protein's activity off. In this sense, GAPs function is opposite to that of guanine nucleotide exchange factors (GEFs), which serve to enhance G protein signaling.
G protein-coupled receptor kinases are a family of protein kinases within the AGC group of kinases. Like all AGC kinases, GRKs use ATP to add phosphate to Serine and Threonine residues in specific locations of target proteins. In particular, GRKs phosphorylate intracellular domains of G protein-coupled receptors (GPCRs). GRKs function in tandem with arrestin proteins to regulate the sensitivity of GPCRs for stimulating downstream heterotrimeric G protein and G protein-independent signaling pathways.
G-protein-coupled receptor kinase 2 (GRK2) is an enzyme that in humans is encoded by the ADRBK1 gene. GRK2 was initially called Beta-adrenergic receptor kinase, and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK3(βARK2).
The Gs alpha subunit is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding member of one of the four families of heterotrimeric G proteins, defined by the alpha subunits they contain: the Gαs family, Gαi/Gαo family, Gαq family, and Gα12/Gα13 family. The Gs-family has only two members: the other member is Golf, named for its predominant expression in the olfactory system. In humans, Gsα is encoded by the GNAS complex locus, while Golfα is encoded by the GNAL gene.
Gq protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gq/11 (Gq/G11) family or Gq/11/14/15 family to include closely related family members. G alpha subunits may be referred to as Gq alpha, Gαq, or Gqα. Gq proteins couple to G protein-coupled receptors to activate beta-type phospholipase C (PLC-β) enzymes. PLC-β in turn hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to diacyl glycerol (DAG) and inositol trisphosphate (IP3). IP3 acts as a second messenger to release stored calcium into the cytoplasm, while DAG acts as a second messenger that activates protein kinase C (PKC).
Regulator of G protein signaling 4 also known as RGP4 is a protein that in humans is encoded by the RGS4 gene. RGP4 regulates G protein signaling.
The alpha-1B adrenergic receptor (α1B-adrenoreceptor), also known as ADRA1B, is an alpha-1 adrenergic receptor, and also denotes the human gene encoding it. The crystal structure of the α1B-adrenergic receptor has been determined in complex with the inverse agonist (+)-cyclazosin.
Guanine nucleotide-binding protein G(q) subunit alpha is a protein that in humans is encoded by the GNAQ gene. Together with GNA11, it functions as a Gq alpha subunit.
Guanine nucleotide-binding protein G(i), alpha-2 subunit is a protein that in humans is encoded by the GNAI2 gene.
Regulators of G protein signaling (RGS) are protein structural domains or the proteins that contain these domains, that function to activate the GTPase activity of heterotrimeric G-protein α-subunits.
Guanine nucleotide-binding protein G(o) subunit alpha is a protein that in humans is encoded by the GNAO1 gene.
Regulator of G-protein signaling 19 is a protein that in humans is encoded by the RGS19 gene.
Guanine nucleotide-binding protein G(t) subunit alpha-1 is a protein that in humans is encoded by the GNAT1 gene.
Regulator of G-protein signaling 1 is a protein that in humans is encoded by the RGS1 gene.
Regulator of G-protein signaling 20 is a protein that in humans is encoded by the RGS20 gene.
Regulator of G-protein signaling 12 is a protein that in humans is encoded by the RGS12 gene.
Regulator of G-protein signaling 8 is a protein that in humans is encoded by the RGS8 gene.
Regulator of G-protein signalling 9, also known as RGS9, is a human gene, which codes for a protein involved in regulation of signal transduction inside cells. Members of the RGS family, such as RGS9, are signaling proteins that suppress the activity of G proteins by promoting their deactivation.[supplied by OMIM]
Regulator of G-protein signaling 13 (RGS13) is a protein that in humans is encoded by the RGS13 gene.
PDB gallery | |
|---|---|
|
