G-protein alpha subunit, group S (Gprotein_alpha_S)
Type: Family

Guanine nucleotide binding proteins (G-proteins) are membrane-associated, heterotrimeric proteins composed of three subunits: alpha (

), beta (

) and gamma (

) . G proteins and their receptors (GPCRs) form one of the most prevalent signalling systems in mammalian cells, regulating systems as diverse as sensory perception, cell growth and hormonal regulation . At the cell surface, the binding of ligands such as hormones and neurotransmitters to a GPCR activates the receptor by causing a conformational change, which in turn activates the bound G protein on the intracellular-side of the membrane. The activated receptor promotes the exchange of bound GDP for GTP on the G protein alpha subunit. GTP binding changes the conformation of switch regions within the alpha subunit, which allows the bound trimeric G protein (inactive) to be released from the receptor, and to dissociate into active alpha subunit (GTP-bound) and beta/gamma dimer. The alpha subunit and the beta/gamma dimer go on to activate distinct downstream effectors, such as adenylyl cyclase, phosphodiesterases, phospholipase C, and ion channels. These effectors in turn regulate the intracellular concentrations of secondary messengers, such as cAMP, diacylglycerol, sodium or calcium cations, which ultimately lead to a physiological response, usually via the downstream regulation of gene transcription. The cycle is completed by the hydrolysis of alpha subunit-bound GTP to GDP, resulting in the re-association of the alpha and beta/gamma subunits and their binding to the receptor, which terminates the signal . The length of the G protein signal is controlled by the duration of the GTP-bound alpha subunit, which can be regulated by RGS (regulator of G protein signalling) proteins or by covalent modifications .

G protein alpha subunits are 350-400 amino acids in length and have molecular weights in the range 40-45kDa. Seventeen distinct types of alpha subunit have been identified in mammals. These fall into 4 main groups on the basis of both sequence similarity and function: alpha-S (

), alpha-Q (

), alpha-I (

)and alpha-12(

) .

The specific combination of subunits in heterotrimeric G proteins affects not only which receptor it can bind to, but also which downstream target is affected, providing the means to target specific physiological processes in response to specific external stimuli . G proteins carry lipid modifications on one or more of their subunits to target them to the plasma membrane and to contribute to protein interactions.

This family consists of the G protein alpha subunit group S (stimulatory) which transduces signals from various cell surface receptors to the cAMP-generating enzyme adenylyl cyclase. The G alpha-S subunit is encoded by GNAS, a complex imprinted gene that uses multiple promoters to generate several gene products. G alpha-S is imprinted in a tissue-specific manner, and is expressed primarily from the maternal allele in renal proximal tubules, thyroid, pituitary and ovary . Several disease states are linked to the G alpha-S, including McCune-Albright syndrome, pseudohypoparathyroidism, adenomas, testotoxicosis and the action of cholera toxin. G alpha-olf is a specialised form of G alpha-S expressed in olfactory neuroepithelial cells, brain and pancreas. In addition to its interaction with adenylyl cyclase, G alpha-S also activates ion channels, such as atrial voltage gated sodium channels and dihydropyridine-sensitive calcium channels in skeletal muscle.