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Amplified NO/cGMP‐mediated relaxation and ryanodine receptor‐to‐BK Ca channel signalling in corpus cavernosum smooth muscle from phospholamban knockout mice
Author(s) -
Joshi Shreena,
Nelson Mark T,
Werner Matthias E
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01569.x
Subject(s) - ryanodine receptor , endocrinology , medicine , chemistry , endoplasmic reticulum , phospholamban , contraction (grammar) , bk channel , muscle contraction , muscle relaxation , phenylephrine , potassium channel , biology , biochemistry , blood pressure
BACKGROUND AND PURPOSE Relaxation of corpus cavernosum smooth muscle (CCSM) is induced by NO. NO promotes the formation of cGMP, which activates cGMP‐dependent protein kinase I (PKGI). The large conductance calcium‐activated potassium (BK Ca ) channel is regarded as a major target of NO/cGMP signalling; however, the mechanism of BK Ca activation remains unclear. The aim of the present study was to determine whether sarcoplasmic reticulum (SR) Ca 2+ load and Ca 2+ release from the SR via ryanodine receptors (RyRs) is important for BK Ca channel activation in response to NO/cGMP. EXPERIMENTAL APPROACH In vitro myography was performed on CCSM strips from wild‐type and PLB knockout (PLB −/− ) mice to evaluate contraction and relaxation in response to pharmacological agents and electrical field stimulation (EFS). KEY RESULTS In CCSM strips from PLB −/− mice, a model of increased SR Ca 2+ load, contractile force in response to EFS or phenylephrine (PE) was increased by nearly 100%. EFS of strips precontracted with PE induced transient relaxation in CCSM, an effect that was significantly larger in PLB −/− strips. Likewise, the relaxation of PE‐induced contraction in response to SNP and cGMP was greater in PLB −/− , as demonstrated by a shift in the concentration–response curve towards lower concentrations. Blocking RyRs and BK Ca channels diminished the induced relaxations and eliminated the difference between wild‐type and PLB −/− . CONCLUSIONS AND IMPLICATIONS NO/cGMP activates BK Ca channels through RyR‐mediated Ca 2+ release. This signalling pathway is responsible for approximately 40% of the NO/cGMP effects and is amplified by increased SR Ca 2+ concentrations.