Ca2+ Microdomains in T-Lymphocytes

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.

Integration of nicotinic acid adenine dinucleotide phosphate (NAADP)‐dependent calcium signalling

“…In these unique microenvironments, Ca 2+ microdomains can be formed due to the restricted volume and diffusion (Penny et al . ; Wolf & Guse, ). Further, Ca 2+ , as well as other signalling molecules, can be directly transmitted, for example, from the extracellular space to the ER (Manjarrés et al .…”

“…Analysis of membrane contact sites is difficult due to the small gap – only ∼30 nm – between apposing membranes, which is below the spatial resolution of a classical light microscope (∼200 nm) and even super‐resolution imaging (∼50 nm; Penny et al . ; Wolf & Guse, ).…”

ORAI1, STIM1/2, and RYR1 shape subsecond Ca 2+ microdomains upon T cell activation

“…Then, ligation of the T cell receptor/CD3 complex by major histocompatibility complex (MHC) molecules evokes juxtacrine signaling. The first intracellular signals occurring within tens and hundreds of milliseconds are local Ca 2+ release events, termed Ca 2+ microdomains (1, reviewed in 9). Using a high-resolution live-cell-imaging technique, we recently showed that RYR1 and NAADP are important players in local Ca 2+ release events, called Ca 2+ microdomains, early during T cell activation, (1).…”

What’s Bred in the Bone: Calcium Channels in Lymphocytes

“…Also, it is not uncommon that Ca 2+ channels are expressed as novel splice variants, often modifying their gating characteristics (4). Another phenomenon that adds to the complexity of Ca 2+ signaling is the formation of so-called Ca 2+ microdomains, which refer to the spatiotemporal organization of Ca 2+ currents (5). For example, the translocation of NFAT1 into the nucleus is dependent on local Ca 2+ increases in proximity to open Ca 2+ release-activated Ca 2+ (CRAC) channels instead of a global increase of Ca 2+ levels in the entire cytoplasm (6).…”