Agonist-independent inactivation and agonist-induced desensitization of the G protein-activated K+ channel (GIRK) in Xenopus oocytes

• Published in: Pflügers Archiv 1998-06, Vol.436 (1), p.56-68
• Main Authors: Vorobiov, D, Levin, G, Lotan, I, Dascal, N
• Format: Article
• Language: English
• Subjects: Acetylcholine - pharmacology; Animals; Drug Tolerance; Electric Conductivity; Enzyme Activation - drug effects; Female; GTP-Binding Proteins - physiology; Kinases; Oocytes - physiology; Potassium - administration & dosage; Potassium Channels - drug effects; Potassium Channels - physiology; Protein Kinase C - metabolism; Proteins; Receptor, Muscarinic M2; Receptors, Muscarinic - physiology; Sodium - administration & dosage; Sodium - metabolism; Tetradecanoylphorbol Acetate - pharmacology; Xenopus laevis
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s004240050604

The G-protein-activated K+ channels of the GIRK (Kir 3) family are activated by Gbetagamma subunits of heterotrimeric Gi/Go proteins. Atrial GIRK currents evoked by acetylcholine (ACh)1 via muscarinic m2 receptors (m2R) display prominent desensitization. We studied desensitization of basal and ACh-evoked whole-cell GIRK currents in Xenopus oocytes. In the absence of receptor and/or agonist, the basal GIRK activity showed inactivation which was prominent when the preparation was bathed in a low-Na+, high-K+ extracellular solution (96 mM [K+]out and 2 mM [Na+]out) but did not occur in a normal physiological solution. Ion substitution experiments showed that this basal, agonist-independent inactivation was caused by the decrease in [Na+]out rather than by the increased [K+]out. We hypothesize that it reflects a depletion of intracellular Na+. ACh-evoked GIRK currents desensitized faster than the basal ones. The agonist-induced desensitization was present when the preparation was bathed in all solutions tested, independently of [Na+]out. A protein kinase C (PKC) activator inhibited the GIRK currents both in high and low [Na+]out, apparently mimicking agonist-induced desensitization; however, a potent serine/threonine protein kinase blocker, staurosporine, blocked only a minor part of desensitization. We conclude that basal inactivation and agonist-induced desensitization are separate processes, the former caused by changes in Na+ concentrations, and the latter by unknown factor(s) with only a minor contribution of PKC.