Role of Ryanodine Receptor Subtypes in Initiation and Formation of Calcium Sparks in Arterial Smooth Muscle: Comparison with Striated Muscle
Putative role of sorcin, homer1, and calstabins in calcium spark regulation in smooth muscle. Sorcin (soluble resistance-related binding protein) is a negative regulator of calcium sparks in SMCs. It is activated by increases in cytosolic (EC50 = 1.5 M). Stimulatory effects on C1.2 channels and SERCA have also been reported. Calstabin2 (FKBP12.6) associates with RyR2 and stabilizes RyR2 channels in their closed state. FK506, an immunodepressant drug, binds to calstabin2 and can cause dissociation of calstabin2-RyR2 complex and therefore stimulation of calcium sparks in some smooth muscle tissues. Scaffold protein Homer1 (Ves1) has been shown to stimulate both RyR2 (at doses 50 nM) and C1.2 channels in nonarterial smooth muscle. Based on these findings, Homer1 can be expected to be a positive regulator of local calcium release calcium in this type of smooth muscle, which, however, has not been demonstrated so far. With respect to arterial smooth muscle, it is likely that calstabin2 and Homer1 play no role or only a minor role in calcium spark generation. This speculation is based on our findings that cytosolic itself contributes minimally to the acute triggering of physiologically relevant proportion of calcium sparks. Instead the most efficacious calcium spark trigger appears to be the luminal SR , which is slowly loaded via influx through C1.2 channels. Arrows indicate positive (red, +) and negative (blue, −) regulation of corresponding targets.
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