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The Journal of Neuroscience, May 16, 2007, 27(20):5523-5532; doi:10.1523/JNEUROSCI.4378-06.2007

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Cellular/Molecular
Phosphatidylinositol-4,5-Bisphosphate Regulates NMDA Receptor Activity through -Actinin

Ioannis E. Michailidis,¹ Thomas D. Helton,² Vasileios I. Petrou,¹ Tooraj Mirshahi,¹ Michael D. Ehlers,^2,3 and Diomedes E. Logothetis¹

¹Department of Molecular Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York 10029, and ²Department of Neurobiology and ³Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710

Correspondence should be addressed to Diomedes E. Logothetis, Department of Molecular Physiology and Biophysics, Mount Sinai School of Medicine, New York, NY 10029. Email: diomedes.logothetis{at}mssm.edu

Phosphatidylinositol-4,5-bisphosphate (PIP₂) has been shown to regulate many ion channels, transporters, and other signaling proteins, but it is not known whether it also regulates neurotransmitter-gated channels. The NMDA receptors (NMDARs) are gated by glutamate and serve as a critical control point in synaptic function. Here we demonstrate that PIP₂ supports NMDAR activity. In Xenopus oocytes, overexpression of phospholipase C (PLC) or preincubation with 10 µM wortmannin markedly reduced NMDA currents. Stimulation of the epidermal growth factor receptor (EGFR) promoted the formation of an immunocomplex between PLC and NMDAR subunits. Stimulation of EGFR or the PLCß-coupled M₁ acetylcholine receptor produced a robust transient inhibition of NMDA currents. Wortmannin application blocked the recovery of NMDA currents from the inhibition. Using mutagenesis, we identified the structural elements on NMDAR intracellular tails that transduce the receptor-mediated inhibition, which pinpoint to the binding site for the cytoskeletal protein -actinin. Mutation of the PIP₂-binding residues of -actinin dramatically reduced NMDA currents and occluded the effect of EGF. Interestingly, EGF or wortmannin affected the interaction between NMDAR subunits and -actinin, suggesting that this protein mediates the effect of PIP₂ on NMDARs. In mature hippocampal neurons, expression of the mutant -actinin reduced NMDA currents and accelerated inactivation. We propose a model in which -actinin supports NMDAR activity via tethering their intracellular tails to plasma membrane PIP₂. Thus, our results extend the influence of PIP₂ to the NMDA ionotropic glutamate receptors and introduce a novel mechanism of "indirect" regulation of transmembrane protein activity by PIP₂.

Key words: NMDA; PIP₂; -actinin; PLC; oocytes; neurons

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Received Oct. 6, 2006; revised Feb. 21, 2007; accepted March 27, 2007.

Correspondence should be addressed to Diomedes E. Logothetis, Department of Molecular Physiology and Biophysics, Mount Sinai School of Medicine, New York, NY 10029. Email: diomedes.logothetis{at}mssm.edu

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