TY - JOUR T1 - Essential Role for Phosphatidylinositol 4,5-Bisphosphate in the Expression, Regulation, and Gating of the Slow Afterhyperpolarization Current in the Cerebral Cortex JF - The Journal of Neuroscience JO - J. Neurosci. SP - 18303 LP - 18312 DO - 10.1523/JNEUROSCI.3203-11.2011 VL - 31 IS - 50 AU - Claudio Villalobos AU - Robert C. Foehring AU - Jonathan C. Lee AU - Rodrigo Andrade Y1 - 2011/12/14 UR - http://www.jneurosci.org/content/31/50/18303.abstract N2 - 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 Gαq-11 and Gαs 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)P2] and that this dependence accounts for its inhibition by 5-HT2A receptors. Furthermore, we show that PtdIns(4,5)P2 regulates the calcium sensitivity of IsAHP 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-HT2A receptors and point to a key role for PtdIns(4,5)P2 in the gating of this current. ER -