Endothelin-1 induces intracellular [Ca2+] increase via Ca 2+ influx through the L-type Ca2+ channel, Ca 2+ -induced Ca2+ release and a pathway involving ET A receptors, PKC, PKA and AT1 receptors in cardiomyocytes.
Using fura-2-acetoxymethyl ester (AM) fluorescence imaging and patch clamp techniques, we found that endothelin-1 (ET-1) significantly elevated the intracellular calcium level ([Ca(2+)](i)) in a dose-dependent manner and activated the L-type Ca(2+) channel in cardiomyocytes isolated from rats. The effect of ET-1 on [Ca(2+)](i) elevation was abolished in the presence of the ET(A) receptor blocker BQ123, but was not affected by the ET(B) receptor blocker BQ788. ET-1-induced an increase in [Ca(2+)](i), which was inhibited 46.7% by pretreatment with a high concentration of ryanodine (10 micromol/L), a blocker of the ryanodine receptor. The ET-1-induced [Ca(2+)](i) increase was also inhibited by the inhibitors of protein kinase A (PKA), protein kinase C (PKC) and angiotensin type 1 receptor (AT1 receptor). We found that ET-1 induced an enhancement of the amplitude of the whole cell L-type Ca(2+) channel current and an increase of open-state probability (NPo) of an L-type single Ca(2+) channel. BQ123 completely blocked the ET-1-induced increase in calcium channel open-state probability. In this study we demonstrated that ET-1 regulates calcium overload through a series of mechanisms that include L-type Ca(2+) channel activation and Ca(2+)-induced Ca(2+) release (CICR). ETA receptors, PKC, PKA and AT1 receptors may also contribute to this pathway.
Zeng
QingHua
Q
Laboratory of Molecular & Cellular Physiology, School of Life Sciences, Northeast Normal University, Changchun 130024, China. ZengQH707@gmail.com
Li
XingTing
X
Zhong
GuoGan
G
Zhang
WenJie
W
Sun
ChengWen
C
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D019332:Endothelin-1 / Q000502:physiology*; D005260:Female; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D044022:Receptor, Endothelin A / Q000378:metabolism*; D011945:Receptors, Angiotensin / Q000378:metabolism*
D020746:Calcium Channels, L-Type; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D011945:Receptors, Angiotensin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D002118:Calcium