Phosphatidylinositol (4,5)-bisphosphate regulation of N-methyl-D-aspartate receptor channels in cortical neurons.
The membrane phospholipid phosphatidylinositol (4,5)-bisphosphate (PIP(2)) has been implicated in the regulation of several ion channels and transporters. In this study, we examined the impact of PIP(2) on N-methyl-D-aspartate receptors (NMDARs) in cortical neurons. Blocking PIP(2) synthesis by inhibiting phosphoinositide-4 kinase, or stimulating PIP(2) hydrolysis via activation of phospholipase C (PLC), or blocking PIP(2) function with an antibody caused a significant reduction of NMDAR-mediated currents. On the other hand, inhibition of PLC or application of PIP(2) caused an enhancement of NMDAR currents. These electrophysiological effects were accompanied by changes in NMDAR surface clusters induced by agents that manipulate PIP(2) levels. The PIP(2) regulation of NMDAR currents was abolished by the dynamin inhibitory peptide, which blocks receptor internalization. Agents perturbing actin stability prevented PIP(2) regulation of NMDAR currents, suggesting the actin-dependence of this effect of PIP(2). Cofilin, a major actin depolymerizing factor, which has a common binding sequence for actin and PIP(2), was required for PIP(2) regulation of NMDAR currents. It is noteworthy that the PIP(2) regulation of NMDAR channels was impaired in a transgenic mouse model of Alzheimer's disease, probably because of the amyloid-beta disruption of PIP(2) metabolism. Taken together, our data suggest that continuous synthesis of PIP(2) at the membrane might be important for the maintenance of NMDARs at the cell surface. When PIP(2) is lost, cofilin is released from the PIP(2) 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.
Mandal
Madhuchhanda
M
Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY, USA.
Yan
Zhen
Z
D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D018721:Muscarinic Agonists / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D000077191:Wortmannin
D016564:Amyloid beta-Protein Precursor; D000730:Androstadienes; D018721:Muscarinic Agonists; D019269:Phosphatidylinositol 4,5-Diphosphate; D047428:Protein Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D002217:Carbachol; D000077191:Wortmannin