| First Author | Farhy Tselnicker I | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 13 | Pages | 5018-23 |
| PubMed ID | 24639496 | Mgi Jnum | J:207373 |
| Mgi Id | MGI:5556304 | Doi | 10.1073/pnas.1316425111 |
| Citation | Farhy Tselnicker I, et al. (2014) Dual regulation of G proteins and the G-protein-activated K+ channels by lithium. Proc Natl Acad Sci U S A 111(13):5018-23 |
| abstractText | Lithium (Li(+)) is widely used to treat bipolar disorder (BPD). Cellular targets of Li(+), such as glycogen synthase kinase 3beta (GSK3beta) 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 Galpha and Gbetagamma subunits. Li(+) did not impair direct activation of GIRK channels by Gbetagamma, suggesting that inhibition of Ievoked results from an action of Li(+) on Galpha, probably through inhibition of GTP-GDP exchange. In direct binding studies, Li(+) promoted GPCR-independent dissociation of Galphai(GDP) from Gbetagamma by a Mg(2+)-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 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. |
