REGULATION OF IRK3 INWARD RECTIFIER K-RECEPTOR AND INTRACELLULAR MAGNESIUM( CHANNEL BY M1 ACETYLCHOLINE)

Inward rectifier K+ channels control the cell's membrane potential and neuronal excitability. We report that the IRK3 but not the IRK1 inwar d rectifier K+ channel activity is inhibited by mi muscarinic acetylch oline receptor. This m1 modulation cannot be accounted for by protein kinase C, Ca2+, or channel phosphorylation, but can be mimicked by Mg2 +. Based on quantitative analyses of IRK3 and two different IRK1 mutan t channels bestowed with sensitivity to m1 modulation, we suggest that the resting Mg2+ level causes chronic inhibition of IRK3 channels, an d m1 receptor stimulation may lead to an increase of cytoplasmic Mg2concentration and further channel inhibition, due to the ability of Mg 2+ to lead these channels into a prolonged inactivated state.