Regulation of smooth muscle calcium sensitivity: KCl as a calcium-sensitizing stimulus

Abstract

KCl has long been used as a convenient stimulus to bypass G protein-coupled receptors (GPCR) and activate smooth muscle by a highly reproducible and relatively “simple” mechanism involving activation of voltage-operated Ca 2+ channels that leads to increases in cytosolic free Ca 2+ ([Ca 2+]i), Ca 2+-calmodulin-dependent myosin light chain (MLC) kinase activation, MLC phosphorylation and contraction. This KCl-induced stimulus-response coupling mechanism is a standard tool-set used in comparative studies to explore more complex mechanisms generated by activation of GPCRs. One area where this approach has been especially productive is in studies designed to understand Ca 2+ sensitization, the relationship between [Ca 2+]i and force produced by GPCR agonists. Studies done in the late 1980s demonstrated that a unique relationship between stimulus-induced [Ca 2+]i and force does not exist: for a given increase in [Ca 2+]i, GPCR activation can produce greater force than KCl, and relaxant agents can produce the opposite effect to cause Ca 2+ desensitization. Such changes in Ca 2+ sensitivity are now known to involve multiple cell signaling strategies, including translocation of proteins from cytosol to plasma membrane, and activation of enzymes, including RhoA kinase and protein kinase C. However, recent studies show that KCl can also cause Ca 2+ sensitization involving translocation and activation of RhoA kinase. Rather than complicating the Ca 2+ sensitivity story, this surprising finding is already providing novel insights into mechanisms regulating Ca 2+ sensitivity of smooth muscle contraction. KCl as a “simple” stimulus promises to remain a standard tool for smooth muscle cell physiologists, whose focus is to understand mechanisms regulating Ca 2+ sensitivity.