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The non-guanylate cyclase-coupled form of natriuretic peptide receptor (NPR) is activated by C-type natriuretic peptides (CNP) and structurally related peptides that share a common cyclic structure (Cys-Gln-Ala-Gly-Cys). In the present study, we compared the potencies of synthetic C-terminal peptides of natriuretic peptides and cyclic guanosine 3′,5′-monophosphate (cGMP) in the activation of intracellular cAMP. The peptides at the C-terminus of the human natriuretic peptide receptor, NPR-C, were synthesized as Cys-Cys-Phe-Gly (CCPG), Cys-Cys-Cys-Ala (CCCAA), Cys-Cys-Arg-Cys (CCRC) and Cys-Cys-Gly-Ala (CCGA). The peptides were tested for their ability to stimulate guanylate cyclase activity in HEK-293 cells transfected with NPR-C. Only the CCPG peptide was active as a potent natriuretic peptide receptor agonist in the stimulation of cyclase activity in transfected HEK-293 cells (EC50 = 1.7 +/- 0.2 nM). The following peptides were inactive at natriuretic peptide receptor: CCPGamide (EC50 > 1 microM), CCCAAamide (EC50 = 58 microM), CCRamide (EC50 > 1 microM), GCRamide (EC50 > 100 microM), CCGAAamide (EC50 > 100 microM) and CCGGAamide (EC50 > 100 microM). The potency of CCPG in activating cyclase activity was similar to that of the full-length natriuretic peptide, CNP (EC50 = 1.6 +/- 0.1 nM). The results suggested that CCPG is a potent agonist for the natri
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