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 Ca(2+) release but their role in Ca(2+) signalling is not clear. Here, we show that activation of endogenous and recombinant TRPMLs with synthetic agonists evoked global Ca(2+) 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 Ca(2+) release and Ca(2+) entry. Ca(2+) release required lysosomal and ER Ca(2+) stores suggesting that TRPMLs, like other endo-lysosomal Ca(2+) channels, are capable of 'chatter' with ER Ca(2+) channels. Our data identify new modalities for TRPML1 action