T cell Ca2+ microdomains through the lens of computational modeling

Abstract

Cellular Ca²⁺ signaling is highly organized in time and space. Locally restricted and short-lived regions of Ca²⁺ increase, called Ca²⁺ microdomains, constitute building blocks that are differentially arranged to create cellular Ca²⁺ signatures controlling physiological responses. Here, we focus on Ca²⁺ microdomains occurring in restricted cytosolic spaces between the plasma membrane and the endoplasmic reticulum, called endoplasmic reticulum-plasma membrane junctions. In T cells, these microdomains have been finely characterized. Enough quantitative data are thus available to develop detailed computational models of junctional Ca²⁺ dynamics. Simulations are able to predict the characteristics of Ca²⁺ increases at the level of single channels and in junctions of different spatial configurations, in response to various signaling molecules. Thanks to the synergy between experimental observations and computational modeling, a unified description of the molecular mechanisms that create Ca²⁺ microdomains in the first seconds of T cell stimulation is emerging.

Keywords: 3D computational model; Ca2+ microdomains; Orai; nicotinic acid adenine dinucleotide phosphate (NAADP); store-operated Ca2+ entry (SOCE).