Endo-lysosomal TRP mucolipin-1 channels trigger global ER Ca2+ release and Ca2+ influx

Transient receptor potential (TRP) mucolipins (TRPMLs), encoded by the MCOLN genes, are patho-physiologically relevant endo-lysosomal ion channels crucial for membrane trafficking. Several lines of evidence suggest that TRPMLs mediate localised CA²⁺ release but their role in CA²⁺ signalling is not clear. Here, we show that activation of endogenous and recombinant TRPMLs with synthetic agonists evoked global CA²⁺ signals in human cells. These signals were blocked by a dominant-negative TRPML1 construct and a TRPML antagonist. We further show that, despite a predominant lysosomal localisation, TRPML1 supports both CA²⁺ release and CA²⁺ entry. CA²⁺ release required lysosomal and ER CA²⁺ stores suggesting that TRPMLs, like Other endo-lysosomal CA²⁺ channels, are capable of 'chatter' with ER CA²⁺ channels. Our data identify new modalities for TRPML1 action.