Abstract
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 approximately 0.5 mM. Substitution of nonhydrolyzable ATP analogs for ATP slowed or prevented recovery. ADPbetaS 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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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1-Phosphatidylinositol 4-Kinase / antagonists & inhibitors
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1-Phosphatidylinositol 4-Kinase / metabolism
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Adenosine Diphosphate / metabolism
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Adenosine Diphosphate / pharmacology
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Adenosine Triphosphate / analogs & derivatives
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Adenosine Triphosphate / metabolism
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Adenosine Triphosphate / pharmacology
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Animals
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Cells, Cultured
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Enzyme Inhibitors / pharmacology
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GTP-Binding Proteins / drug effects
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GTP-Binding Proteins / metabolism
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Glucose / metabolism
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Glucose / pharmacology
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KCNQ2 Potassium Channel
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KCNQ3 Potassium Channel
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Male
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Muscarinic Agonists / pharmacology
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Neural Inhibition / drug effects
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Neural Inhibition / physiology*
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism*
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Phosphatidylinositol 4,5-Diphosphate / biosynthesis*
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Phosphorylation
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Potassium Channels / drug effects
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Potassium Channels / genetics
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Potassium Channels / metabolism*
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Potassium Channels, Voltage-Gated
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Rats
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Rats, Sprague-Dawley
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Receptors, Muscarinic / drug effects
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Receptors, Muscarinic / metabolism*
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Superior Cervical Ganglion / cytology
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Superior Cervical Ganglion / drug effects
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Superior Cervical Ganglion / metabolism*
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology
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Type C Phospholipases / antagonists & inhibitors
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Type C Phospholipases / metabolism
Substances
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Enzyme Inhibitors
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KCNQ2 Potassium Channel
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KCNQ3 Potassium Channel
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Kcnq2 protein, rat
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Kcnq3 protein, rat
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Muscarinic Agonists
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Phosphatidylinositol 4,5-Diphosphate
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Potassium Channels
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Potassium Channels, Voltage-Gated
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Receptors, Muscarinic
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Adenosine Diphosphate
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Adenosine Triphosphate
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1-Phosphatidylinositol 4-Kinase
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Type C Phospholipases
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GTP-Binding Proteins
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Glucose