Calcium Signaling Mechanisms in Cellular Functions and Responses

Calcium ions (Ca2+) serve as ubiquitous second messengers that orchestrate a diverse array of cellular activities, from muscle contraction and neurotransmission to gene expression and programmed cell death. Under resting conditions the cytosolic free Ca2+ concentration is maintained at nanomolar levels, whereas stimuli such as ligand binding, mechanical stress or membrane depolarisation trigger transient or oscillatory Ca2+ elevations. Entry pathways include voltage-gated channels, receptor-operated conduits and the central store-operated calcium entry (SOCE) mechanism, in which endoplasmic reticulum (ER) Ca2+ depletion is sensed by STIM proteins that couple to plasma-membrane Orai channels. Organellar channels, including inositol 1,4,5-trisphosphate receptors (IP₃Rs) and two-pore channels (TPCs), shape the spatial and temporal heterogeneity of Ca2+ signals. Downstream decoding by EF-hand proteins, calcineurin–NFAT circuits and other Ca2+-binding modules ensures precise control of proliferation, metabolism, secretion and apoptosis, with dysregulation linked to immune disorders, cancer and neurodegeneration.

Research from Nature Portfolio

Recent studies have demonstrated that blockade of Orai1 and Orai2 channels in group 2 innate lymphoid cells markedly diminishes cytokine production and metabolic support, attenuating airway hyperreactivity in both murine models and humanised systems. This work highlights the therapeutic potential of targeting CRAC channel components in allergic inflammation. Investigations into ORAI2 function have revealed that ORAI2 forms heteromeric complexes with ORAI1 in T lymphocytes, fine-tuning store-operated calcium entry (SOCE) and thereby modulating antiviral immunity and autoimmune responses. The combined ablation of ORAI1 and ORAI2 abolishes SOCE and impairs T cell-dependent immunity, emphasising the non-redundant roles of Orai isoforms. Foundational biophysical research on STIM1 conformational switching has delineated how endoplasmic reticulum luminal Ca2+ depletion induces transmembrane reorganisation and unmasks cytosolic domains, driving ORAI1 channel gating and defining the molecular basis of inside-out Ca2+ signalling.

Calcium Signaling Mechanisms in Cellular Functions and Responses publication trend

The graph below shows the total number of articles in calcium signaling mechanisms in cellular functions and responses across all publications each year (not limited to Nature Index journals).

Technical terms

Store-operated calcium entry (SOCE): A pathway in which ER Ca2+ depletion triggers STIM–Orai coupling to admit extracellular Ca2+.
Calcium release-activated calcium (CRAC) channel: A highly Ca2+-selective plasma-membrane channel formed by Orai subunits.
Stromal interaction molecule 1 (STIM1): An ER-luminal Ca2+ sensor that oligomerises and translocates to activate Orai channels upon store depletion.
Orai proteins: Plasma-membrane channel subunits that form the pore of CRAC channels and determine SOCE amplitude.
Inositol 1,4,5-trisphosphate receptor (IP₃R): An ER membrane channel that releases Ca2+ in response to IP₃ generated by receptor signalling.
Two-pore channel 2 (TPC2): A lysosomal membrane channel that mediates Ca2+ release and interacts with ER channels to shape cellular Ca2+ signals.

References

1. Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models. Nature Communications (2023).
2. Crosstalk between TPC2 and IP3R regulates Ca2+ signals. Trends in Cell Biology (2024).
3. Calcium Channels and Pumps in Cancer: Changes and Consequences*. Journal of Biological Chemistry (2012).
4. Near-infrared photoactivatable control of Ca2+ signaling and optogenetic immunomodulation. eLife (2015).
5. The Role of Calcium–Calcineurin–NFAT Signaling Pathway in Health and Autoimmune Diseases. Frontiers in Immunology (2020).
6. ORAI2 modulates store-operated calcium entry and T cell-mediated immunity. Nature Communications (2017).
7. Inside-out Ca2+ signalling prompted by STIM1 conformational switch. Nature Communications (2015).