Neglected wardens: T lymphocyte ryanodine receptors

Ryanodine receptors (RyRs) are intracellular Ca²⁺ release channels ubiquitously expressed in various cell types. RyRs were extensively studied in striated muscle cells due to their crucial role in muscle contraction. In contrast, the role of RyRs in Ca²⁺ signalling and functions in non-excitable cells, such as T lymphocytes, remains poorly understood. Expression of different isoforms of RyRs was shown in primary T cells and T cell lines. In T cells, RyRs co-localize with the plasmalemmal store-operated Ca²⁺ channels of the Orai family and endoplasmic reticulum Ca²⁺ sensing Stim family proteins and are activated by store-operated Ca²⁺ entry and pyridine nucleotide metabolites, the intracellular second messengers generated upon stimulation of T cell receptors. Experimental data indicate that together with d-myo-inositol 1,4,5-trisphosphate receptors, RyRs regulate intercellular Ca²⁺ dynamics by controlling Ca²⁺ concentration within the lumen of the endoplasmic reticulum and, consequently, store-operated Ca²⁺ entry. Gain-of-function mutations, genetic deletion or pharmacological inhibition of RyRs alters T cell Ca²⁺ signalling and effector functions. The picture emerging from the collective data shows that RyRs are the essential regulators of T cell Ca²⁺ signalling and can be potentially used as molecular targets for immunomodulation or T cell-based diagnostics of the disorders associated with RyRs dysregulation.