title: 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 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.
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Villalobos
authors.forename: Robert C
authors.initials: RC
authors.lastname: Foehring
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Lee
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Andrade
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism
chemical_list: D019269:Phosphatidylinositol 4,5-Diphosphate; D044402:Receptor, Serotonin, 5-HT2A; D011188:Potassium; D002118:Calcium