Figure 3. A schematic representation of the role of TPC and TRPML channels in membrane fusion. Left panel: The classic scheme of membrane fusion in presynaptic terminals: Ca²⁺ influx through the voltage-regulated L-type CaV channels (orange) triggers conformational change in SNARE complexes (not shown) and membrane fusion (green). This influx it triggered by a change in the membrane potential (red). Right panel: Membrane fusion in the endocytic pathway. Ca²⁺ efflux out of the H⁺- and Ca²⁺- rich endo/lysosomes (orange) through TPC and TRPML channels triggers conformational change in SNARE complexes (not shown) and membrane fusion (green). Ca²⁺ efflux through TPC channels is triggered by NAADP and modulated by membrane potential (red) and Ca²⁺. TRPML Ca²⁺ fluxes are activated by PI(3,5)P₂ and TRPML1 activity is terminated by cleavage.