Coordinating activation of endo‐lysosomal two‐pore channels and TRP mucolipins

Two‐pore channels and TRP mucolipins are ubiquitous endo‐lysosomal cation channels of pathophysiological relevance. Both are Ca2+‐permeable and regulated by phosphoinositides, principally PI(3,5)P2. Accumulating evidence has uncovered synergistic channel activation by PI(3,5)P2 and endogenous metabolites such as the Ca2+ mobilizing messenger NAADP, synthetic agonists including approved drugs and physical cues such as voltage and osmotic pressure. Here, we provide an overview of this coordination. figure legend Schematic depicting flux through a lysosomal ion channel in response to two agonists applied singly (left and right) and synergistic activation upon combined stimulation (centre).