Evolution of the melanocortin-2 receptor in tetrapods: studies on Xenopus tropicalis MC2R and Anolis carolinensis MC2R.

The tetrapods are a diverse assemblage of vertebrates, and that diversity is reflected in the sequences of tetrapod melanocortin-2 receptors (MC2Rs). In this review, the features common to human (mammal), Gallus gallus (bird), Anolis carolinensis (reptile), and Xenopus tropicalis (amphibian) MC2Rs in terms of ligand selectivity, requirements for interaction with MRAP1, and the effects of alanine substitutions to three amino acid motifs in the ligand hACTH(1-24) are discussed. Analysis of the effects of alanine substitutions to the H(6)F(7)R(8)W(9) and the K(15)K(16)R(17)R(18)P(19) motifs of hACTH(1-24) indicated that activation of A. carolinensis MC2R and X. tropicalis MC2R was more adversely affected by alanine substitutions at these positions as compared to the response of human MC2R to these same analogs. Furthermore, single alanine substitutions in the G(10)K(11)P(12)V(13)G(14) motif of hACTH(1-24) had negative affects on activation of both A. carolinensis MC2R and X. tropicalis MC2R that were not observed for human MC2R. The implications of responses to the various analogs of hACTH(1-24) in terms of the mechanism for mediating the activation of these various tetrapod melanocortin-2 receptors are discussed.