Addictive drugs modulate GIRK-channel signaling by regulating RGS proteins

Abstract

Regulator of G-protein signaling (RGS) proteins are strong modulators of G-protein-mediated pathways in the nervous system. One function of RGS proteins is to accelerate the activation-deactivation kinetics of G-protein-coupled inwardly rectifying potassium (GIRK) channels. The opening of GIRK channels reduces the firing rates of neurons. Recent studies indicate that RGS proteins also modulate the coupling efficiency between gamma-aminobutyric acid type B (GABA(B)) receptors and GIRK channels in dopamine neurons of the ventral tegmental area (VTA), the initial target for addictive drugs in the brain reward pathway. Chronic drug exposure can dynamically regulate the expression levels of RGS. Functional and behavioral studies now reveal that levels of RGS2 protein, through selective association with GIRK3, critically determine whether GABA(B) agonists are excitatory or inhibitory in the VTA. The regulation of RGS protein in the reward pathway might underlie adaptation to different types of addictive drugs.

Figure 1. Macromolecular signaling complex

A preassembled complex exists between the dimeric GABA_B R1 and R2 subunits, the heterotrimeric G-proteins, GIRK2/3 channels and RGS2. Note that RGS2 interacts selectively with GIRK3 subunits, and heterotrimeric G-proteins associate directly with GIRK and GABA_B receptors, thus enabling RGS to modulate the coupling efficiency (i.e. EC₅₀) between GABA_B receptors and GIRK channels.

Figure 2. Chronic GHB-dependent decrease in RGS2 protein in VTA-DA neurons changes the neuronal excitability and behavioural response to GHB

Acute administration of GHB stimulates GABA_B receptors (upper panel) coupled to GIRK channels in GABA neurons green). DA neurons (red) are unresponsive to GHB because high levels of RGS2 reduce the coupling efficiency (high EC₅₀) between GABA_B receptors and GIRK channels. Opening of GIRK channels in GABA neurons disinhibits DA neurons and promotes DA release in the NAc. Chronic exposure to GHB (lower panel) reduces RGS2 expression in DA neurons, strengthening the GABA_B receptor-GIRK coupling efficiency. In this situation, acute administration of GHB also stimulates GABA_B receptors coupled to GIRK channels in DA neurons, thereby directly inhibiting DA activity and reducing DA release in the NAc. The unique expression of GIRK2 and GIRK3 channels in DA neurons, the lower Gβγ affinity of GIRK2/3 heteromeric channels, and the selective association of RGS2 with GIRK3 enable the up- or down-regulation of DA activity.