The acid test: the discovery of two-pore channels (TPCs) as NAADP-gated endolysosomal Ca(2+) release channels - PubMed (original) (raw)

Review

The acid test: the discovery of two-pore channels (TPCs) as NAADP-gated endolysosomal Ca(2+) release channels

Antony Galione et al. Pflugers Arch. 2009 Sep.

Abstract

In this review, we describe the background and implications of our recent discovery that two-pore channels (TPCs) comprise a novel class of calcium release channels gated by the intracellular messenger nicotinic acid adenine dinucleotide phosphate (NAADP). Their localisation to the endolysosomal system highlights a new function for these organelles as targets for NAADP-mediated Ca(2+) mobilisation. In addition, we describe how TPCs may also trigger further Ca(2+) release by coupling to the endoplasmic reticular stores through activation of IP(3) receptors and ryanodine receptors.

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Figures

Fig. 1

Fig. 1. Two-pore channels: relationships with other voltage-gated channels and structure organization

a. A phylogenetic tree generated by ClustalW (

http://align.genome.jp

) and plotted using Neighbour-Joining algorithm for TPCs and selected members of the superfamily of voltage-gated channels. The second transmembrane (TM) domain of TPCs and the fourth TM domain of Cav and Nav were aligned with the TM domains (including all six TM segments and the pore-loop) of representative Kv, CNG, TRP, and CatSper channels. b. A single TPC subunit contains 12 putative TM segments that can be divided into two 6-TM homologous domains, each containing also a pore-loop (P-loop). Based on orientation of voltage-gated channels, the amino and carboxyl termini, as well as the large loop in between the two domains, are on the cytoplasmic side of the endolysosomal membranes. Red branches indicate a putative glycosylation site in human TPC2. c. 3-D projection model of an assembled TPC channel, which is most likely a dimer.

Fig. 2

Fig. 2. NAADP regulation of TPCs

Model outlining how NAADP-regulated TPCs expressed at acidic Ca2+ stores might modulate the activity of closely apposed Ca2+-sensitive channels in, a the plasma membrane or b, endoplasmic reticulum via local Ca2+ (represented by the green fill). a, Ca2+-sensitive ion channels in the plasma membrane are arbitrarily depicted with six transmembrane domains and might be cation- or anion-selective, inward or outward currents (double-headed arrow). NAADP-evoked Ca2+ release from sub-plasmalemmal acidic stores produces a local Ca2+ signal that activates plasma membrane channels (7, 8, 9). In turn, this may drive changes in the plasma membrane potential. b, A two-pool model of Ca2+ spiking where a highly localized trigger Ca2+ released via TPCs recruits CICR channels on the ER (8). Abbreviations: CHX, Ca2+/H+ exchanger; SERCA, sarco(endo)plasmic reticulum Ca2+-ATPase; IP3R, IP3 receptor; ER, endoplasmic reticulum; CICR, Ca2+-induced Ca2+ release; X+, cations; Y−, anions; Ψ, membrane potential. Drawn by Dr Anthony Morgan.

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