Gαi Signaling

The heterotrimeric G-proteins are signaling molecules that transduce signals from 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 G-proteins and subsequently route the signals to several distinct intracellular signaling pathways. Heterotrimeric G-proteins are composed of an α, β, and γ subunit. Classically, G-proteins are divided into four families: G-αi/o, G-αs, G-αq/11, and G-α12/13, based on sequence similarity of their α-subunits. The G-α-subunit contains 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. Upon activation GDP that is bound to the heterotrimeric G-protein is released. The G-α subunit dissociates from the G-βγ heterodimer and binds GTP. Both G-α-GTP and G-βγ are then free to activate downstream effectors.G-αi/o proteins are widely expressed. The G-αi/o family is divided into eight subtypes: GNAI1, GNAI2, GNAI3, GNAO, GNAZ, GNAT3, GNAT1 and GNAT2. In general, G-αi protein subtypes inhibit adenylate cyclase (AC) and decrease intracellular cAMP levels leading to reduced PKA activation. Thus, G-αi negatively regulates PKA signaling. Many important hormones and neurotransmitters, including epinephrine, acetylcholine, dopamine and serotonin, use the G-αi pathway to evoke physiological responses. G-αi also activates Src leading to STAT3-mediated signal transduction. Active Src stimulates the Ras/Raf/MEK/ERK signaling pathway. Other interactions of G-αi involve Rap1GAP. Rap1GAP specifically stimulates the GTP hydrolytic activity of Rap1 and thus is believed to function as a downregulator of Rap1 signaling. Rap1 belongs to the Ras subfamily of small GTP-binding proteins, which is known to control cell growth, differentiation and survival. Recently, the intracellular RGS proteins have been discovered to serve additional, mostly negative, modulatory roles in G-α-mediated signal transduction. RGS proteins are able to inhibit the effects of G-αi on AC activity. The G-proteins regulate important cellular components, such as metabolic enzymes, ion channels, and the transcriptional machinery. G-protein mediated pathways interact with one another to form a network that regulates metabolic enzymes, ion channels, transporters, and other components of the cellular machinery controlling a broad range of cellular processes, including transcription, motility, contractility, and secretion. The resulting alterations in cellular behavior and function are manifested in many critical systemic functions, including embryonic development, learning and memory, and organismal homeostasis.