Presynaptic signaling by heterotrimeric G-proteins

Abstract

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 Go, Gq and Gs. Go 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 Go 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. Gs and Gq 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. © 2008 Springer-Verlag Berlin Heidelberg.