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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Tsemakhovich, Vladimir Dascal, Nathan Kahanovitch, Uri Dessauer, Carmen W. Farhy Tselnicker, Isabella Rishal, Ida |
| Description | Author Affiliation: Farhy Tselnicker I ( Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel and Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030.); |
| Abstract | 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 $Gα_{i}^{GDP}$ 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 13 |
| Volume Number | 111 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2014-04-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | G Protein-Coupled Inwardly-Rectifying Potassium Channels Metabolism GTP-Binding Proteins Lithium Pharmacology Animals Guanosine Diphosphate Heterotrimeric GTP-Binding Proteins Hippocampus Cytology Mice Models, Biological Neurons Drug Effects Patch-Clamp Techniques Protein Binding Receptors, G-Protein-Coupled Xenopus Laevis Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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