Acidic Ca2+ stores: Form. Function. Failure.

Calcium increases within our cells drive just about all cellular processes. My lab focuses on the role of acidic organelles, such as lysosomes, in Ca²⁺ signalling in both health and disease. Central to signalling through these so called ‘acidic Ca²⁺ stores is the Ca²⁺ mobilizing messenger NAADP and the endo-lysosomal two-pore channels (TPCs). Much evidence has accrued showing that NAADP can evoke global Ca²⁺ signals through secondary recruitment of Ca²⁺ channels on the endoplasmic reticulum during signalling. But increasing evidence suggests that the local NAADP-evoked Ca²⁺ signals deriving directly from acidic organelles may act in their own right to regulate endocytic form and function. Consistent with this is proteomic analyses identifying association of TPCs with trafficking proteins. And the reversal of lysosomal morphology defects by inhibiting TPC2. TPC1 maintains formation of membrane contact sites between late endosomes and the endoplasmic reticulum to regulate EGF receptor signalling. Recent studies have identified several clinically approved drugs as TPC blockers. These drugs offer scope for combatting diseases such as Parkinson’s in which TPCs are increasingly implicated.