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

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 IP ₃ receptors (IP₃ Rs) 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 IP₃ Rs impacts their functionality, and reciprocally IP₃ R activity impacts their organization within native ER membranes. Here, we (i) review experimental data that lead to our understanding of the "functional architecture" of IP₃ Rs within the ER, (ii) propose an updated terminology to span the organizational hierarchy of IP₃ Rs observed in intact cells, and (iii) speculate on the physiological significance of IP₃ R socialization in Ca ²⁺ dynamics, and consequently the emerging need for modeling studies to move beyond gridded, planar, and static simulations of IP₃ R clustering even over short experimental timescales.