Maqoud Fatima, Cetrone Michela, Mele Antonietta, Tricarico Domenico
Department of Pharmacy-Drug Science, University of Bari, Bari, Italy.
Faculty of Science, Chouaib Doukkali University, El Jadida, Morocco.
Physiol Genomics. 2017 Jun 1;49(6):306-317. doi: 10.1152/physiolgenomics.00121.2016. Epub 2017 Apr 28.
The large-conductance Ca-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 (Ca). 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 β- and γ-subunits. The association of the α-subunit with β- or with γ-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 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.
大电导钙激活钾（BK）通道广泛表达于各种哺乳动物细胞和组织中，如神经元、骨骼肌（肌膜BK）和平滑肌。这些通道可被膜电位变化和细胞内钙离子（Ca）浓度升高激活。BK通道受到多种机制的影响，这些机制增加了BK通道α亚基基因的多样性。这些通道确实会发生可变剪接、辅助亚基调节、翻译后修饰以及蛋白质-蛋白质相互作用。BK通道可被多种分子调节，这些分子可能会导致通道活性增加或降低。已发现这些通道与许多细胞内代谢物和信号通路相关联，以及它们受细胞外天然因子的调节，在许多生理过程中都具有重要意义。BK通道的多样性是通过可变剪接以及调节性β和γ亚基实现的。α亚基与β或γ亚基的结合可以改变BK通道在不同组织中的表型、功能多样性和药理特性。就骨骼肌BK通道（肌膜BK通道）而言，我们确定调节BK通道多样性的主要机制是编码α亚基的基因的可变剪接，从而在肌肉表型中产生不同的剪接异构体。这一发现有助于设计选择性靶向骨骼肌亚型的分子。使用选择性靶向骨骼肌BK通道的药物是治疗影响肌肉骨骼系统的家族性疾病（包括高钾血症和低钾血症周期性麻痹）的一种有前景的策略。
