Gordon Research Conference on Ca²⁺ Signalling 2017 Editorial

The 2017 Gordon Research Conference on Ca²⁺ signalling took place in Lucca, Italy, 18–23 June, and was sponsored, in part, by The Journal of Physiology.

Changes in intracellular Ca²⁺ concentration influence numerous physiological responses, and dysregulated Ca²⁺ signalling is tightly linked to various human diseases. One prominent example of how aberrant Ca²⁺ signalling promotes disease progression is acute pancreatitis, a devastating condition for which there is currently no effective therapy. Whilst much is known about how different pancreatic cell types are affected by and contribute to this disease, how the different cells communicate with one another is unclear. An unexpected and important new role for pancreatic stellate (PS) cells has been uncovered in a series of elegant experiments by Ole Petersen and colleagues. PS cells are thought to mediate chronic inflammatory responses and, under physiological conditions, respond to bradykinin but not to the serine protease trypsin or membrane depolarisation to increase intracellular Ca²⁺ concentration. However, this changes dramatically when pancreatic lobules are either exposed to a mixture of ethanol and palmitoleic acid (to mimic acute pancreatitis in vitro) or are derived from mice in which acute pancreatitis has been induced in vivo. PS cells are now less responsive to bradykinin but respond strongly to trypsin, and this is likely to contribute to a positive feedback cycle that promotes acute pancreatitis progression (Gryshchenko et al. 2018; Hegyi, 2018).

An interesting twist on how an intracellular Ca²⁺ rise can promote disease progression has been identified in cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells (Zhou et al. 2018). These immune cells are crucial for elimination of cancer cells and operate best at extracellular Ca²⁺ concentrations that are well below physiological levels; activation of Ca²⁺ influx pathways at these extracellular Ca²⁺ levels impairs the perforin‐dependent killing of cancer cells by CTLs, thus contributing to cancer progression. Downregulation of the major Ca²⁺ influx pathway in CTLs, store‐operated Orai1 channels, results in increased lytic granule release and subsequent cancer cell death. From a therapeutic perspective, these findings could be potentially very important. A store‐operated Orai1 channel inhibitor would reduce Ca²⁺ influx in CTLs at physiological external Ca²⁺, and therefore should increase the CTL‐dependent killing of cancer cells.

Immune cells are also involved in defence mechanisms against pathogen invasion and colonisation. Neutrophils play a particularly important role as a first line of defence, and numerous functions are dependent on functional STIM proteins (Saul & Demaurex, 2018). STIM1 and 2 are Ca²⁺ sensing proteins that span the endoplasmic reticulum (ER) membrane and are required for the gating of store‐operated channels. Following the loss of Ca²⁺ from the ER, STIM proteins oligomerise and then migrate to regions of the ER adjacent to the plasma membrane, where they bind to and gate Orai channels, thereby initiating store‐operated Ca²⁺ entry. The exact roles that STIM proteins play in neutrophil function are not entirely clear, and conflicting reports as to their impact on chemotaxis need resolving, but what is emerging is that the two isoforms contribute to distinct processes, both individually and synergistically.

At sites of store‐operated Ca²⁺ entry, the ER and plasma membrane are very close to one another, which enables the CRAC activation domain or STIM–Orai Activation Region on cytosolic STIM1 to bind to the carboxy terminus of plasma membrane Orai1 and open the channel. One intriguing difference between plasma and intracellular membranes is their lipid composition, and much evidence points towards a critical role for lipids in modulating STIM and Orai function. Lipid transfer between the two membranes takes place at ER plasma membrane contact sites via several distinct processes. Intriguingly, cytosolic Ca²⁺ can affect protein function at the ER plasma membrane site as well as the distribution of lipids in both membranes (Balla, 2018).

Mitochondrial Ca²⁺ homeostasis is tightly linked to energy metabolism, and hence understanding its regulation is of critical importance (Arduino & Perocchi, 2018). Ca²⁺ enters mitochondria via the mitochondrial calcium uniporter (MCU) protein, which is the pore‐forming subunit in a macromolecular complex with several other regulatory proteins, including MICU1. MICU1 has several roles including acting as a scaffold for the assembly of the uniporter channel, assembly of complex IV and regulation of Ca²⁺‐induced mitochondrial permeability transition. An additional protein component of the MCU complex called Essential MCU Regulator (EMRE) is involved in the rectification of MCU Ca²⁺ flux, acts as a scaffold for MCU and MICU and is a mitochondrial matrix Ca²⁺ sensor. Mitochondrial efflux is mediated by mitochondrial Na⁺/Ca²⁺ and H⁺/Ca²⁺ exchangers (mNCLX and mHCX, respectively). Deletion or impairment of the function of any of these proteins gives rise to severe pathological phenotypes, and this is particularly well established for the heart, a muscle that can be metabolically challenged by a variety of stresses. Accordingly, there is much interest in developing drugs and drug‐screening platforms that can modulate Ca²⁺ import and export across mitochondria.

Although inositol 1,4,5‐trisphosphate (IP₃) is the best characterised Ca²⁺‐releasing second messenger, other messengers have been described, including nicotinic acid adenine dinucleotide phosphate (NAADP). NAADP is produced upon cell stimulation, though the exact synthesis pathways remain unclear, and triggers Ca²⁺ release from intracellular Ca²⁺ stores at low nanomolar concentrations. There is considerable debate as to which organelles and ion channels are targeted by NAADP. The review by Guse and Diercks (2018) discusses how NAADP‐binding proteins that act as NAADP receptors might couple with different ion channels located on different Ca²⁺ stores. This unifying hypothesis can help explain some of the conflicting results in the field and would allow for a highly versatile and flexible use of NAADP as an intracellular Ca²⁺ releasing agent.

During the meeting, Tullio Pozzan paid a moving and personal tribute to Roger Tsien (1952–2016), one of the giants in the Ca²⁺ signalling field. Tullio described the many seminal contributions Professor Tsien had made to the field of Ca²⁺ signalling, how the tools he had made had advanced the field dramatically and how helpful and engaging a colleague he was. The tribute highlighted just how much this field owes to one individual.

Additional information

Competing interests

None declared.

Funding

None