Serotonin (5-HT) paiticipates in the development of cardiac hypertrophy through 5-HT2A serotonin receptors. The hypertrophic growth of cardiomyoblasts induced by 5-HT2A receptors involves the activation of the Ca2+ responsive calcineurin/NFAT pathway However, the mechanism whereby NFAT is activated by 5-HT2A receptors remains indeterminate In this study, we examined whether transient receptor potential canonical (TRPC) channels participate in NFAT activation and hypertrophic response triggered by 5-HT We demonstrate that TRPC1 expression is upregulated in 5-HT-treated rat cardiomyoblasts whereas TRPC6 is induced in a mouse Model of heart hypertrophy Moreover, TRPC1 knockdown by small interfering RNA inhibits NFAT activation and hypertrophic response mediated by 5-HT2A receptors These findings provide new insights about a mechanistic basis for the activation of the calcineurin/NFAT pathway by 5-HT2A receptors and highlight the critical role of TRPC1 in the development of cardiac hypertrophy. (C) 2009 Elsevier Inc. All rights reserved