Pharmacological characterization of vampire bat-derived CGRP at the human CGRP receptor in the Xenopus oocyte system

Vampire bats (Desmodus rotundus) possess an oral venom system consisting of submandibular glands that produce bioactive compounds, delivered to prey via their sharp incisors. The venom has long been recognized for its anticoagulant and proteolytic properties, which disrupt blood clot formation and interfere with the coagulation cascade. A peptide with high structural similarity to human calcitonin gene-related peptide (hCGRP), a potent vasodilator, was recently discovered in the venom of Desmodus rotundus. This vampire bat-derived CGRP (vCGRP) elicited relaxation of pre-contracted rat mesenteric arteries, displaying efficacy and potency comparable to hCGRP. The authors proposed that vCGRP mediates vasorelaxation through activation of CGRP receptors (CGRPR) and voltage-dependent potassium (Kv) channels, thereby enhancing blood meal absorption via sustained blood flow. Our study builds on these findings by demonstrating that vCGRP is a potent agonist of hCGRPR and activates G protein-coupled inwardly rectifying potassium (GIRK1/2) channels. While the observed GIRK1/2 activation is consistent with membrane hyperpolarization mechanisms that may support vascular relaxation, our findings do not directly demonstrate vasodilation. Instead, they provide a detailed functional assessment of vCGRP-CGRPR signaling and downstream GPCR-ion channel activation. Notably, from the system studied here we found no involvement of Gs or Gq proteins, nor of Kv channels, in this signaling pathway. With a potency of 9 nM, vCGRP represents a highly effective mimic evolved to specifically and potently engage CGRPR in prey.