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The ΔC splice‐variant of TRPM2 is the hypertonicity‐induced cation channel in HeLa cells, and the ecto‐enzyme CD38 mediates its activation

•  Hypertonicity‐induced cation channels (HICCs) are key players in proliferation and apoptosis but their molecular identity has remained elusive. •  We report that in HeLa cells, intracellular adenosine diphosphate ribose (ADPr) and cyclic ADPr (cADPr), as activators of TRPM2 cation channels, elicited currents that are identical to the osmotic activation of HICCs. •  siRNA‐mediated silencing of the expression of TRPM2 and CD38 (as the supposed source of ADPr and cADPr) inhibited HICC and nucleotide‐induced currents and the osmotic volume response of cells. •  Quantification of intracellular cADPr and extracellular application of nucleotides revealed that the outwardly directed gradient rather than the intracellular activity of ADPr and cADPr is the triggering factor for TRPM2. •  Cloning of TRPM2 identified the ΔC‐splice variant as the molecular correlate of the HICC, which was supported by quantification of Ca2+ selectivity. •  Immunoprecipation and FRET/FLIM assays revealed the interaction of TRPM2 and CD38 and we propose a transport‐related nucleotide export via CD38 as a novel mechanism of TRPM2 activation.