TY - JOUR T1 - Phosphatidylinositol (4,5)-Bisphosphate Regulation of <em>N</em>-Methyl-<span class="sc">d</span>-aspartate Receptor Channels in Cortical Neurons JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1349 LP - 1359 DO - 10.1124/mol.109.058701 VL - 76 IS - 6 AU - Madhuchhanda Mandal AU - Zhen Yan Y1 - 2009/12/01 UR - http://molpharm.aspetjournals.org/content/76/6/1349.abstract N2 - The membrane phospholipid phosphatidylinositol (4,5)-bisphosphate (PIP2) has been implicated in the regulation of several ion channels and transporters. In this study, we examined the impact of PIP2 on N-methyl-d-aspartate receptors (NMDARs) in cortical neurons. Blocking PIP2 synthesis by inhibiting phosphoinositide-4 kinase, or stimulating PIP2 hydrolysis via activation of phospholipase C (PLC), or blocking PIP2 function with an antibody caused a significant reduction of NMDAR-mediated currents. On the other hand, inhibition of PLC or application of PIP2 caused an enhancement of NMDAR currents. These electrophysiological effects were accompanied by changes in NMDAR surface clusters induced by agents that manipulate PIP2 levels. The PIP2 regulation of NMDAR currents was abolished by the dynamin inhibitory peptide, which blocks receptor internalization. Agents perturbing actin stability prevented PIP2 regulation of NMDAR currents, suggesting the actin-dependence of this effect of PIP2. Cofilin, a major actin depolymerizing factor, which has a common binding sequence for actin and PIP2, was required for PIP2 regulation of NMDAR currents. It is noteworthy that the PIP2 regulation of NMDAR channels was impaired in a transgenic mouse model of Alzheimer's disease, probably because of the amyloid-β disruption of PIP2 metabolism. Taken together, our data suggest that continuous synthesis of PIP2 at the membrane might be important for the maintenance of NMDARs at the cell surface. When PIP2 is lost, cofilin is released from the PIP2 complex and is rendered free to depolymerize actin. With the actin cytoskeleton no longer intact, NMDARs are internalized via a dynamin/clathrin-dependent mechanism, leading to reduced NMDAR currents.© 2009 The American Society for Pharmacology and Experimental Therapeutics ER -