{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:30:26Z","timestamp":1791275426584,"version":"4.1.0"},"reference-count":63,"publisher":"National Academy of Sciences","issue":"6","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2003,3,18]]},"abstract":"<jats:p>\n                    Voltage-gated Na\n                    <jats:sup>+<\/jats:sup>\n                    channels are composed of pore-forming \u03b1 and auxiliary \u03b2 subunits. The majority of Na\n                    <jats:sup>+<\/jats:sup>\n                    channels in the heart contain tetrodotoxin (TTX)-insensitive Na\n                    <jats:sub>v<\/jats:sub>\n                    1.5 \u03b1 subunits, but TTX-sensitive brain-type Na\n                    <jats:sup>+<\/jats:sup>\n                    channel \u03b1 subunits are present and functionally important in the transverse tubules of ventricular myocytes. Sinoatrial (SA) nodal cells were identified in cardiac tissue sections by staining for connexin 43 (which is expressed in atrial tissue but not in SA node), and Na\n                    <jats:sup>+<\/jats:sup>\n                    channel localization was analyzed by immunocytochemical staining with subtype-specific antibodies and confocal microscopy. Brain-type TTX-sensitive Na\n                    <jats:sub>v<\/jats:sub>\n                    1.1 and Na\n                    <jats:sub>v<\/jats:sub>\n                    1.3 \u03b1 subunits and all four \u03b2 subunits were present in mouse SA node, but Na\n                    <jats:sub>v<\/jats:sub>\n                    1.5 \u03b1 subunits were not. Na\n                    <jats:sub>v<\/jats:sub>\n                    1.1 \u03b1 subunits were also present in rat SA node. Isolated mouse hearts were retrogradely perfused in a Langendorff preparation, and electrocardiograms were recorded. Spontaneous heart rate and cycle length were constant, and heart rate variability was small under control conditions. In contrast, in the presence of 100 nM TTX to block TTX-sensitive Na\n                    <jats:sup>+<\/jats:sup>\n                    channels specifically, we observed a significant reduction in spontaneous heart rate and markedly greater heart rate variability, similar to sick-sinus syndrome in man. We hypothesize that brain-type Na\n                    <jats:sup>+<\/jats:sup>\n                    channels are required because their more positive voltage dependence of inactivation allows them to function at the depolarized membrane potential of SA nodal cells. Our results demonstrate an important contribution of TTX-sensitive brain-type Na\n                    <jats:sup>+<\/jats:sup>\n                    channels to SA nodal automaticity in mouse heart and suggest that they may also contribute to SA nodal function and dysfunction in human heart.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2627986100","type":"journal-article","created":{"date-parts":[[2003,3,18]],"date-time":"2003-03-18T18:15:05Z","timestamp":1048011305000},"page":"3507-3512","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":170,"title":["An unexpected requirement for brain-type sodium channels for control of heart rate in the mouse sinoatrial node"],"prefix":"10.1073","volume":"100","author":[{"given":"Sebastian K. 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