Two-pore channels: going with the flows

Abstract

In recent years, our understanding of the structure, mechanisms and functions of the endo-lysosomal TPC (two-pore channel) family have grown apace. Gated by the second messengers, NAADP and PI(3,5)P2, TPCs are an integral part of fundamental signal-transduction pathways, but their array and plasticity of cation conductances (Na+, Ca2+, H+) allow them to variously signal electrically, osmotically or chemically. Their relative tissue- and organelle-selective distribution, together with agonist-selective ion permeabilities provides a rich palette from which extracellular stimuli can choose. TPCs are emerging as mediators of immunity, cancer, metabolism, viral infectivity and neurodegeneration as this short review attests.

Timing mechanisms to control heart rhythm and initiate arrhythmias: roles for intracellular organelles, signalling pathways and subsarcolemmal Ca2+

“…In many cell types NAADP acts as a Ca 2+ mobilizing agent provoking Ca 2+ release from lysosomes [14,16,21,[150][151][152], though there may be a binding protein that mediates the effects ( [33] see discussion in [27]). Whether these effects are direct or not, photorelease of NAADP from a caged compound increased the amplitude of Ca 2+ transients accompanying APs in guinea pig ventricular myocytes [147].…”

“…Ca 2+ accumulation in the lysosome is dependent on the pH gradient, probably via H + –Ca 2+ exchange in the lysosomal membrane. Bafilomycin inhibits vacuolar H + -ATP-ase and is a very useful experimental tool, since the collapse of the pH gradient suppresses accumulation of Ca 2+ within lysosomes [ 32 , 33 ]. Bafilomycin, therefore, abolishes both the ability of the lysosome to take up Ca 2+ and any functional effects that depend on lysosomal Ca 2+ release.…”

“…Organelles in the endolysosome family have many diverse functions [ 21 , 32 , 33 ]. It is difficult to distinguish subtypes, particularly by light microscopy.…”

“…Some have questioned the selectivity of TPCs for Ca 2+ , and in addition these channels can be activated by both NAADP and PI(3,5)2. These controversies have been extensively discussed in a recent review [ 33 ]. The bulk of the experimental evidence shows that Ca 2+ is a major component of NAADP-mediated ion efflux via lysosomal TPC2 channels, and the presence of lipid enhances Ca 2+ selectivity [ 27 , 33 ].…”

“…These controversies have been extensively discussed in a recent review [ 33 ]. The bulk of the experimental evidence shows that Ca 2+ is a major component of NAADP-mediated ion efflux via lysosomal TPC2 channels, and the presence of lipid enhances Ca 2+ selectivity [ 27 , 33 ]. The selectivity of TPC1 channels may be lower [ 33 ] but the significance of this difference in a cardiac muscle context has yet to be explored.…”