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Amplified NO/cGMP-mediated relaxation and ryanodine receptor-to-BKCa channel signalling in corpus cavernosum smooth muscle from phospholamban knockout mice.

Joshi, Shreena; Nelson, Mark T; Werner, Matthias E

British journal of pharmacology. 2012;165(2):455-66.

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Abstract

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.

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Manchester eScholar ID:
uk-ac-man-scw:201856
Created by:
Nelson, Mark
Created:
19th July, 2013, 13:40:06
Last modified by:
Nelson, Mark
Last modified:
19th July, 2013, 13:40:06

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