Calmodulin mediates norepinephrine-induced receptor-operated calcium entry in preglomerular resistance arteries

Calmodulin mediates norepinephrine-induced receptor-operated calcium entry in preglomerular resistance arteries. Am J Physiol Renal Physiol 289: F127 - F136, 2005. First published February 8, 2005; doi:10.1152/ajprenal. 00397.2004. Although L-type voltage-dependent calcium channels play a major role in mediating vascular smooth muscle cell contraction in the renal vasculature, non-L-type calcium entry mechanisms represent a significant component of vasoactive agonist-induced calcium entry in these cells as well. To investigate the role of these non-voltage-dependent calcium entry pathways in the regulation of renal microvascular reactivity, we have characterized the function of store-and receptor-operated channels (SOCs and ROCs) in renal cortical interlobular arteries (ILAs) of rats. Using fura 2-loaded, microdissected ILAs, we find that the L-type channel antagonist nifedipine blocks less than half the rise in intracellular calcium concentration ([Ca(2+)](i)) elicited by norepinephrine. SOCs were activated in these vessels using the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) inhibitors cyclopiazonic acid and thapsigargin and were dose dependently blocked by the SOC antagonists Gd(3+) and 2-aminoethoxydiphenyl borate (2-APB) and the combined SOC/ROC antagonist SKF-96365. Gd(3+) had no effect on the non-L-type Ca(2+) entry activated by 1 mu M NE. A low concentration of SKF-96365 that did not affect thapsigargin-induced store-operated Ca(2+) entry blocked 60 - 70% of the NE-induced Ca(2+) entry. Two different calmodulin inhibitors (W-7 and trifluoperazine) also blocked the NE-induced Ca(2+) entry. These data suggest that in addition to L-type channels, NE primarily activates ROCs rather than SOCs in ILAs and that this receptor-operated Ca(2+) entry mechanism is regulated by calmodulin. Interestingly, 2-APB completely blocked the NE-induced non-L-type Ca(2+) entry, implying that SOCs and ROCs in preglomerular resistance vessels share a common molecular structure.