TPC2-A1-P is a powerful and membrane permeable agonist of two pore channel 2 (TPC2) with an EC50 of 10.5 μM. TPC2-A1-P plays its role by mimicking the physiological actions of PI(3,5)P2. TPC2-A1-P also shows higher potency to induce Na2+ mobilisation from TPC2 than TPC-A1-N . TPC2-A1-P can be used to probe different functions of TPC2 channels in intact cells[1][2][3].

Two-pore channels (TPC1-3) are ancient members of the voltage-gated ion channel superfamily. TPCs are expressed throughout the endo-lysosomal system and regulates the trafficking of various cargoes[1].TPC2 can mediate different physiological and possibly pathophysiological effects depending on how it is activated. The ion selectivity of TPC2 is not fixed but rather agonist-dependent. TPC2 is a unique example of an ion channel that conducts different ions in response to different activating ligands[1].TPC2-A1-P (10 μM) reproducibly evokes Ca2+ signals, and TPC2-A1-P response reachs its plateau slower than TPC2-A1-N . The EC50 in full concentration-effect relationships for the plateau response is 10.5 μM for TPC2-A1-P in a cell line stably expressing TPC2L11A/L12A.TPC2-A1-P (10-30 μM) induces Ca2+ signals in Hela cells expressing TPC2 in the presence but not absence of extracellular Ca2+. However, the responses are smaller and delayed compared to TPC2-A1-N , consistent with the results obtained in cells stably expressing TPC2L11A/L12A. TPC2-A1-P fails to induce Ca2+ signals in cells expressing ’pore-dead’ TPC2L11A/L12A/L265P and also fails to evoke Ca2+ signals in cells expressing human TRPML1 re-routed to the plasma membrane (TRPML1δNC)[1].In endo-lysosomal patch-clamp experiments, TPC2-A1-P (10 μM) evokes currents in endo-lysosomes isolated from cells expressing TPC2 and TPC2M484L, the currents evoked by TPC2-A1-P are significantly larger than those evoked by TPC2-A1-N in both wild-type and gain-of-function variant,and exhibits an EC50 value of 0.6 μM for TPC2-A1-P[1].

TPC2-A1-P;TPC2-A1-P

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