Inositol (1,4,5)-Trisphosphate Receptor Microarchitecture Shapes Ca2+ Puff Kinetics

Abstract

Inositol (1,4,5)-trisphosphate receptors (IP3Rs) release intracellular Ca2+ as localized Ca2+ signals (Ca2+ puffs) that represent the activity of small numbers of clustered IP3Rs spaced throughout the endoplasmic reticulum. Although much emphasis has been placed on estimating the number of active Ca2+ release channels supporting Ca2+ puffs, less attentionhas been placed on understanding the role of cluster microarchitecture. This is important as recent data underscores the dynamic nature of IP3R transitions between heterogeneous cellular architectures and the differential behavior of IP3Rs socialized into clusters. Here, we applied a high-resolution model incorporating stochastically gating IP3Rs within a three-dimensionalcytoplasmic space to demonstrate: 1), Ca2+ puffs are supported by a broad range of clustered IP3R microarchitectures; 2), cluster ultrastructure shapes Ca2+ puff characteristics; and 3), loosely corralled IP3R clusters (>200 nm interchannel separation) fail to coordinate Ca2+ puffs, owing to inefficient triggering and impaired coupling due to reduced Ca2+ -induced Ca2+ release microwave velocity (<10 nm/s) throughout the channel array. Dynamic microarchitectural considerations may therefore influence Ca2+ puff occurrence/properties in intact cells, contrasting with a more minimal role for channel number over the same simulated conditions in shaping local Ca2+ dynamics.