Abstract
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.