Calcium: InsP₃ hosts a receptor get-together

Lipidomics Gateway (1 May 2009) [doi:10.1038/lipidmaps.2009.4]

Downstream responses to inositol lipid signaling are tuned by receptor clustering

* This is a revised version of an original article: Calcium: InsP₃ hosts a receptor get-together, from Nature Reviews Molecular Cell Biology 10, 238-239, (April 2009) [doi:10.1038/nrm2660]

PHOTODISC

Intracellular Ca²⁺ concentration is regulated in part by the activity of inositol-1,4,5-trisphosphate (InsP₃) receptors (InsP₃Rs). The second messenger InsP₃ is generated by phospholipase C-mediated cleavage of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), as part of the inositol lipid signaling pathway. InsP₃R tetramers function as Ca2⁺ channels that release Ca2⁺ from the endoplasmic reticulum in response to InsP₃ and Ca2⁺. Low concentrations of ₃ can stimulate a 'blip' of Ca2⁺ release from a single InsP₃R channel; the Ca2⁺ released then stimulates additional InsP₃Rs, generating a 'puff' of Ca2⁺. This puff of Ca2⁺ feeds forward to stimulate subsequent waves of Ca2⁺ release as InsP₃ and Ca2⁺ concentrations increase. However, the biochemical mechanism that underlies receptor clustering and the escalating response to ₃ and Ca2⁺ is not fully understood. Colin Taylor and colleagues now report in Nature that InsP₃ promotes receptor clustering, which tunes receptor sensitivity to InsP₃ and Ca2⁺ to regulate channel activity.

InsP₃R activity was studied in patches of outer nuclear envelope membranes. At resting Ca2⁺ concentrations, InsP₃ treatment caused InsP₃Rs to assemble reversibly into clusters of about four InsP₃Rs. However, these clusters exhibited decreased channel activity and were open for half as long as single InsP₃Rs. The reduced activity of clustered InsP₃Rs was not due to Ca2⁺ passing through active neighbors, suggesting that InsP₃ brings InsP₃Rs into physical contact, which attenuates their responses to InsP₃. Clustering decreased the distance between InsP₃Rs from an average of 1 μm to 20 nm — whereas single InsP₃Rs are insulated from neighboring channel activity, clustered InsP₃Rs are immediately exposed to the Ca2⁺ that is released by their neighbors. It remains to be determined whether the biochemical properties of InsP₃ binding are different for single channels compared with clusters of channels.

What, then, is the purpose of receptor clustering? Clustering ensures that Ca2⁺ released by one InsP₃R can regulate its neighbors. In addition, in a cluster, Ca2⁺ both reversed the diminished InsP₃ sensitivity and promoted coupled gating. If one channel opened, the other channel also opened, and these simultaneously open states were prolonged. Thus, clustering ensures that InsP₃Rs are more likely to be exposed to Ca2⁺ and exaggerates their responses to Ca2⁺.

These data provide insight into how InsP₃R activity is coordinated by InsP₃ and Ca2⁺. At resting Ca2⁺ concentrations, InsP₃ drives InsP₃R clustering, which restrains the release of Ca2⁺ but primes InsP₃R for Ca2⁺-mediated activity. Blips of Ca2⁺ release are then amplified into subsequent puffs and waves owing to the unique biochemical properties that clustering imparts on InsP₃Rs. It will be interesting to resolve the precise structural events that decrease the response to InsP₃ but increase Ca2⁺ sensitivity when InsP₃Rs are assembled in clusters.

Emily J. Chenette