Molecular evolution of neuropeptide receptors with regard to maintaining high affinity to their authentic ligands.
Recently, we cloned many of the bullfrog neuropeptide G protein-coupled receptors (GPCRs), including receptors for vasotocin (VT), mesotocin, gonadotropin-releasing hormone (GnRH), neurotensin, apelin, and metastin. Bullfrog GPCRs usually have high affinity for bullfrog ligands but relatively low affinity for mammalian ligands. Reciprocally, synthetic agonists and antagonists developed based upon mammalian ligands display lower affinity at bullfrog receptors. Studies using chimeric or domain-swapped receptors indicate that the motifs responsible for differential ligand selectivity usually reside within transmembrane domain 6 (TMD6)-extracellular loop 3 (ECL3)-transmembrane domain 7 (TMD7). Triple mutation of mammalian V1aR (Phe(6.51) to Tyr, Ile(6.53) to Thr, and Pro(7.33) to Thr) increases VT affinity but greatly reduces arginine vasopressin affinity. This binding profile is similar to that of bullfrog VT1R. Changing just three amino acids in the bullfrog GnRH receptor-1 (i.e. Ser-Gln-Ser in the ECL3) to those found in the type-I mammalian GnRH receptor (i.e. Ser-Glu-Pro) reverses GnRH selectivity. In conclusion, specific receptor motifs that govern ligand selectivity can be determined by comparative molecular analyses of GPCRs and their ligands. Such analysis provides clues for understanding how GPCRs maintain high affinity to their authentic ligands.
Cho
Hyun Ju
HJ
Graduate School of Medicine, Korea University, Seoul 136-705, Republic of Korea.
Acharjee
Sujata
S
Moon
Mi Jin
MJ
Oh
Da Young
DY
Vaudry
Hubert
H
Kwon
Hyuk Bang
HB
Seong
Jae Young
JY
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019143:Evolution, Molecular; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D009479:Neuropeptides / Q000235:genetics; D011966:Receptors, LHRH / Q000235:genetics; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D018045:Receptors, Oxytocin / Q000235:genetics; D017483:Receptors, Vasopressin / Q000235:genetics; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D008024:Ligands; D009479:Neuropeptides; D011966:Receptors, LHRH; D018013:Receptors, Neuropeptide; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin