Cold increases cutaneous vasoconstriction by unmasking the contractile activity of _2C-adrenoceptors (_2C-ARs) in vascular smooth muscle cells (VSMCs), which is mediated by cold-induced mobilization of _2C-ARs from the transGolgi to the cell surface. The expression of _2C-ARs in human cutaneous VSMCs is under dual regulation by cyclic AMP: gene transcription is inhibited by cyclic AMP acting through protein kinase A (PKA), but is increased by cyclic AMP acting through EPAC (exchange protein directly activated by cyclic AMP) and the GTP binding protein Rap1. Experiments were performed to further characterize the Rap1 signaling pathway. Forskolin (10 µM), the selective EPAC activator, 8-pCPT-2'-O-Me-cyclic AMP (CMC, 100 µM) or a constitutively-active mutant of Rap1 (Rap1CA) increased activity of c-Jun N-terminal kinase (JNK) in human cutaneous VSMCs. This was associated with increased phosphorylation of c-Jun and activation of an AP-1 reporter construct, which were inhibited by the JNK inhibitor, SP600125 (3 µM). Rap1CA increased the activity of an _2C-AR promoter-reporter construct, which was inhibited by SP600125 (3 µM) or by mutation of an AP-1 binding site in the _2C-AR promoter. Furthermore, forskolin (10 µM) or 8-CPT (100 µM) increased expression of _2C-AR protein, and these effects were inhibited by SP600125 (3 µM). Therefore, cyclic AMP increases expression of _2C-ARs in cutaneous VSMCs by activating a novel Rap1 signaling pathway, mediated by activation of JNK, AP1 and subsequent transcriptional activation of the _2C-AR gene. By increasing expression of cold-responsive _2C-ARs, this pathway may contribute to enhanced cold-induced vasoconstriction in the cutaneous circulation, including Raynaud's phenomenon.