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

Inositol 1,4,5-trisphosphate (IP(3))-evoked Ca(2+) signals display great spatiotemporal malleability. This malleability depends on diversity in both the cellular organization and in situ functionality of IP(3) receptors (IP(3)Rs) that regulate Ca(2+) 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 IP(3)Rs impacts their functionality, and reciprocally IP(3)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 IP(3)Rs within the ER, (ii) propose an updated terminology to span the organizational hierarchy of IP(3)Rs observed in intact cells, and (iii) speculate on the physiological significance of IP(3)R socialization in Ca(2+) dynamics, and consequently the emerging need for modeling studies to move beyond gridded, planar, and static simulations of IP(3)R clustering even over short experimental timescales.