Two-pore cation (TPC) channel: not a shorthanded one

Two-pore cation (TPC) channels form functional dimers in membranes, delineating acidic intracellular compartments such as vacuoles in plants and lysosomes in animals. TPC1 is ubiquitously expressed in thousands of copies per vacuole in terrestrial plants, where it is known as slow vacuolar (SV) channel. An SV channel possesses high permeability for Na+, K+, Mg2+, and Ca2+, but requires high (tens of mM) cytosolic Ca2+ and non-physiological positive voltages for its full activation. Its voltage dependent activation is negatively modulated by physiological concentrations of vacuolar Ca2+, Mg2+ and H+. Double control of the SV channel activity from cytosolic and vacuolar sides keeps its open probability at a minimum and precludes a potentially harmful global Ca2+ release. But this raises the question of what such' inactive' channel could be good for? One possibility is that it is involved in ultra-local Ca2+ signalling by generating 'hotspots' - microdomains of extremely high cytosolic Ca2+. Unexpectedly, recent studies have demonstrated the essential role of the TPC1 in the systemic Ca2+ signalling, and the crystal structure of plant TPC1, which became available this year, unravels molecular mechanisms underlying voltage and Ca2+ gating. This review emphasises the significance of these ice-breaking findings and sets a new perspective for the TPC1-based Ca2+ signalling.