Dual Regulation of G Proteins and the G Protein-Activated Potassium Channels (GIRK) by Lithium

Cellular targets of Li+, such as glycogen synthase kinase 3β and G proteins, have been long implicated in bipolar disorder (BPD) etiology. However, recent genetic studies link BPD to other proteins, in particular ion channels. Li+ affects neuronal excitability, but the underlying mechanisms and the relevance to putative BPD targets are unknown. We discovered a novel, dual regulation of G protein-gated K+ channels (GIRK) by Li+, and determined the underlying molecular mechanisms. In hippocampal neurons, therapeutic doses of Li+, 0.5-2 mM, increased GIRK basal current (Ibasal) but attenuated neurotransmitter-evoked GIRK currents (Ievoked) mediated by Gi/o-coupled G protein-coupled receptors (GPCRs). Molecular mechanisms of these regulations were studied with heterologously expressed GIRK1/2. In excised membrane patches, Li+ increased Ibasal but reduced GPCR-induced GIRK currents. Both regulations were membrane-delimited and G protein-dependent, requiring both Gα and Gβγ subunits. Li+ did not impair direct activation of GIRK by Gβγ, suggesting that inhibition of Ievoked results from a Li+ action on Gα, probably through inhibition of GTP-GDP exchange. In direct binding studies, Li+ promoted GPCR-independent dissociation of GαiGDP from Gβγ by a Mg2+-independent mechanism. This previously unknown Li+ action on G proteins explains the second effect of Li+, the enhancement of GIRK's Ibasal. The dual effect of Li+ on GIRK may profoundly regulate inhibitory effects of neurotransmitters acting via GIRKs. Our findings link between Li+, neuronal excitability, and both cellular and genetic targets of BPD: GPCRs, G proteins and ion channels.