Localization and socialization: experimental insights into the functional architecture of IP₃ receptors

Abstract

Inositol 1,4,5-trisphosphate (IP₃)-evoked Ca²⁺ signals display great spatiotemporal malleability. This malleability depends on diversity in both the cellular organization and in situ functionality of IP₃ receptors (IP₃Rs) that regulate Ca²⁺ release from the endoplasmic reticulum (ER). Recent experimental data imply that these considerations are not independent, such that—as with other ion channels—the local organization of IP₃Rs impacts their functionality, and reciprocally IP₃R activity impacts their organization within native ER membranes. Here, we (i) review experimental data that lead to our understanding of the “functional architecture” of IP₃Rs within the ER, (ii) propose an updated terminology to span the organizational hierarchy of IP₃Rs observed in intact cells, and (iii) speculate on the physiological significance of IP₃R socialization in Ca²⁺ dynamics, and consequently the emerging need for modeling studies to move beyond gridded, planar, and static simulations of IP₃R clustering even over short experimental timescales.