McCarron John G, Chalmers Susan, Muir Thomas C
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, John Arbuthnott Building, 27 Taylor Street, Glasgow G4 0NR, UK.
J Cell Sci. 2008 Jan 1;121(Pt 1):86-98. doi: 10.1242/jcs.017541. Epub 2007 Dec 11.
Smooth muscle responds to activation of the inositol (1,4,5)-trisphosphate receptor [Ins(1,4,5)P(3)R] with a graded concentration-dependent ("quantal") Ca2+ release from the sarcoplasmic reticulum (SR) store. Graded release seems incompatible both with the finite capacity of the store and the Ca2+-induced Ca2+ release (CICR)-like facility, at Ins(1,4,5)P3Rs, that, once activated, should release the entire content of SR Ca2+. The structural organization of the SR and the regulation of Ins(1,4,5)P3R activity by inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] and Ca2+ have each been proposed to explain ;quantal' Ca2+ release. Here, we propose that regulation of Ins(1,4,5)P3R activity by lumenal Ca2+ acting at the cytoplasmic aspect of the receptor might explain ;quantal' Ca2+ release in smooth muscle. The entire SR store was found to be lumenally continuous and Ca2+ could diffuse freely throughout: peculiarities of SR structure are unlikely to account for ;quantal' release. While Ca2+ release was regulated by [Ca2+] within the SR, the velocity of release increased (accelerated) during the release process. The extent of acceleration of release determined the peak cytoplasmic [Ca2+] and was attenuated by a reduction in SR [Ca2+] or an increase in cytoplasmic Ca2+ buffering. Positive feedback by released Ca2+ acting at the cytoplasmic aspect of Ins(1,4,5)P3Rs (i.e. CICR-like) might (a) account for the acceleration, (b) provide the regulation of release by SR [Ca2+] and (c) explain the ;quantal' release process itself. During Ca2+ release, SR [Ca2+] and thus unitary Ins(1,4,5)P3R currents decline, CICR reduces and stops. With increasing [Ins(1,4,5)P3], coincidental activation of several neighbouring Ins(1,4,5)P3Rs offsets the reduced Ins(1,4,5)P3R current to renew CICR and Ca2+ release.
平滑肌对肌醇（1,4,5）-三磷酸受体[Ins(1,4,5)P(3)R]的激活作出反应，通过从肌浆网（SR）储存库中进行分级浓度依赖性（“量子化”）的Ca2+释放。分级释放似乎既与储存库的有限容量不相符，也与Ins(1,4,5)P3Rs处类似Ca2+诱导的Ca2+释放（CICR）的机制不相符，因为一旦被激活，该机制应该释放SR Ca2+的全部内容。SR的结构组织以及肌醇（1,4,5）-三磷酸[Ins(1,4,5)P3]和Ca2+对Ins(1,4,5)P3R活性的调节，都曾被提出用于解释“量子化”的Ca2+释放。在此，我们提出，作用于受体胞质面的腔内Ca2+对Ins(1,4,5)P3R活性的调节，可能解释平滑肌中的“量子化”Ca2+释放。发现整个SR储存库在腔内是连续的，Ca2+可以在其中自由扩散：SR结构的特殊性不太可能解释“量子化”释放。虽然Ca2+释放受SR内[Ca2+]的调节，但释放速度在释放过程中会增加（加速）。释放加速的程度决定了胞质[Ca2+]的峰值，并因SR [Ca2+]的降低或胞质Ca2+缓冲的增加而减弱。释放的Ca2+作用于Ins(1,4,5)P3Rs的胞质面产生的正反馈（即类似CICR）可能（a）解释加速现象，（b）提供由SR [Ca2+]对释放的调节，以及（c）解释“量子化”释放过程本身。在Ca2+释放过程中，SR [Ca2+]以及因此单个Ins(1,4,5)P3R电流会下降，CICR减少并停止。随着[Ins(1,4,5)P3]的增加，几个相邻Ins(1,4,5)P3Rs的同时激活会抵消Ins(1,4,5)P3R电流的减少，从而恢复CICR和Ca2+释放。
