TPC2-mediated lysosomal Ca2+ release puts the brakes on store-operated Ca2+ entry.

Lysosomal Ca2+ release can trigger endoplasmic reticulum (ER) Ca2+ mobilisation, which would be expected to activate store-operated Ca2+ entry (SOCE). Recent work by Lee et al. reveals that activation of the lysosomal two-pore channel TPC2 instead suppresses SOCE despite ER Ca2+ depletion. TPC2-derived Ca2+ signals recruit calmodulin to promote STIM1 inactivation, imparing STIM oligomerisation and coupling to Orai1. These findings identify a lysosomal feedback pathway that restrains Ca2+ influx and expand the role of TPC2 from an initiator of intracellular Ca2+ release to a brake on SOCE.