{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T03:43:34Z","timestamp":1773287014354,"version":"3.50.1"},"reference-count":58,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2004,3,30]],"date-time":"2004-03-30T00:00:00Z","timestamp":1080604800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2004,4]]},"abstract":"<jats:p>Studies have suggested that integration of kinase and phosphatase activities maintains the steady\u2010state L\u2010type Ca<jats:sup>2+<\/jats:sup> current in ventricular myocytes, a balance disrupted in failing hearts. As we have recently reported that the PP1\/PP2A inhibitor calyculin A evokes pronounced increases in L\u2010type <jats:italic>I<\/jats:italic><jats:sub><jats:bold>Ca<\/jats:bold><\/jats:sub>, the goal of this study was to identify the counteracting kinase and phosphatase that determine \u2018basal\u2019<jats:italic>I<\/jats:italic><jats:sub><jats:bold>Ca<\/jats:bold><\/jats:sub> in isolated mouse ventricular myocytes. Whole\u2010cell voltage\u2010clamp studies, with filling solutions containing 10 m<jats:sc>m<\/jats:sc> EGTA, revealed that calyculin A (100 n<jats:sc>m<\/jats:sc>) increased <jats:italic>I<\/jats:italic><jats:sub><jats:bold>Ca<\/jats:bold><\/jats:sub> at test potentials between \u221242 and +49mV (44% at 0mV) from a holding potential of \u221280mV. It also shifted the <jats:italic>V<\/jats:italic><jats:sub>0.5<\/jats:sub> (membrane potential at half\u2010maximal) of both activation (from \u221217 to \u221225mV) and steady\u2010state inactivation (from \u221232 to \u221237mV) in the hyperpolarizing direction. The broad\u2010spectrum protein kinase inhibitor, staurosporine (300 n<jats:sc>m<\/jats:sc>), was without effect on <jats:italic>I<\/jats:italic><jats:sub><jats:bold>Ca<\/jats:bold><\/jats:sub> when added after calyculin A. However, by itself, staurosporine decreased <jats:italic>I<\/jats:italic><jats:sub><jats:bold>Ca<\/jats:bold><\/jats:sub> throughout the voltage range examined (50% at 0mV) and blocked the response to calyculin A, indicating that the phosphatase inhibitor's effects depend upon an opposing kinase activity. The PKA inhibitors Rp\u2010cAMPs (100 \u03bc<jats:sc>m<\/jats:sc> in the pipette) and H89 (1 \u03bc<jats:sc>m<\/jats:sc>) failed to reduce basal <jats:italic>I<\/jats:italic><jats:sub><jats:bold>Ca<\/jats:bold><\/jats:sub> or to block the calyculin A\u2010evoked increase in <jats:italic>I<\/jats:italic><jats:sub><jats:bold>Ca<\/jats:bold><\/jats:sub>. Likewise, calyculin A was still active with 10 m<jats:sc>m<\/jats:sc> intracellular BAPTA or when Ba<jats:sup>2+<\/jats:sup> was used as the charge carrier. These data eliminate roles for protein kinase A (PKA) and calmodulin\u2010dependent protein kinase II (CaMKII) as counteracting kinases. However, the protein kinase C (PKC) inhibitors Ro 31\u20108220 (1 \u03bc<jats:sc>m<\/jats:sc>) and G\u00f6 6976 (200 n<jats:sc>m<\/jats:sc>) decreased steady\u2010state <jats:italic>I<\/jats:italic><jats:sub><jats:bold>Ca<\/jats:bold><\/jats:sub> and blunted the effect of calyculin A. PP2A is not involved in this regulation as intracellular applications of 10\u2013100 n<jats:sc>m<\/jats:sc> okadaic acid or 500 n<jats:sc>m<\/jats:sc> fostriecin failed to increase <jats:italic>I<\/jats:italic><jats:sub><jats:bold>Ca<\/jats:bold><\/jats:sub>. However, PP1 is important, as dialysis with 2 \u03bc<jats:sc>m<\/jats:sc> okadaic acid or 500 n<jats:sc>m<\/jats:sc> inhibitor\u20102 mimicked the increases in <jats:italic>I<\/jats:italic><jats:sub><jats:bold>Ca<\/jats:bold><\/jats:sub> seen with calyculin A. These <jats:italic>in situ<\/jats:italic> studies identify constitutive activity of PP1 and the counteracting activity of certain isoforms of PKC, in pathways distinct from receptor\u2010mediated signalling cascades, as regulatory components that determine the steady\u2010state level of cardiac L\u2010type <jats:italic>I<\/jats:italic><jats:sub><jats:bold>Ca<\/jats:bold><\/jats:sub>.<\/jats:p>","DOI":"10.1113\/jphysiol.2003.059329","type":"journal-article","created":{"date-parts":[[2004,1,27]],"date-time":"2004-01-27T01:24:35Z","timestamp":1075166675000},"page":"79-93","source":"Crossref","is-referenced-by-count":40,"title":["Protein phosphatase 1 and an opposing protein kinase regulate steady\u2010state L\u2010type Ca<sup>2+<\/sup> current in mouse cardiac myocytes"],"prefix":"10.1113","volume":"556","author":[{"given":"William H.","family":"DuBell","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terry 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