Simultaneous measurements of cytoplasmic Ca
2+ level ([Ca
2+]
1) and muscle contraction in smooth muscle indicated that [Ca
2+]
1 gradually decreases during sustained contraction. This time-dependent dissociation has been explained by the latch bridge hypothesis, positive cooperativity between phosphorylated and non-phosphorylated crossbridges, involvement of cytoskeleton phosphorylation, or connection between myosin and actin filaments by caldesmon. Furthermore, it has been found that receptor agonists induce greater contraction than high K
+ for a given increase in [Ca
2+]
1. This stimulus-dependent dissociation may be due to the receptor agonists-induced activation of protein kinase C which in turn decreases the inhibitory effect of calponin on the actin-myosin interaction, resulting in an apparent Ca
2+ sensitization. Thus, the contractions induced by receptor agonists are due not only to the increase in [Ca
2+]
1 but also to the increase in Ca
2+ sensitivity of contractile elements. Ca
2+ channel blockers inhibit the increase in [Ca
2+]
1 but not the Ca
2+ sensitization, and this may be the reason why these blockers are relatively weak inhibitors of the contraction induced by receptor agonists. By contrast, cyclic AMP and cyclic GMP decrease the Ca
2+ sensitivity of contractile elements in addition to their effects to decrease [Ca
2+]
1.
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