Essential role for phosphatidylinositol 4,5-bisphosphate in the expression, regulation, and gating of the slow afterhyperpolarization current in the cerebral cortex

Abstract

Many neurons of the CNS and peripheral nervous system express a slow after hyperpolarization that is mediated by a slow calcium activated potassium current. Previous work has shown that this after current regulates repetitive firing and is an important target for neuro modulators signaling through receptors coupled to G-proteins of the Gα q-11 and Gαs suptypes. Yet, despite considerable effort, a molecular-level understanding of the potassium current underlying the slow after hyperpolarization and its modulation has proven elusive. Here, we use a combination of pharmacological and molecular biological approaches in cortical brain slices to show that the functional expression of the slow calcium-activated after hyperpolarizing current in pyramidal cells is critically dependent on membrane phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P 2] and that this dependence accounts for its inhibition by 5-HT 2A receptors. Furthermore, we show that PtdIns(4,5)P 2 regulates the calcium sensitivity of I sAHP in a manner that suggests it acts downstream from the rise in intracellular calcium. These results clarify key functional aspects of the slow after hyperpolarization current and its modulation by 5-HT 2A receptors and point to a key role for PtdIns(4,5)P 2 in the gating of this current. © 2011 the authors.