Clustering of IP3 receptors by IP3 retunes their regulation by IP3 and Ca2+

By Taufiq-Ur-Rahman, A. Skupin, Martin Falcke, C. Taylor. Nature, 2009

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The versatility of Ca2+ signals derives from their spatio-temporal organization1,2. For Ca2+ signals initiated by inositol trisphosphate (IP3) this requires local interactions between IP3 receptors (IP3R)3,4 mediated by their rapid stimulation and slower inhibition4 by cytosolic Ca2+. This allows hierarchical recruitment of Ca2+ release events as the IP3 concentration increases5. Single IP3R respond first, then clustered IP3R open together giving a local Ca2+ puff, and as puffs become more frequent they ignite regenerative Ca2+ waves1,5-9. We demonstrate, using nuclear patch-clamp recording10, that IP3R are initially randomly distributed with an estimated separation of ~1 μm. Low concentrations of IP3 cause IP3R to aggregate rapidly and reversibly into small clusters of ~4 closely associated IP3R. At resting cytosolic [Ca2+], clustered IP3R open independently, but with lower open probability (Po), shorter open time, and lesser IP3 sensitivity than lone IP3R. Increasing cytosolic [Ca2+] reverses the inhibition caused by clustering, IP3R gating becomes coupled, and the duration of multiple openings is prolonged. Clustering both exposes IP3R to local Ca2+ rises and increases the effects of Ca2+. Dynamic regulation of clustering by IP3 tunes IP3R sensitivity to IP3 and Ca2+, facilitating hierarchical recruitment of the elementary events that underlie all IP3-evoked Ca2+ signals3,5.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d5728be6c53a88cc9807f7e0aadc04b06dcb091b