Two-pore channels for integrative Ca signaling

Abstract

Two-pore channels (TPCs) are related to voltage-gated Ca(2+) and Na(+) channels. They most likely work as dimers with each of the two TPC protein subunits containing two pore-forming domains. Recent studies suggest that TPCs are expressed on the membranes of endosomes and lysosomes where they form receptors for nicotinic acid adenine dinucleotide phosphate (NAADP), the most potent Ca(2+) mobilizing messenger inside cells. Upon activation by NAADP, Ca(2+) release from endolysosomal stores through TPCs triggers cytoplasmic Ca(2+) signals. Because of discrete localizations of these acidic vesicles and their small, albeit variable, sizes, the Ca(2+) signals from endolysosomes are local and, perhaps, represent unique elementary Ca(2+) events. These localized signals can be converted into regenerative global Ca(2+) waves by triggering Ca(2+)-induced Ca(2+) release from endoplasmic reticulum. We will discuss the implications of these findings and the significance of TPCs in integrative Ca(2+) signaling in animal cells.

Keywords: Ca2+ channels; Ca2+ mobilization; NAADP; endoplasmic reticulum; endosomes; lysosomes.

Figure 1

The proposed role for two-pore channels in integrative Ca²⁺ signaling. Flow chart shows pathways for NAADP, cADPR and IP₃ production and their effects on intracellular Ca²⁺. The drawings at the bottom depict elementary Ca²⁺ signals generated by TPCs (left, lighter color and higher position for higher Ca²⁺ concentrations) and global Ca²⁺ signals generated by activating IP₃Rs and/or RyRs (right). Red dashed lines indicate alternative pathways. The green pathway on the left shows an alternative consequence of TPC-mediated Ca²⁺ release. ARC, ADP-ribose cyclase, including CD38, PLC, phospholipase C, Ψ, membrane potential. I_Ca, Ca²⁺ current through plasma membrane.