AbstractCa2+‐signaling of human melanoma is in the focus of intensive research since the identification of the role of WNT‐signaling in melanomagenesis. Genomic and functional studies pointed to the important role of various Ca2+ channels in melanoma, but these data were contradictory. In the present study we clearly demonstrate, in a number of different ways including microarray analysis, DNA sequencing and immunocytochemistry, that various human melanoma cell lines and melanoma tissues overexpress ryanodine receptor type 2 (RyR2) and express P2X7 channel proteins as compared to melanocytes. These channels, although retain some of their usual characteristics and pharmacological properties, display unique features in melanoma cells, including a functional interaction between the two molecules. Unlike P2X7, RyR2 does not function as a calcium channel. On the other hand, the P2X7 receptor has an antiapoptotic function in melanoma cells, since ATP‐activation suppresses induced apoptosis, while knock down of the gene expression significantly enhances that. © 2007 Wiley‐Liss, Inc.