The MLCK‐mediated α1‐adrenergic inotropic effect in atrial myocardium is negatively modulated by PKCɛ signaling
Open Access
- 1 August 2006
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 148 (7), 991-1000
- https://doi.org/10.1038/sj.bjp.0706803
Abstract
1 The present study examined the role of myosin light chain kinase (MLCK), PKC isozymes, and inositol 1,4,5-trisphosphate (IP3) receptor in the positive inotropic effect of α1-adrenergic stimulation in atrial myocardium. 2 We measured inotropic effects of phenylephrine (0.3–300 μM) in isolated left atrial preparations (1 Hz, 37°C, 1.8 mM Ca2+, 0.3 μM nadolol) from male 8-week FVB mice (n=200). Phenylephrine concentration-dependently increased force of contraction from 1.5±0.1 to 2.8±0.1 mN (mean±s.e.m., n=42), which was associated with increased MLC-2a phosphorylation at serine 21 and 22 by 67% and translocation of PKCɛ but not PKCα to membrane (+30%) and myofilament (+50%) fractions. 3 MLCK inhibition using ML-7 or wortmannin right-shifted the concentration–response curve of phenylephrine, reducing its inotropic effect at 10 μM by 73% and 81%, respectively. 4 The compound KIE1-1 (500 nM), an intracellularly acting PKCɛ translocation inhibitor peptide, prevented PKCɛ translocation and augmented the maximal inotropic effect of phenylephrine by 40%. In contrast, inhibition of Ca2+-dependent PKC translocation (KIC1-1, 500 nM) had no effect. Chelerythrine, a PKC inhibitor, decreased basal force without changing the inotropic effect of phenylephrine. 5 The IP3 receptor blocker 2-APB (2 and 20 μM) concentration-dependently decreased basal force, but did not affect the concentration–response curve of phenylephrine. 6 These results indicate that activation of MLCK is required for the positive inotropic effect of α1-adrenergic stimulation, that the Ca2+-independent PKCɛ negatively modulates this effect, and that PKCα and IP3 receptor activation is not involved. British Journal of Pharmacology (2006) 148, 991–1000. doi:10.1038/sj.bjp.0706803This publication has 79 references indexed in Scilit:
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