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Journal Article

DRPEER: a motif in the extracellular vestibule conferring high Ca2+ flux rates in NMDA receptor channels.

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Beck,  Christine
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

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Kuner,  Thomas
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;
Department of Cell Physiology, Max Planck Institute for Medical Research, Max Planck Society;

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Wollmuth,  Lonnie P.
Department of Cell Physiology, Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Watanabe, J., Beck, C., Kuner, T., Premkumar, L. S., & Wollmuth, L. P. (2002). DRPEER: a motif in the extracellular vestibule conferring high Ca2+ flux rates in NMDA receptor channels. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience, 22(23), 10209-10216. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12451122.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0029-7D37-5
Abstract
The high flux rate of Ca2+ through NMDA receptor (NMDAR) channels is critical for their biological function and may depend on a Ca2+ binding site in the extracellular vestibule. We screened substitutions of hydrophilic residues exposed in the vestibule and identified a cluster of charged residues and a proline, the DRPEER motif, positioned C terminal to M3, that is unique to the NR1 subunit. Charge neutralization or conversion of residues in DRPEER altered fractional Ca2+ currents in a manner consistent with its forming a binding site for Ca2+. Similarly, in a mutant channel in which all of the negative charges are neutralized (ARPAAR), the block by extracellular Ca2+ of single-channel current amplitudes is attenuated. In these same channels, the block by extracellular Mg2+is unaffected. DRPEER is located extracellularly, and its contribution to Ca2+ influx is distinct from that of the narrow constriction. We conclude that key residues in DRPEER, acting as an external binding site for Ca2+, along with a conserved asparagine in the M3 segment proper, contribute to the high fractional Ca2+ currents in these channels under physiological conditions. Therefore, these domains represent critical molecular determinants of NMDAR function in synaptic physiology.