Functional architecture of inositol 1,4,5-trisphosphate signaling in restricted spaces of myoendothelial projections

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Abstract
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.