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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-04, Vol.111 (13), p.5018-5023
• Main Authors: Tselnicker, Isabella Farhy, Tsemakhovich, Vladimir, Rishal, Ida, Kahanovitch, Uri, Dessauer, Carmen W., Dascal, Nathan
• Format: Article
• Language: English
• Subjects: Animals; Binding sites; Biological Sciences; Bipolar disorder; Cells; G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism; Gene expression regulation; Genetics; Glycoproteins; GTP-Binding Proteins - metabolism; Guanosine Diphosphate - metabolism; Heterotrimeric GTP-Binding Proteins - metabolism; Hippocampus - cytology; Ion channels; Lithium; Lithium - pharmacology; Medical genetics; Medical treatment; Mice; Models, Biological; Molecular mechanisms of action; Neurons; Neurons - drug effects; Neurons - metabolism; Neurotransmitters; Oocytes; Patch-Clamp Techniques; Physiological regulation; Potassium; Protein Binding - drug effects; Receptors, G-Protein-Coupled - metabolism; Xenopus laevis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1316425111

Lithium (Li ⁺) is widely used to treat bipolar disorder (BPD). Cellular targets of Li ⁺, such as glycogen synthase kinase 3β (GSK3β) 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 (I bₐₛₐₗ) but attenuated neurotransmitter-evoked GIRK currents (I ₑᵥₒₖₑd) mediated by G ᵢ/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 I bₐₛₐₗ 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 channels by Gβγ, suggesting that inhibition of I ₑᵥₒₖₑd results from an action of Li ⁺ on Gα, probably through inhibition of GTP–GDP exchange. In direct binding studies, Li ⁺ promoted GPCR-independent dissociation of Gα ᵢᴳᴰᴾ from Gβγ 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 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.