Background and PurposeCGRP is a potent vasodilator and nociceptive neuropeptide linked to migraine. CGRP receptors are heterodimers of receptor activity modifying protein 1 (RAMP1) and either calcitonin receptor‐like receptor (CLR; forms canonical CGRP receptor) or calcitonin receptor (CT receptor; forms AMY1 receptor). The goal of this study was to test whether transgenic mice globally expressing human RAMP1 have increased CGRP receptor activity and whether the receptors are sensitive to human selective antagonist telcagepant.Experimental ApproachcAMP production was measured in primary cultures of aortic smooth muscle and trigeminal ganglia neurons from global hRAMP1 mice and non‐transgenic littermates. Functional activity and inhibition were compared with clonal cell lines expressing combinations of CLR or CT receptors with RAMP1.Key ResultsCultured smooth muscle from global hRAMP1 mice had a 10‐fold greater CGRP‐induced cAMP maximal response (Rmax) than non‐transgenic littermates, with similar EC50s. In contrast, cultured trigeminal ganglia from global hRAMP1 mice had a 40‐fold leftward shift of the EC50, with similar Rmax values as littermates. In both hRAMP1 cultures, telcagepant blocked CGRP‐induced cAMP production, but was not effective in non‐transgenic cultures. IC50 values were closer to those observed for CT receptor/hRAMP1 than CLR/hRAMP1 in clonal cell lines.Conclusions and ImplicationsOverexpression of hRAMP1 increases CGRP signalling by changing the maximal response or ligand sensitivity, depending on tissue type. Furthermore, telcagepant inhibited transgenic hRAMP1 CGRP receptors, but the degree of inhibition suggests that the transgenic mice are only partially humanized or both canonical CGRP and AMY1 receptors are functional in trigeminal ganglia neurons and vascular smooth muscle.