Abstract
Early Ca2+ signaling is characterized by occurrence of Ca2+ microdomains formed by opening of single or clusters of Ca2+ channels, thereby initiating first signaling and subsequently activating global Ca2+ signaling mechanisms. However, only few data are available focusing on the first seconds and minutes of Ca2+ microdomain formation and related signaling pathways in activated T-lymphocytes. In this review, we condense current knowledge on Ca2+ microdomain formation in T-lymphocytes and early Ca2+ signaling, function of Ca2+ microdomains, and microdomain organization. Interestingly, considering the first seconds of T cell activation, a triphasic Ca2+ signal is becoming apparent: (i) initial Ca2+ microdomains occurring in the first second of T cell activation, (ii) amplification of Ca2+ microdomains by recruitment of further channels in the next 5–10 s, and (iii) a transition to global Ca2+ increase. Apparently, the second messenger nicotinic acid adenine dinucleotide phosphate is the first second messenger involved in initiation of Ca2+ microdomains. Ryanodine receptors type 1 act as initial Ca2+ release channels in CD4+ T-lymphocytes. Regarding the temporal correlation of Ca2+ 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 Ca2+ channels and organelles, such as the Ca2+ buffering mitochondria, is discussed. Future research developments will comprise analysis of the causal relation between these temporally coordinated signaling events. Taken together, high-resolution Ca2+ imaging techniques applied to T cell activation in the past years paved the way to detailed molecular understanding of initial Ca2+ signaling mechanisms in non-excitable cells.
Highlights
Ca2+ signaling modulates a large variety of intracellular downstream targets
Since in T cells, the endogenous nicotinic acid adenine dinucleotide phosphate (NAADP) concentration increases upon TCR/CD3 stimulation within seconds, there is good evidence that this Ca2+-mobilizing second messenger plays a major role in Ca2+ microdomain formation
The current picture of the mechanisms underlying initial Ca2+ microdomains consists of three phases: (i) initial Ca2+ microdomains occurring in the first second of T cell activation, (ii) recruitment of further channels within the 5–10 s, and (iii) transition to global Ca2+ signaling by massive Ca2+ entry with tens of seconds (Figure 2)
Summary
Ca2+ signaling modulates a large variety of intracellular downstream targets. How Ca2+ signals are converted into meaningful cell responses has been a major area of interest in the past years [1]. Since in T cells, the endogenous NAADP concentration increases upon TCR/CD3 stimulation within seconds, there is good evidence that this Ca2+-mobilizing second messenger plays a major role in Ca2+ microdomain formation. Such a model is supported by data from T cells showing NAADP-evoked Ca2+ microdomains and subsequent increase of global [Ca2+]i, dependent on RyR1 expression [19, 32, 33].
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