Gαs Signaling

G-proteins are heterotrimers, consisting of an α, β, and γ subunit. They are involved in signal transduction for a number of types of ligands such as hormones, neurotransmitters and chemokines. These extracellular signals are received by members of a large superfamily of receptors, the GPCRs, that activate the G-proteins, which then route the signals to several distinct intracellular signaling pathways thus initiating changes in cell behavior. In the inactive heterotrimeric state, GDP is bound to the G-α subunit. Upon activation, GDP is released, GTP binds to G-α, and subsequently G-α-GTP dissociates from the G-βγ heterodimer and from the receptor. Both G-α-GTP and G-βγ are then free to activate downstream effectors. The duration of the signal is determined by the intrinsic GTP hydrolysis rate of the G-α-subunit and the subsequent re-association of G-α-GDP with G-βγ.Four classes of heterotrimeric G-α proteins are found in eukaryotes: G-αi/o, G-αs, G-αq/11, and G-α12/13. As with all G-protein α-subunits, G-αs consists of two domains: a GTPase domain that is involved in the binding and hydrolysis of GTP and a helical domain that buries the GTP within the core of the protein. The G-αs family of G-proteins consists of 3 members: GNAS, GNASXL and GNAL. The most well characterized function of G-αs is in the regulation of adenylate cyclase (AC). Once active, AC produces the second messenger cAMP. The main downstream targets of cAMP are PKA and the GTP-exchange protein, EPACs. cAMP activates Rap1A through a PKA-independent and EPAC-dependent pathway. Rap1A activates the B-Raf/MEK/ERK pathway. A major target of PKA is the calcium channel RyR1. RyR1 function is modulated by proteins that bind to its large cytoplasmic scaffold domain, including PKA. Besides activating AC, G-αs also stimulates the kinase activity of Src and Hck, members of Src-family tyrosine kinases. G-αs binds to the catalytic domain and changes the conformation of Src, leading to increased accessibility of the active site to substrates. Src activated by direct interaction with GPCRs or components of the GPCR signaling machinery including G-αs is associated with the regulation of G-protein function, receptor desensitization, and endocytosis. The activity of the G-αs subunit can be markedly reduced by RGS proteins. RGS proteins are multifunctional, GTPase-accelerating proteins that promote G-αs subunit GTP hydrolysis, thereby directly terminating α subunit signaling and indirectly terminating the G-βγ dimer signaling through α subunit binding.