Clustering of InsP3 receptors by InsP3 retunes their regulation by InsP3 and Ca2+

Item Type:	Article
Title:	Clustering of InsP3 receptors by InsP3 retunes their regulation by InsP3 and Ca2+
Creators Name:	Taufiq-Ur-Rahman, and Skupin, A. and Falcke, M. and Taylor, C.W.
Abstract:	The versatility of Ca2+ signals derives from their spatio-temporal organization. For Ca2+ signals initiated by inositol-1,4,5-trisphosphate (InsP3), this requires local interactions between InsP3 receptors (InsP3Rs) mediated by their rapid stimulation and slower inhibition\ by cytosolic Ca2+. This allows hierarchical recruitment of Ca2+ release events as the InsP3 concentration increases. Single InsP3Rs respond first, then clustered InsP3Rs open together giving a local 'Ca2+ puff', and as puffs become more frequent they ignite regenerative Ca2+ waves. Using nuclear patch-clamp recording, here we demonstrate that InsP3Rs are initially randomly distributed with an estimated separation of 1 m. Low concentrations of InsP3 cause InsP3Rs to aggregate rapidly and reversibly into small clusters of about four closely associated InsP3Rs. At resting cytosolic [Ca2+], clustered InsP3Rs open independently, but with lower open probability, shorter open time, and less InsP3 sensitivity than lone InsP3Rs. Increasing cytosolic [Ca2+] reverses the inhibition caused by clustering, InsP3R gating becomes coupled, and the duration of multiple openings is prolonged. Clustering both exposes InsP3Rs to local Ca2+ rises and increases the effects of Ca2+. Dynamic regulation of clustering by InsP3 retunes InsP3R sensitivity to InsP3 and Ca2+, facilitating hierarchical recruitment of the elementary events that underlie all InsP3-evoked Ca2+ signals.
Keywords:	Calcium, Calcium Signaling, Cell Line, Cytosol, Inositol 1,4,5-Trisphosphate, Inositol 1,4,5-Trisphosphate Receptors, Ion Channel Gating, Patch-Clamp Techniques, Protein Transport, Animals, Rats
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	458
Number:	7238
Page Range:	655-659
Date:	2 April 2009
Additional Information:	Authors' reply in Nature 478(7368), E2-E3.
Official Publication:	https://doi.org/10.1038/nature07763
PubMed:	View item in PubMed

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