33 research outputs found
Molecular structure and function of big calcium-activated potassium channels in skeletal muscle: Pharmacological perspectives
No full textThe large-conductance Ca2+-activated K+(BK) channel is broadly expressed in various mammalian cells and tissues such as neurons, skeletal muscles (sarco-BK), and smooth muscles. These channels are activated by changes in membrane electrical potential and by increases in the concentration of intracellular calcium ion (Ca2+). The BK channel is subjected to many mechanisms that add diversity to the BK channel α-subunit gene. These channels are indeed subject to alternative splicing, auxiliary subunits modulation, posttranslational modifications, and protein-protein interactions. BK channels can be modulated by diverse molecules that may induce either an increase or decrease in channel activity. The linkage of these channels to many intracellular metabolites and pathways, as well as their modulation by extracellular natural agents, have been found to be relevant in many physiological processes. BK channel diversity is obtained by means of alternative splicing and modulatory Î2- and Î3-subunits. The association of the α-subunit with Î2- or with Î3-subunits can change the BK channel phenotype, functional diversity, and pharmacological properties in different tissues. In the case of the skeletal muscle BK channel (sarco-BK channel), we established that the main mechanism regulating BK channel diversity is the alternative splicing of the KCNMA1/slo1 gene encoding for the α-subunit generating different splicing isoform in the muscle phenotypes. This finding helps to design molecules selectively targeting the skeletal muscle subtypes. The use of drugs selectively targeting the skeletal muscle BK channels is a promising strategy in the treatment of familial disorders affecting muscular skeletal apparatus including hyperkalemia and hypokalemia periodic paralysis
Drugs targeting the metabolically regulated ATP-sensitive potassium channels and big calcium-activated potassium channels in skeletal muscles: Pharmacological perspectives and therapeutic use
No full textActivation of the ATP-sensitive and calcium activated K+-channels by small synthetic molecules is a well-established pharmacodynamic concept for the treatment of hypertension and cardiac disorders, baldness and hyperglycemia.The sarcolemma ATP-sensitive K+ (sarco-KATP) and the big calcium-activated K+ (sarco-BK) channel subunits show muscle-phenotype-dependent functional and pharmacological properties that are associated with different molecular composition of the sarco-KATP and sarco-BK channels in the fast-twitch and slow-twitch fibers.The diversity of the sarco-KATP channels are due to a hybrid assembly of the sulphonylureas receptor SUR2A, SUR1 and SUR2B subunits and the inwardly rectifying potassium channel Kir6.2 in the muscle phenotypes.In the case of the sarco-BK channel, we established that the main mechanism regulating BK channel diversity is the alternative splicing of the KCNMA1/slo1 gene encoding for the alpha subunit generating different splicing isoform in the muscle phenotypes.This finding helps to design molecules selectively targeting the skeletal muscle subtypes.The use of drugs selectively targeting the skeletal muscle KATP and BK channels is a promising strategy in the treatment of familial disorders affecting muscular skeletal apparatus including hyperkalemic and hypokalemic periodic paralysis
Evaluation of drug efficacy on muscular dystrophy by in vivo treatments in exercised mdx mouse
No full textEvaluation of drug efficacy on muscular dystrophy by in vivo treatments in exercised mdx mouse
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