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 EC50 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 (PIP2) was blocked by lipid kinase inhibitors. Lipid phosphorylation by PI 4-kinase is required for recovery from muscarinic modulation of M current.
| Original language | English |
|---|---|
| Pages (from-to) | 507-520 |
| Number of pages | 14 |
| Journal | Neuron |
| Volume | 35 |
| Issue number | 3 |
| DOIs | |
| State | Published - 1 Aug 2002 |
Bibliographical note
Funding Information:We thank Wiebke Schledermann for tutorials on patch clamping, Wiebke Schledermann and Lisa Horowitz for many discussions of the data and for critical comments, Ken Mackie for much help with molecular biology and for critical comments, Mark Shapiro and Margaret Byers for advice on preparing SCG neurons, and Lea Miller for technical assistance. This work was supported by National Institutes of Health Grants NS08174 and DA00286.