S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Physiology (생리학교실) Journal Papers (저널논문_생리학교실)
Constitutive CaMKII activity regulates Na(+) channel in rat ventricular myocytes
- Yoon, Jin-Young; Ho, Won-Kyung; Kim, Seong-Tae; Cho, Hana
- Issue Date
- ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
- JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY; Vol.47 4; 475-484
- Voltage-gated Na(+) channel; Ca(2+)/CaM-dependent protein kinase; Patch clamp; Ventricular myocytes; KN-93
- The cardiac voltage-gated Na(+) channel controls the upstroke of action potential and membrane excitability. The Na(+) channel associates with Ca(2+)/CaM-dependent protein kinase (CaMKII), but the role of CaMKII on Na(+) channel activity in the resting state is not clear. In this report, we investigated whether CaMKII constitutively regulates Na(+) currents (I(Na)), independent of Ca(2+) influx in rat ventricular myocytes using patch clamp technique. CaMKII inhibition (by KN93 or autocamtide-related inhibitory peptide) caused a negative shift in I(Na) steady-state inactivation and delayed recovery from slow inactivation, limiting channel availability. The reduction of I(Na) was 29.47 +/- 3.01% at a holding potential (V(h)) of -120 mV and it increased to 77.70 +/- 7.92% when V(h) was -70 mV, suggesting that near the resting membrane potential, three-quarters of I(Na) depends on CaMKII action. CaMKII inhibition also enhanced intermediate inactivation, as well as delayed recovery from fast inactivation, and decreased late I(Na). KN92, an inactive analog of KN93, had no effect on I(Na). Using an antibody against phosphorylated (activated) CaMKII, we found that constitutively active CaMKII coimmuno-precipitated with Na(+) channels under resting conditions. CaMKII inhibitors reduced the level of phosphorylated CaMKII, which correlated with the degree of reduction in channel availability. These data suggest that CaMKII in an active form contributes to regulating I(Na). Finally, we observed a drastic reduction in the upstroke velocity of action potentials upon CaMKII inhibition. In conclusion, CaMKII constitutively regulates cardiac Na(+) channel and this regulatory mechanism is important for the maintenance of Na(+) channel characteristics under physiological conditions. (C) 2009 Elsevier Inc. All rights reserved.
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