Dual regulation of G proteins and the G-protein-activated K+ channels by lithium

Isabella Farhy Tselnicker, Vladimir Tsemakhovich, Ida Rishal, Uri Kahanovitch, Carmen W. Dessauer, Nathan Dascal

Research output: Contribution to journalArticlepeer-review

Abstract

Lithium (Li+) is widely used to treat bipolar disorder (BPD). Cellular targets of Li+, such as glycogen synthase kinase 3ß (GSK3ß) and G proteins, have long been implicated in BPD etiology; however, recent genetic studies link BPD to other proteins, particularly ion channels. Li+ affects neuronal excitability, but the underlying mechanisms and the relevance to putative BPD targets are unknown. We discovered a dual regulation of G protein-gated K+ (GIRK) channels by Li +, and identified the underlying molecular mechanisms. In hippocampal neurons, therapeutic doses of Li+ (1-2 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 Ga and Gß? subunits. Li+ did not impair direct activation of GIRK channels by Gß?, suggesting that inhibition of Ievoked results from an action of Li+ on Ga, probably through inhibition of GTP-GDP exchange. In direct binding studies, Li+ promoted GPCR-independent dissociation of Gai GDP from Gß? by a Mg2+-independent mechanism. This previously unknown Li+ action on G proteins explains the second effect of Li+, the enhancement of GIRK's I basal. The dual effect of Li+ on GIRK may profoundly regulate the inhibitory effects of neurotransmitters acting via GIRK channels. Our findings link between Li+, neuronal excitability, and both cellular and genetic targets of BPD: GPCRs, G proteins, and ion channels.

Original languageEnglish
Pages (from-to)5018-5023
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number13
DOIs
StatePublished - 1 Apr 2014

Keywords

  • Drug
  • Psychiatric disorder

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