Structural determinants of the melanocortin peptides required for activation of melanocortin-3 and melanocortin-4 receptors.
The melanocortins are peptide products of proopiomelanocortin post-translational processing that, among other functions, are thought to influence cognition. Recently, we isolated genes encoding two human melanocortin receptors, the melanocortin-3 receptor (hMC3R) and the melanocortin-4 receptor (hMC4R), which are expressed primarily in brain. We undertook the present studies to examine the structural features of melanocortins that determine activation of these two receptors. For our studies we expressed the coding regions of the hMC3R and hMC4R genes in Hepa cells using the eukaryotic expression vector CMVneo and examined the generation of intracellular cyclic 3',5'-adenosine monophosphate in response to stimulation with various melanocortins. Our findings indicate that the core heptapeptide sequence common to most of the melanocortins (amino acids 4-10 of adrenocorticotropic hormone [ACTH]) is the primary determinant for activation of hMC3R but, in addition, tyrosine2 is necessary for maximal response. Activity of hMC4R is heavily dependent on proline12, but full activity also requires a contribution by tyrosine2. These findings may provide insight into the development of targeted ligands for the brain melanocortin receptors.
Miwa
H
H
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, USA.
Gantz
I
I
Konda
Y
Y
Shimoto
Y
Y
Yamada
T
T
D000324:Adrenocorticotropic Hormone / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D009074:Melanocyte-Stimulating Hormones / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D051381:Rats; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000187:drug effects*; D018000:Receptors, Peptide / Q000187:drug effects*; D013329:Structure-Activity Relationship
D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D018000:Receptors, Peptide; D000324:Adrenocorticotropic Hormone; D009074:Melanocyte-Stimulating Hormones; D000242:Cyclic AMP