FIGURE 9.

Model summarizing NAADP modulation of TPC2 channel gating. Without NAADP present, TPC2 P_o is very low, but it still gates with occasional brief openings, and therefore, it is in a constitutively active state (1). Low [NAADP] increases P_o to optimum levels when Ca²⁺ loading of the stores is high (2). Ca²⁺ release depletes the stores of Ca²⁺, leading to a reduced P_o, but causes alkalinization within the stores, which could lead to irreversible binding of NAADP to TPC2 (3). Both state (2) and state (3) represent NAADP-activated states. As the acidic pH is restored, NAADP dissociates from TPC2, and luminal Ca²⁺ stores are replenished. High [NAADP] inactivates the channel (P_o = 0) in a reversible manner (4); we term this state the inactive state.