New insights into Ca²⁺ channel function in health and disease

This issue of The Journal of Physiology contains reviews from a meeting held in Honolulu, sponsored in part by The Physiological Society and organized by Andrea Fleig, Anant Parekh and Reinhold Penner. The primary focus was on recent advances in our understanding of Ca²⁺‐permeable ion channels, how channel function can be hijacked in disease, and how this might be corrected therapeutically.

A rise in cytosolic Ca²⁺ is an evolutionarily conserved intracellular signal that regulates myriad responses over a wide temporal bandwidth. At one end of the spectrum is Ca²⁺‐dependent neurotransmitter release, which operates on a submillisecond time scale, and at the other is Ca²⁺‐dependent regulation of cell growth and differentiation, which can manifest hours to days after the Ca²⁺ signal has disappeared. Inherent to the use of the multifarious Ca²⁺ signal is the question of specificity: how are some Ca²⁺‐dependent responses activated and not others when all are gated by cytosolic Ca²⁺? What is now becoming clear, and what emerged as a recurrent theme at the meeting, is that the location of the Ca²⁺ signal is critical for activating specific responses. Ca²⁺‐permeable channels differ in their selectivity profiles, unitary conductance and subcellular distribution. Hence Ca²⁺ flux through different channels produces distinct subcellular Ca²⁺ patterns, which can be decoded by different downstream targets to elicit discrete functional responses.

The first review, by Petersen et al. (2017), describes a mechanism for tunnelling Ca²⁺ from a site of Ca²⁺ uptake to a site of Ca²⁺ release by diffusion through the lumen of the endoplasmic reticulum (ER). Tunnelling is a three step process: it requires Ca²⁺ that has entered the cytoplasm through store‐operated Ca²⁺ channels to be taken up by SERCA pumps on junctional ER located just below the plasma membrane; the Ca²⁺ diffuses through the ER and is then released into the cytosol at more distal sites by InsP ₃ receptors. Ca²⁺ tunnelling is therefore an effective vehicle for transporting Ca²⁺ to release sites without the free ion diffusing through the intervening cytoplasm, obviating the risk of inappropriate activation of numerous Ca²⁺‐dependent pathways en route.

Specialized epithelial cells called ameloblasts are involved in the formation of enamel, which gives teeth its strength. A crucial element in the biomineralization of enamel is Ca²⁺. The review by Nurbaeva et al. (2017) describes Ca²⁺ transport pathways in ameloblasts and how store‐operated Ca²⁺ entry in particular plays a central role in the mineralization of dental enamel.

Ca²⁺ channels populating the ER and SR can be activated by cytosolic Ca²⁺, resulting in Ca²⁺‐induced Ca²⁺ release. This is particularly important in the heart, where it enables the Ca²⁺ signal to spread quickly into the myocyte. The review by Santuli et al. (2017) describes new features of the release channels, how they influence other Ca²⁺ signalling organelles like mitochondria and why they are attractive therapeutic targets for a range of diseases.

Receptor stimulation often evokes oscillation in cytosolic Ca²⁺, considered the physiological form of Ca²⁺ signalling (Parekh, 2011). Oscillations in non‐excitable cells arise from InsP ₃‐dependent regenerative Ca²⁺ release with the ER refilling through store‐operated Ca²⁺ entry. The review by Samanta and Parekh (2017) describes how Ca²⁺ microdomains near open InsP ₃ receptors in the ER membrane are propagated rapidly into the mitochondria to regulate metabolism. Ca²⁺ microdomains generated by store‐operated Ca²⁺ channels signal to the nucleus to activate gene transcription. Hence, in addition to amplitude and frequency of the Ca²⁺ oscillations, the subcellular spatial profile of the Ca²⁺ spikes provides additional means for extracting information.

Given the gamut of responses regulated by cytosolic Ca²⁺, it comes as no surprise that aberrant Ca²⁺ signalling is linked to a range of human disease. Iamshanova et al. (2017) describe the multiple roles of cytosolic Ca²⁺ in the process of metastasis. Different Ca²⁺ channels elicit distinct subcellular Ca²⁺ signals that determine which underlying pathways will be activated and to what extent. Dissecting the role of the various Ca²⁺ channels in cancer cells opens up the possibility of rational therapeutic intervention. Another leading cause of death is stroke. The review by Sun et al. (2017) describes how silencing of TRPM7, a divalent cation‐permeable channel, not only reduced neuronal cell death but maintained nerve cell activity following global cerebral ischaemia in adult rats. Targeting TRPM7 might therefore be of benefit in stroke. Although there are currently no inhibitors available for clinical use, studies on the organic extract of the soft coral Sarcothelia edmondsoni identified waixenicin A as potent, specific and intracellular Mg²⁺‐dependent inhibitor of the channels (IC₅₀ of 16 nM for recombinant channels in a whole‐cell patch clamp assay; Zierler et al. 2011).

Developing blockers of store‐operated Ca²⁺ channels has proven challenging, but valuable insight into drug–channel interaction has come from the small molecule inhibitor 2‐aminoethoxyodiphenyl borate (2‐APB). Although it has been known for some time that low concentrations of 2‐APB potentiate the size of the store‐operated current, Ali et al. (2017) describe how this is accomplished. 2‐APB dilates Orai1, the pore‐forming subunit of the store‐operated channel, from 3.8 to 4.6 Å, rendering the normally Ca²⁺‐selective channel permeable to Ca²⁺ and Na⁺. Potentiation only occurs when Orai1 is in the open state, providing a possible starting point for the development of drugs that enhance the size of Ca²⁺ entry, although the change in ion selectivity would impact on Na⁺ transporters with complex consequences.

Much of our understanding of Ca²⁺ signalling has been extracted from isolated cells, but in vivo recordings are essential to place findings in a physiological context. The final review, by Tischbirek et al. (2017), describes the insights gleaned from a new red shifted fluorescent dye, Cal‐590, which enables measurements as far as ∼900 μm below the surface and from all six cortical layers. Dyes like Cal‐590 with good signal to noise ratios and fast kinetics permit the detection of Ca²⁺ signals in neuronal circuits at depths that were previously inaccessible.

Although the meeting nicely highlighted the rapid progress being made in our understanding of the properties and functions of Ca²⁺‐permeable ion channels, it reinforced the need for the development of selective and potent inhibitors of non‐voltage‐activated Ca²⁺ channels as potential treatments for a range of diseases.

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Competing interests

None declared.