{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,4]],"date-time":"2025-05-04T04:40:01Z","timestamp":1746333601829,"version":"3.40.4"},"reference-count":57,"publisher":"Rockefeller University Press","issue":"3","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,9,1]]},"abstract":"<jats:p>Voltage-gated calcium (CaV) channels deliver Ca2+ to trigger cellular functions ranging from cardiac muscle contraction to neurotransmitter release. The mechanism by which these channels select for Ca2+ over other cations is thought to involve multiple Ca2+-binding sites within the pore. Although the Ca2+ affinity and cation preference of these sites have been extensively investigated, the effect of voltage on these sites has not received the same attention. We used a neuronal preparation enriched for N-type calcium (CaV2.2) channels to investigate the effect of voltage on Ca2+ flux. We found that the EC50 for Ca2+ permeation increases from 13 mM at 0 mV to 240 mM at 60 mV, indicating that, during permeation, Ca2+ ions sense the electric field. These data were nicely reproduced using a three-binding-site step model. Using roscovitine to slow CaV2.2 channel deactivation, we extended these measurements to voltages &amp;lt;0 mV. Permeation was minimally affected at these hyperpolarized voltages, as was predicted by the model. As an independent test of voltage effects on permeation, we examined the Ca2+-Ba2+ anomalous mole fraction (MF) effect, which was both concentration and voltage dependent. However, the Ca2+-Ba2+ anomalous MF data could not be reproduced unless we added a fourth site to our model. Thus, Ca2+ permeation through CaV2.2 channels may require at least four Ca2+-binding sites. Finally, our results suggest that the high affinity of Ca2+ for the channel helps to enhance Ca2+ influx at depolarized voltages relative to other ions (e.g., Ba2+ or Na+), whereas the absence of voltage effects at negative potentials prevents Ca2+ from becoming a channel blocker. Both effects are needed to maximize Ca2+ influx over the voltages spanned by action potentials.<\/jats:p>","DOI":"10.1085\/jgp.201411201","type":"journal-article","created":{"date-parts":[[2014,8,12]],"date-time":"2014-08-12T04:37:19Z","timestamp":1407818239000},"page":"207-220","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Voltage control of Ca2+ permeation through N-type calcium (CaV2.2) channels"],"prefix":"10.1085","volume":"144","author":[{"given":"Zafir","family":"Buraei","sequence":"first","affiliation":[{"name":"Department of Biology and Health Sciences, Pace University, New York, NY 10038 1"},{"name":"Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112 2"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haoya","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112 2"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith S.","family":"Elmslie","sequence":"additional","affiliation":[{"name":"Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112 2"},{"name":"The Baker Laboratory of Pharmacology, Department of Pharmacology, Kirksville College of Osteopathic Medicine, A.T. 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