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1 Physiology & Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
* To whom correspondence should be addressed. E-mail: perrinob{at}unr.edu.
The mechanisms by which nitric oxide (NO) relaxes smooth muscles are unclear. The NO donor sodium nitroprusside (SNP) has been reported to increase the Ca2+ release frequency (Ca2+ sparks) through ryanodine receptors (RyRs) and activate spontaneous transient outward currents (STOCs), resulting in smooth muscle relaxation. Our findings that caffeine relaxes and hyperpolarizes murine gastric fundus smooth muscles and increases phospholamban (PLB) phosphorylation by Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) suggest that PLB phosphorylation by CaM kinase II participates in smooth muscle relaxation by increasing sarcoplasmic reticulum (SR) Ca2+ uptake and the frequencies of SR Ca2+ release events and STOCs. Thus, in the present study, we investigated the roles of CaM kinase II and PLB in SNP-induced relaxation of murine gastric fundus smooth muscles. SNP hyperpolarized and relaxed gastric fundus circular smooth muscles and activated CaM kinase II. SNP-induced CaM kinase II activation was prevented by KN-93. Ryanodine, tetracaine, 2-APB, or CPA inhibited SNP-induced fundus smooth muscle relaxation and CaM kinase II activation. The KCa channel blockers iberiotoxin, or apamin inhibited SNP-induced hyperpolarization and relaxation. The soluble guanlylate cyclase inhibitor ODQ inhibited SNP-induced relaxation and CaM kinase II activation. The membrane permeable cGMP analogue 8-Br-cGMP relaxed gastric fundus smooth muscles and activated CaM kinase II. SNP increased PLB Ser16 and Thr17 phosphorylation. PLBThr17 phosphorylation was inhibited by CPA or KN-93. PLB Ser16 and Thr17 phosphoryl-ation were both ODQ-sensitive. These results demonstrate a novel pathway linking NO/sGC/-cGMP, SR Ca2+ release, PLB, and CaM kinase II to relaxation in gastric fundus smooth muscles.
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