Recovery from Muscarinic Modulation of M Current Channels Requires Phosphatidylinositol 4,5-Bisphosphate Synthesis

• Published in: Neuron (Cambridge, Mass.) Vol. 35; no. 3; pp. 507 - 520
• Main Authors: Suh, Byung-Chang, Hille, Bertil
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2002; Elsevier Limited
• Subjects: 1-Phosphatidylinositol 4-Kinase - antagonists & inhibitors; 1-Phosphatidylinositol 4-Kinase - metabolism; Adenosine Diphosphate - metabolism; Adenosine Diphosphate - pharmacology; Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - metabolism; Adenosine Triphosphate - pharmacology; Animals; Cells, Cultured; Data processing; Enzyme Inhibitors - pharmacology; Glucose - metabolism; Glucose - pharmacology; GTP-Binding Proteins - drug effects; GTP-Binding Proteins - metabolism; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Kinases; Lipids; Male; Membrane Potentials - drug effects; Membrane Potentials - physiology; Muscarinic Agonists - pharmacology; Neural Inhibition - drug effects; Neural Inhibition - physiology; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Phosphatidylinositol 4,5-Diphosphate - biosynthesis; Phosphorylation; Potassium Channels - drug effects; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels, Voltage-Gated; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic - drug effects; Receptors, Muscarinic - metabolism; Superior Cervical Ganglion - cytology; Superior Cervical Ganglion - drug effects; Superior Cervical Ganglion - metabolism; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Type C Phospholipases - antagonists & inhibitors; Type C Phospholipases - metabolism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/S0896-6273(02)00790-0

Suppression of M current channels by muscarinic receptors enhances neuronal excitability. Little is known about the molecular mechanism of this inhibition except the requirement for a specific G protein and the involvement of an unidentified diffusible second messenger. We demonstrate here that intracellular ATP is required for recovery of KCNQ2/KCNQ3 current from muscarinic suppression, with an EC 50 of ∼0.5 mM. Substitution of nonhydrolyzable ATP analogs for ATP slowed or prevented recovery. ADPβS but not ADP also prevented the recovery. Receptor-mediated inhibition was irreversible when recycling of agonist-sensitive pools of phosphatidylinositol-4,5-bisphosphate (PIP 2) was blocked by lipid kinase inhibitors. Lipid phosphorylation by PI 4-kinase is required for recovery from muscarinic modulation of M current.