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Extracellular nucleotides induce apoptosis and inhibit growth of colorectal cancer cells. To understand the underlying signaling pathways, we investigated the role of nucleotide-sensitive P2 receptors and focused on the receptor-mediated signaling of intracellular Ca²⁺ and cyclic adenosine monophosphate (cAMP) in two colorectal carcinoma cell lines (HT29, Colo320 DM). Expression and functionality of P2 receptor subtypes evaluated by RT-PCR and [Ca²⁺]_i imaging revealed that solely metabotropic P2 receptors of the subtype P2Y₂ were expressed on a functional level in both cell lines. Short-term stimulation of P2Y₂ receptors caused Ca²⁺ mobilization from intracellular stores and a subsequent transmembrane Ca²⁺ influx. The receptor-induced [Ca²⁺]_i elevation was shown to increase basal-stimulated [cAMP]_i moderately and to potentiate forskolin-stimulated [cAMP]_i vigorously, since the effects were …