Regulation of SERCA Ca2+ pump expression by cytoplasmic [Ca2+] in vascularsmooth muscle cells

Vascular smooth muscle cells (VSMC) express three isoforms of the sarcoplas mic or endoplasmic reticulum Ca2+-ATPase (SERCA) pump; SERCA2b predominates (91%), whereas SERCA2a (6%) and SERCA3 (3%) are present in much smaller am ounts. Treatment with thapsigargin (Tg) or A-23187 increased the level of m RNA encoding SERCA2b four- to fivefold; SERCA3 increased about 10-fold, whe reas SERCA2a was unchanged. Ca2+ chelation prevented the Tg-induced SERCA2b increase, whereas Ca2+ elevation itself increased SERCA2b expression. Thes e responses were discordant with those of 78-kDa glucose-regulated protein/ immunoglobulin-binding protein (grp78/BiP), an endoplasmic reticulum stress -response protein. SERCA2b mRNA elevation was much larger than could be acc ounted for by the observed increase in message stability. The induction of SERCA2b by Tg did not require protein synthesis, nor was it affected by inh ibitors of calcineurin, protein kinase C, Ca2+/calmodulin-dependent protein kinase, or tyrosine protein kinases. Treatment with the nonselective prote in kinase inhibitor H-7 prevented Tg-induced SERCA2b expression from occurr ing, whereas another nonselective inhibitor, staurosporine, was without eff ect. We conclude that changes in cytosolic Ca2+ control the expression of S ERCA2b in VSMC via a mechanism involving a currently uncharacterized, H-7-s ensitive but staurosporinein-sensitive, protein kinase.