Clustering of InsP(3) receptors by InsP(3) retunes their regulation by InsP(3) and Ca2+

Article

关键词: INOSITOL TRISPHOSPHATE RECEPTOR;    CHANNELS RYANODINE RECEPTORS;    CALCIUM-RELEASE CHANNELS;    IP3 RECEPTORS;    SPATIAL-DISTRIBUTION;    XENOPUS OOCYTES;    INACTIVATION;    MEMBRANE;    PATTERNS;    KINETICS;   

DOI  :  10.1038/nature07763

来源: SCIE

【 摘 要 】

The versatility of Ca2+ signals derives from their spatio-temporal organization(1,2). For Ca2+ signals initiated by inositol-1,4,5-trisphosphate (InsP(3)), this requires local interactions between InsP(3) receptors (InsP(3)Rs)(3,4) mediated by their rapid stimulation and slower inhibition(4) by cytosolic Ca2+. This allows hierarchical recruitment of Ca2+ release events as the InsP(3) concentration increases(5). Single InsP(3)Rs respond first, then clustered InsP(3)Rs open together giving a local 'Ca2+ puff', and as puffs become more frequent they ignite regenerative Ca2+ waves(1,5-9). Using nuclear patch-clamp recording(10), here we demonstrate that InsP(3)Rs are initially randomly distributed with an estimated separation of similar to 1 mu m. Low concentrations of InsP(3) cause InsP(3)Rs to aggregate rapidly and reversibly into small clusters of about four closely associated InsP(3)Rs. At resting cytosolic [Ca2+], clustered InsP(3)Rs open independently, but with lower open probability, shorter open time, and less InsP(3) sensitivity than lone InsP(3)Rs. Increasing cytosolic [Ca2+] reverses the inhibition caused by clustering, InsP(3)R gating becomes coupled, and the duration of multiple openings is prolonged. Clustering both exposes InsP(3)Rs to local Ca2+ rises and increases the effects of Ca2+. Dynamic regulation of clustering by InsP(3) retunes InsP(3)R sensitivity to InsP(3) and Ca2+, facilitating hierarchical recruitment of the elementary events that underlie all InsP(3)-evoked Ca2+ signals(3,5).

【 授权许可】

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