G-protein Signaling


Heterotrimeric G proteins

The heterotrimeric guanine nucleotide binding proteins (G proteins) are signal transducers that communicate signals from hormones, neurotransmitters, chemokines, and autocrine and paracrine factors. The extracellular signals are received by members of GPCRs that activate the G proteins, which route the signals to several distinct intracellular signaling pathways. G proteins are made up of α, β, and γ subunits. Although there are many genes encoding each subunit (20 α, 6 β, and 13 γ, for a maximum of 1560 possible heterotrimeric G protein combinations), four main classes of G proteins can be distinguished. Gαs, whose members include Gαs and GαOLF, activates AC while Gαi inhibits AC. Another class of G proteins, Gαq activates phospholipase C. Finally, G12 and G13 are thought to stimulate phospholipase D, as well as several protein kinases including the tyrosine kinase c-Src and serine/threonine kinases PKC and PKB.

G proteins are inactive in the GDP-bound heterotrimeric state and are activated by receptor-catalyzed guanine nucleotide exchanges resulting in GTP binding to the α subunit. GTP binding leads to dissociation of Gα GTP from its Gβγ subunits. Both Gα GTP and the free Gβγ subunits can regulate downstream G protein effectors. G protein deactivation is rate-limiting for turnoff of the cellular response and occurs when the Gα subunit hydrolyzes GTP to GDP.

The βγ subunits of G protein are heterodimer, which under physiological conditions, and function as a single entity in the G protein cycle. It is now recognized that the Gβγ complex, though originally conceptualized as the passive, stabilizing binding partner for Gα subunit at the completion of a signaling cycle, carries an independent signal to many types of cellular effectors upon G protein activation.

There are many reports that show the involvement of the Gβγ dimer complex in the regulation of various effectors, including PLC-p2, MAPK/ERK, JNK/SAPK, phosphatidylinositol 3-kinase, and several AC isozymes.

 

Regulators of G protein signaling

The regulators of G protein signaling (RGS) family are GTPase-activating proteins (GAPs) that accelerate hydrolysis of GTP bound to the a subunits of certain heterotrimeric G proteins. RGS proteins can function as negative regulators of G protein mediated signal transduction by speeding deactivation of the active form of Gα subunits, thereby promoting formation of inactive G protein heterotrimers (GαGDPβγ).

RGS proteins form a superfamily of at least 25 proteins, which are highly diverse in structure, expression patterns, and function. They share a 120 amino acid homology domain (RGS domain), which exhibits GTPase accelerating activity for a-subunits of heterotrimeric G-proteins, and thus, are negative regulators of G-protein-mediated signaling.

 

Inhibitors/promotors
Substrate

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