Presynaptic Signaling by Heterotrimeric G-Proteins

G-proteins (guanine nucleotide-binding proteins) are membrane-attached proteins composed of three subunits, α, β, and γ. They transduce signals from G-protein coupled receptors (GPCRs) to target effector proteins. The agonistactivated receptor induces a conformational change in the G-protein trimer so that the α-subunit binds GTP in exchange for GDP and α-GTP, and βγ-subunits separate to interact with the target effector. Effector-interaction is terminated by the α-subunit GTPase activity, whereby bound GTP is hydrolyzed to GDP. This is accelerated in situ by RGS proteins, acting as GTPase-activating proteins (GAPs). Gα-GDP and Gβγ then reassociate to form the Gαβγ trimer. G-proteins primarily involved in the modulation of neurotransmitter release are G_o, G_q and G_s. G_o mediates the widespread presynaptic auto-inhibitory effect of many neurotransmitters (e.g., via M2/M4 muscarinic receptors, α₂ adrenoreceptors, μ/δ opioid receptors, GABAB receptors). The G_o βγ-subunit acts in two ways: first, and most ubiquitously, by direct binding to CaV2 Ca²⁺ channels, resulting in a reduced ensitivity to membrane depolarization and reduced Ca²⁺ influx during the terminal action potential; and second, through a direct inhibitory effect on the transmitter release machinery, by binding to proteins of the SNARE complex. G_s and G_q are mainly responsible for receptor-mediated facilitatory effects, through activation of target enzymes (adenylate cyclase, AC and phospholipase-C, PLC respectively) by the GTP-bound α-subunits.