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. 2019 Apr 24;11:89. doi: 10.3389/fnagi.2019.00089

FIGURE 2.

FIGURE 2

GPCR and G-proteins activation models. (A) Classical GPCR/G protein activation model. When inactive, heterotrimeric G proteins exist as a complex comprising the α subunit (bound to GDP) and the βγ subunit. (1a) The binding of a ligand (as a neurotransmitter) to a GPCR results in a conformational change that allows (1b) the binding of the receptor to the G protein. (2) This in turn causes a second conformational change on the α-subunit that results in the exchange of its GDP by GTP, and the separation of the α and βγ subunits. (3) At this point the G protein is active, and both the α and βγ subunits interact with downstream effectors to modulate different signaling pathways. (4) The G protein activation is terminated by the hydrolysis of the GTP molecule into GDP, a reaction that can be accelerated by the binding of Regulators of G-protein Signaling (RGS) to the α subunit. (5) The GTP hydrolysis results in the re-formation of the trimeric complex, bringing the G protein back to its inactive state. (B) Pre-coupled model(s). New mechanisms of GPCRs’ activation have emerged from various studies, particularly on Gi/o-coupled GPCRs. In these, inactive GPCRs monomers (left) or homo/hetero dimers (right) exist in an inactive G protein-binding state. In some cases, effector proteins (as adenylyl cyclase, AC) can even be part of the inactive pre-coupled receptorsome complex (not shown). (1) When the GPCR is activated by a ligand (as dopamine, serotonin, etc.) (2) its coupled G protein becomes active by exchanging GDP by GTP and either dissociates from the GPCR and its βγ subunit to initiate the signaling response (left) or remain associated to the complex and activate downstream effector proteins at the membrane (right). (3) In either case, the GTPase activity (accelerated, e.g., by binding to RGS proteins) terminates the activation cycle for that G protein, and the GPCR-inactive G protein complex reassembles/is reinstalled. Note that, in both classical and pre-coupled models, when an active Gα subunit dissociates from the GPCR, another cytosolic inactive heterotrimeric G protein can bind to the activated GPCR to get activated, in an amplification mechanism. GIRK, G-protein activated Inwardly Rectifying K+ channel; PLC, phospholipase C; PDE 6, phosphodiesterase 6.