The splicing of the rSlo gene affects molecular composition and drug response of Ca2+activated K+channels in skeletal muscle: implications for therapy

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Abstract

The molecular composition and drug response of calcium-activated-K+ (BK) channels of skeletal muscle are unknown. Patch-clamp experiments in parallel with transcript scanning of the Kcnma1 gene encoding the alpha subunit of the BK channel were performed in slow-twitch soleus (Sol) and fast-twitch flexor-digitorum-brevis (FDB) rat skeletal muscles. Five splicing products of the Kcnma1 gene were isolated in Sol and FDB such as the e17, e22, +29 aa, Slo27 and Slo0 variants. RT-PCR showed that the expression of the e22 and Slo0 were 80-90% higher in FDB with respect to Sol; while the expression of Slo27 was 60% higher in Sol with respect to FDB; the +29aa variant was equally expressed. No beta1-4 subunits were detected. In Sol, a large BK current with low Ca2+-sensitivity was recorded. The BK channel of Sol also showed a reduced response to the BK channel openers such as NS1619, acetazolamide and related drugs. In FDB, a reduced BK current with high Ca2+-sensitivity and enhanced drug response was recorded. The total BK-RNA content, which was 200% more abundant in Sol than in FDB, was correlated to the BK currents in both muscles. The drug responses were mostly correlated to the e22 and Slo0 expression levels in the FDB, while to the Slo27 expression in the Sol muscle. In conclusion, the phenotype-dependent BK channel biophysical and pharmacological properties were correlated to the variants expression levels in the muscles. This can be relevant in conditions affecting postural muscles such as the prolonged bed-rest, and in diseases affecting fast-twitch muscle such as the periodic paralysis. Down-regulation or up-regulation of these variants associated with pathological conditions may affects the channel composition and drug response.

Autore Pugliese

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  • MELE A.;CONTE D.;TRICARICO D.;CAMERINO G.M.

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Anno di pubblicazione

2012

ISSN

1932-6203

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Numero di citazioni Scopus

21

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Settori ERC

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