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The Journal of Neuroscience, March 31, 2004, 24(13):3413-3420; doi:10.1523/JNEUROSCI.5429-03.2004
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Cellular/Molecular
Contribution of Calcium Ions to P2X Channel Responses
Terrance M. Egan1,2 andBaljit S. Khakh1 1Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom, and 2Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, St. Louis, Missouri 63104
Ca2+ entry through transmitter-gated cation channels, including ATP-gated P2X channels, contributes to an array of physiological processes in excitable and non-excitable cells, but the absolute amount of Ca2+ flowing through P2X channels is unknown. Here we address the issue of precisely how much Ca2+ flows through P2X channels and report the finding that the ATP-gated P2X channel family has remarkably high Ca2+ flux compared with other channels gated by the transmitters ACh, serotonin, protons, and glutamate. Several homomeric and heteromeric P2X channels display fractional Ca2+ currents equivalent to NMDA channels, which hitherto have been thought of as the largest source of transmitter-activated Ca2+ flux. We further suggest that NMDA and P2X channels may use different mechanisms to promote Ca2+ flux across membranes. We find that mutating three critical polar amino acids decreases the Ca2+ flux of P2X2 receptors, suggesting that these residues cluster to form a novel type of Ca2+ selectivity region within the pore. Overall, our data identify P2X channels as a large source of transmitter-activated Ca2+ influx at resting membrane potentials and support the hypothesis that polar amino acids contribute to Ca2+ selection in an ATP-gated ion channel.
Key words: ATP; P2X; synapse; calcium; permeability; channel
Received Dec 9, 2003; revised February 17, 2004; accepted February 17, 2004.
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