PT - JOURNAL ARTICLE AU - Madhuchhanda Mandal AU - Zhen Yan TI - PIP<sub>2</sub> Regulation of NMDA Receptor Channels in Cortical Neurons AID - 10.1124/mol.109.058701 DP - 2009 Sep 21 TA - Molecular Pharmacology PG - mol.109.058701 4099 - http://molpharm.aspetjournals.org/content/early/2009/09/21/mol.109.058701.short 4100 - http://molpharm.aspetjournals.org/content/early/2009/09/21/mol.109.058701.full AB - 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 NMDA receptors 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. Interestingly, the PIP2 regulation of NMDAR channels was impaired in a transgenic mouse model of Alzheimer's disease (AD), probably due to the Aβ 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.The American Society for Pharmacology and Experimental Therapeutics