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C-type natriuretic peptide (CNP) stimulates bone growth by activating natriuretic peptide receptor 2 (NPR2) which is equipped with guanylate cyclase on the cytoplasmic side, but its signaling pathway is unclear in growth plate chondrocytes. We previously reported that transient receptor potential melastatin-like 7 (TRPM7) channels mediate intermissive Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx in growth plate chondrocytes, leading to activation of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \/calmodulin-dependent protein kinase II (CaMKII) for promoting bone growth. In this report, we provide evidence from experiments using mutant mice, indicating a functional link between CNP and TRPM7 channels. Our pharmacological data suggest that CNP-evoked NPR2 activation elevates cellular cGMP content and stimulates big-conductance Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -dependent K\n                    <jats:sup>+<\/jats:sup>\n                    (BK) channels as a substrate for cGMP-dependent protein kinase (PKG). BK channel-induced hyperpolarization likely enhances the driving force of TRPM7-mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry and seems to accordingly activate CaMKII. Indeed, ex vivo organ culture analysis indicates that CNP-facilitated bone growth is abolished by chondrocyte-specific\n                    <jats:italic>Trpm7<\/jats:italic>\n                    gene ablation. The defined CNP signaling pathway, the NPR2-PKG-BK channel\u2013TRPM7 channel\u2013CaMKII axis, likely pinpoints promising target proteins for developing new therapeutic treatments for divergent growth disorders.\n                  <\/jats:p>","DOI":"10.7554\/elife.71931","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T08:15:18Z","timestamp":1646036118000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.71931","source":"Crossref","is-referenced-by-count":26,"title":["C-type natriuretic peptide facilitates autonomic Ca2+ entry in growth plate chondrocytes for stimulating bone growth"],"prefix":"10.7554","volume":"11","author":[{"given":"Yuu","family":"Miyazaki","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02kpeqv85","id-type":"ROR","asserted-by":"publisher"}],"name":"Graduate School of Pharmaceutical Sciences, Kyoto University","place":["Kyoto, 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