"Quantal" Ca2+ release at the cytoplasmic aspect of the Ins(1,4,5)P3R channel in smooth muscle.
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.
McCarron
John G
JG
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, John Arbuthnott Building, 27 Taylor Street, Glasgow G4 0NR, UK. john.mccarron@strath.ac.uk
Chalmers
Susan
S
Muir
Thomas C
TC
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels; D020013:Calcium Signaling; D018929:Cell Culture Techniques; D003106:Colon / Q000166:cytology / Q000502:physiology; D003593:Cytoplasm / Q000502:physiology*; D006168:Guinea Pigs; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology*; D008297:Male; D032342:Muscle Cells / Q000502:physiology; D009130:Muscle, Smooth / Q000502:physiology*; D010782:Photolysis; D012519:Sarcoplasmic Reticulum / Q000502:physiology
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium