Functional architecture of inositol 1,4,5-trisphosphate signaling in restricted spaces of myoendothelial projections.
Calcium (Ca(2+)) release through inositol 1,4,5-trisphosphate receptors (IP(3)Rs) regulates the function of virtually every mammalian cell. Unlike ryanodine receptors, which generate local Ca(2+) events ("sparks") that transmit signals to the juxtaposed cell membrane, a similar functional architecture has not been reported for IP(3)Rs. Here, we have identified spatially fixed, local Ca(2+) release events ("pulsars") in vascular endothelial membrane domains that project through the internal elastic lamina to adjacent smooth muscle membranes. Ca(2+) pulsars are mediated by IP(3)Rs in the endothelial endoplasmic reticulum of these membrane projections. Elevation of IP(3) by the endothelium-dependent vasodilator, acetylcholine, increased the frequency of Ca(2+) pulsars, whereas blunting IP(3) production, blocking IP(3)Rs, or depleting endoplasmic reticulum Ca(2+) inhibited these events. The elementary properties of Ca(2+) pulsars were distinct from ryanodine-receptor-mediated Ca(2+) sparks in smooth muscle and from IP(3)-mediated Ca(2+) puffs in Xenopus oocytes. The intermediate conductance, Ca(2+)-sensitive potassium (K(Ca)3.1) channel also colocalized to the endothelial projections, and blockage of this channel caused an 8-mV depolarization. Inhibition of Ca(2+) pulsars also depolarized to a similar extent, and blocking K(Ca)3.1 channels was without effect in the absence of pulsars. Our results support a mechanism of IP(3) signaling in which Ca(2+) release is spatially restricted to transmit intercellular signals.
Ledoux
Jonathan
J
Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405, USA.
Taylor
Mark S
MS
Bonev
Adrian D
AD
Hannah
Rachael M
RM
Solodushko
Viktoriya
V
Shui
Bo
B
Tallini
Yvonne
Y
Kotlikoff
Michael I
MI
Nelson
Mark T
MT
D000818:Animals; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D022081:Cell Surface Extensions / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000648:ultrastructure*; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000648:ultrastructure; D024681:Potassium Channels, Calcium-Activated / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction
D053496:Inositol 1,4,5-Trisphosphate Receptors; D024681:Potassium Channels, Calcium-Activated; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium