Triggering of Ca²⁺ signals by NAADP-gated two-pore channels: a role for membrane contact sites?

NAADP (nicotinic acid–adenine dinucleotide phosphate) is a potent Ca²⁺-mobilizing messenger implicated in many Ca²⁺-dependent cellular processes. It is highly unusual in that it appears to trigger Ca²⁺ release from acidic organelles such as lysosomes. These signals are often amplified by archetypal Ca²⁺ channels located in the endoplasmic reticulum. Recent studies have converged on the TPCs (two-pore channels) which localize to the endolysosomal system as the likely primary targets through which NAADP mediates its effects. ‘Chatter’ between TPCs and endoplasmic reticulum Ca²⁺ channels is disrupted when TPCs are directed away from the endolysosomal system. This suggests that intracellular Ca²⁺ release channels may be closely apposed, possibly at specific membrane contact sites between acidic organelles and the endoplasmic reticulum.