Questioning regulation of two-pore channels by NAADP.

NAADP is a potent Ca2+ mobilizing messenger [1-3]. Since its discovery in 1995 [4] a considerable volume of literature has shown that NAADP couples cell stimulation to endolysosomal Ca2+ release and thereby the regulation of many cellular functions [5]. However definition of its molecular mechanism of action has proved far from easy. Since 2009, a consensus emerged as several independent groups coalesced upon the two-pore channel (TPC) family as NAADP-activated channels essential for Ca2+ release from endolysosomal Ca2+ stores [6-8]. However this view has been recently challenged by data clearly showing that TPCs function as Na+-selective channels apparently insensitive to NAADP [9;10]. Given the two fundamental characteristics defining an ion channel comprise the opening stimulus and the nature of the permeant ions, scrutiny of these seeming irreconcilable viewpoints is essential. The purpose of this commentary is to distil the remaining consensus while interrogating these divergent viewpoints. From this analysis, critical experimental needs are identified.