{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T20:46:43Z","timestamp":1774644403378,"version":"3.50.1"},"reference-count":46,"publisher":"American Physiological Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[2002,5,1]]},"abstract":"<jats:p>We predict that the type 2 ryanodine receptor isoform (RyR-2) located in the osteoclastic membrane functions as a Ca<jats:sup>2+<\/jats:sup>influx channel and as a divalent cation (Ca<jats:sup>2+<\/jats:sup>) sensor. Cytosolic Ca<jats:sup>2+<\/jats:sup>measurements revealed Ca<jats:sup>2+<\/jats:sup>influx in osteoclasts at depolarized membrane potentials. The cytosolic Ca<jats:sup>2+<\/jats:sup>change was, as expected, not seen in Ca<jats:sup>2+<\/jats:sup>-free medium and was blocked by the RyR modulator ryanodine. In contrast, at basal membrane potentials (\u223c25 mV) ryanodine triggered extracellular Ca<jats:sup>2+<\/jats:sup>influx that was blocked by Ni<jats:sup>2+<\/jats:sup>. In parallel, single-channel recordings obtained from inside-out excised patches revealed a divalent cation-selective \u223c60-pS conductance in symmetric solutions of Ba-aspartate [Ba-Asp; reversal potential ( E<jats:sub>rev<\/jats:sub>) \u223c0 mV]. In the presence of a Ba<jats:sup>2+<\/jats:sup>gradient, i.e., with Ba-Asp in the pipette and Na-Asp in the bath, channel conductance increased to \u223c120 pS and E<jats:sub>rev<\/jats:sub>shifted to 21 mV. The conductance was tentatively classified as a RyR-gated Ca<jats:sup>2+<\/jats:sup>channel as it displayed characteristic metastable states and was sensitive to ruthenium red and a specific anti-RyR antibody, Ab<jats:sup>34<\/jats:sup>. To demonstrate that extracellular Ca<jats:sup>2+<\/jats:sup>sensing occurred at the osteoclastic surface rather than intracellularly, we performed protease protection assays using pronase. Preincubation with pronase resulted in markedly attenuated cytosolic Ca<jats:sup>2+<\/jats:sup>signals triggered by either Ni<jats:sup>2+<\/jats:sup>(5 mM) or Cd<jats:sup>2+<\/jats:sup>(50 \u03bcM). Finally, intracellular application of antiserum Ab<jats:sup>34<\/jats:sup>potently inhibited divalent cation sensing. Together, these results strongly suggest the existence of 1) a membrane-resident Ca<jats:sup>2+<\/jats:sup>influx channel sensitive to RyR modulators; 2) an extracellular, as opposed to intracellular, divalent cation activation site; and 3) a cytosolic CaM-binding regulatory site for RyR. It is likely therefore that the surface RyR-2 not only gates Ca<jats:sup>2+<\/jats:sup>influx but also functions as a sensor for extracellular divalent cations.<\/jats:p>","DOI":"10.1152\/ajprenal.00045.2000","type":"journal-article","created":{"date-parts":[[2015,3,3]],"date-time":"2015-03-03T20:35:05Z","timestamp":1425414905000},"page":"F921-F932","source":"Crossref","is-referenced-by-count":38,"title":["Ca<sup>2+<\/sup>influx through the osteoclastic plasma membrane ryanodine receptor"],"prefix":"10.1152","volume":"282","author":[{"given":"Baljit S.","family":"Moonga","sequence":"first","affiliation":[{"name":"Mount Sinai Bone Program, Departments of Medicine and Geriatrics, Mount Sinai School of Medicine, and the Geriatric Research, Education, and Clinical Center, Bronx Veterans Affairs Medical Center, New York 10029;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sun","family":"Li","sequence":"additional","affiliation":[{"name":"Mount Sinai Bone Program, Departments of Medicine and Geriatrics, Mount Sinai School of Medicine, and the Geriatric Research, Education, and Clinical Center, Bronx Veterans Affairs Medical Center, New York 10029;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jameel","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Mount Sinai Bone Program, Departments of Medicine and Geriatrics, Mount Sinai School of Medicine, and the Geriatric Research, Education, and Clinical Center, Bronx Veterans Affairs Medical Center, New York 10029;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Davidson","sequence":"additional","affiliation":[{"name":"Division of Basic Sciences, New York University Dental School, New York, New York 10010; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vijai S.","family":"Shankar","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cambridge University, Cambridge CB2 3EG, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J. 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