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

Many neurons of the CNS and peripheral nervous system express a slow afterhyperpolarization that is mediated by a slow calcium-activated potassium current. Previous work has shown that this aftercurrent regulates repetitive firing and is an important target for neuromodulators signaling through receptors coupled to G-proteins of the Gα(q-11) and Gα(s) subtypes. Yet, despite considerable effort, a molecular-level understanding of the potassium current underlying the slow afterhyperpolarization 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 afterhyperpolarizing 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 afterhyperpolarization 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.