Ca2+ Microdomains in T-Lymphocytes

Early Ca 2+ signaling is characterized by occurrence of Ca 2+ microdomains formed by opening of single or clusters of Ca 2+ channels, thereby initiating first signaling and subsequently activating global Ca 2+ signaling mechanisms. However, only few data are available focusing on the first seconds and minutes of Ca 2+ microdomain formation and related signaling pathways in activated T-lymphocytes. In this review, we condense current knowledge on Ca 2+ microdomain formation in T-lymphocytes and early Ca 2+ signaling, function of Ca 2+ microdomains, and microdomain organization. Interestingly, considering the first seconds of T cell activation, a triphasic Ca 2+ signal is becoming apparent: (i) initial Ca 2+ microdomains occurring in the first second of T cell activation, (ii) amplification of Ca 2+ microdomains by recruitment of further channels in the next 5–10 s, and (iii) a transition to global Ca 2+ increase. Apparently, the second messenger nicotinic acid adenine dinucleotide phosphate is the first second messenger involved in initiation of Ca 2+ microdomains. Ryanodine receptors type 1 act as initial Ca 2+ release channels in CD4 + T-lymphocytes. Regarding the temporal correlation of Ca 2+ microdomains with other molecular events of T cell activation, T cell receptor-dependent microdomain organization of signaling molecules Grb2 and Src homology [SH2] domain-containing leukocyte protein of 65 kDa was observed within the first 20 s. In addition, fast cytoskeletal changes are initiated. Furthermore, the involvement of additional Ca 2+ channels and organelles, such as the Ca 2+ buffering mitochondria, is discussed. Future research developments will comprise analysis of the causal relation between these temporally coordinated signaling events. Taken together, high-resolution Ca 2+ imaging techniques applied to T cell activation in the past years paved the way to detailed molecular understanding of initial Ca 2+ signaling mechanisms in non-excitable cells.