Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis

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 intr...

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Vydáno v:	Neuron (Cambridge, Mass.) Ročník 35; číslo 3; s. 507
Hlavní autoři:	Suh, Byung-Chang, Hille, Bertil
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 01.08.2002
Témata:	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 Enzyme Inhibitors - pharmacology Glucose - metabolism Glucose - pharmacology GTP-Binding Proteins - drug effects GTP-Binding Proteins - metabolism KCNQ2 Potassium Channel KCNQ3 Potassium Channel 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 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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0896-6273
DOI:	10.1016/s0896-6273(02)00790-0