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 (Hawkey, 1966; Apitz-Castro et al., 1995). More recently, Kakumanu et al. (2019) identified a peptide in D. rotundus venom structurally similar to human calcitonin gene-related peptide (hCGRP), a known vasodilator. 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, acting via Gi/o proteins and activating G protein–coupled inwardly rectifying potassium (GIRK1/2) channels. The observed barium-sensitive GIRK1/2 activation results in membrane hyperpolarization, providing mechanistic evidence linked to the vasodilation of arterioles described by Kakumanu et al. 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.