Evidence that Ca/calmodulin-dependent protein kinase mediates the modulation of the Ca²⁺-dependent K⁺ current, I _AHP, by acetylcholine, but not by glutamate, in hippocampal neurons

Abstract

Muscarinic and metabotropic glutamate receptor agonists increase the excitability of hippocampal and other cortical neurons by suppressing the Ca²⁺-activated K⁺current, I _AHP, which underlies the slow afterhyperpolarization (AHP) and spike frequency adaptation. We have examined the mechanism of action of a muscarinic agonist (carbachol) and a metabotropic glutamate receptor agonist (1-Aminocyclopentane-trans-1,3-dicarboxylic acid; t-ACPD) on I _AHP in hippocampal CA1 neurons in slices, by using highly specific protein kinase inhibitors. We found that inhibition of protein kinase A (PKA) with the adenosine 3′,5′-cyclic monophosphate (cAMP) analogue Rp-adenosine-3′,5′-cyclic phosphorothioate Rp-cAMPS, did not prevent the muscarinic and glutamatergic suppression of I _AHP. In contrast, two specific peptide inhibitors of Ca²⁺/calmodulin-dependent protein kinase II (CaM-K II), each partially blocked the effect of carbachol, but not the effect of t-ACPD on I _AHP. We conclude that CaM-K II, but not PKA, is involved in mediating the muscarinic suppression of I _AHP, although other pathways may also contribute. In contrast, neither CaM-K II nor PKA seems to mediate the metabotropic glutamate receptor action on I _AHP.