RESUMO
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.
Assuntos
Canais de Cálcio , Linfócitos T , Canais de Cálcio/metabolismo , Linfócitos T/metabolismo , Membrana Celular/metabolismo , Retículo Endoplasmático/metabolismo , Simulação por ComputadorRESUMO
During an immune response, T cells migrate from blood vessel walls into inflamed tissues by migrating across the endothelium and through extracellular matrix (ECM). Integrins facilitate T cell binding to endothelial cells and ECM proteins. Here, we report that Ca2+ microdomains observed in the absence of T cell receptor (TCR)/CD3 stimulation are initial signaling events triggered by adhesion to ECM proteins that increase the sensitivity of primary murine T cells to activation. Adhesion to the ECM proteins collagen IV and laminin-1 increased the number of Ca2+ microdomains in a manner dependent on the kinase FAK, phospholipase C (PLC), and all three inositol 1,4,5-trisphosphate receptor (IP3R) subtypes and promoted the nuclear translocation of the transcription factor NFAT-1. Mathematical modeling predicted that the formation of adhesion-dependent Ca2+ microdomains required the concerted activity of two to six IP3Rs and ORAI1 channels to achieve the increase in the Ca2+ concentration in the ER-plasma membrane junction that was observed experimentally and that required SOCE. Further, adhesion-dependent Ca2+ microdomains were important for the magnitude of the TCR-induced activation of T cells on collagen IV as assessed by the global Ca2+ response and NFAT-1 nuclear translocation. Thus, adhesion to collagen IV and laminin-1 sensitizes T cells through a mechanism involving the formation of Ca2+ microdomains, and blocking this low-level sensitization decreases T cell activation upon TCR engagement.
Assuntos
Células Endoteliais , Proteínas da Matriz Extracelular , Camundongos , Animais , Proteínas da Matriz Extracelular/metabolismo , Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Colágeno/metabolismoRESUMO
With the discovery of local Ca2+ signals in the 1990s the concept of 'elementary Ca2+ signals' and 'fundamental Ca2+ signals' was developed. While 'elementary Ca2+signals' relate to optical signals gained by activity of small clusters of Ca2+channels, 'fundamental signals' describe such optical signals that arise from opening of single Ca2+channels. In this review, we discuss (i) concepts of local Ca2+ signals and Ca2+ microdomains, (ii) molecular mechanisms underlying Ca2+ microdomains, (iii) functions of Ca2+ microdomains, and (iv) mathematical modelling of Ca2+ microdomains. We focus on Ca2+ microdomains produced by ORAI channels, D-myo-inositol 1,4,5-trisphosphate receptors, or ryanodine receptors. In summary, research on local Ca2+ signals in different cell models aims to better understand how cells use the Ca2+ toolkit to produce Ca2+ microdomains as relevant signals for specific cellular responses, but also how local Ca2+ signals as building blocks merge into global Ca2+ signaling.