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1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
2 Department of Physiology and Biophysics, University of South Florida, Tampa, Florida, USA
3 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
* To whom correspondence should be addressed. E-mail: jsks{at}welchlink.welch.jhu.edu.
Ca2+ sparks originating from ryanodine receptors (RyRs) are known to cause membrane hyperpolarization and vasorelaxation in systemic arterial myocytes. By contrast, we have found that Ca2+ sparks of pulmonary arterial smooth muscle cells (PASMCs) are associated with membrane depolarization, and activated by endothelin-1 (ET-1), a potent vasoconstrictor which mediate/modulate acute and chronic hypoxic pulmonary vasoconstriction. In this study, we characterized the effects of ET-1 on the physical properties of Ca2+ sparks and probed the signal transduction mechanism for spark activation in rat intralobar PASMCs. Application of ET-1 at 0.1 to 10 nM caused concentration-dependent increases in frequency, duration, and amplitude of Ca2+ sparks. The ET-1 induced increase in spark frequency was inhibited by BQ-123, an ETA-receptor antagonist; by U73122, a phospholipase C inhibitor; and by xestospongin-C and 2-aminoethyl diphenylborate (2-APB), antagonists of IP3 receptors. However, it was unrelated to SR Ca2+ content, activation of L-type Ca2+ channels, protein kinase C or cyclic-ADP ribose. Photo-release of caged-IP3 indicated that Ca2+ release from IP3Rs could cross-activate RyRs to generate Ca2+ sparks. Immunocytochemistry showed that the distributions of IP3Rs and RyRs were similar in PASMCs. Moreover, inhibition of Ca2+ sparks with ryanodine caused a significant rightward-shift in the ET-1 concentration-tension relationship in pulmonary arteries. These results suggest that ET-1 activation of Ca2+ sparks is mediated via the ETA-receptor-phospholipase C-IP3 pathway and local Ca2+ cross-signaling between IP3Rs and RyRs; and this novel signaling mechanism contributes significantly to the ET-1 induced vasoconstriction in pulmonary arteries.
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