Potency of melanocortin agonists at wild-type and mutant MC4 and MC3 receptors measured using cAMP accumulation
| NDP-MSH | α-MSH | THIQ | MTII | ACTH | HfRWK | γ-MSH | γtrp9 | |
|---|---|---|---|---|---|---|---|---|
| MC4R | 8.86 ± 0.07 (1.38) | 7.83 ± 0.06 (14.8) | 8.83 ± 0.15 (1.48) | 9.73 ± 0.05 (0.186) | 8.44 ± 0.09 (3.63) | 8.81 ± 0.03 (1.55) | 6.18 ± 0.19 (661) | 7.65 ± 0.12 (22.4) |
| D122A | 8.35 ± 0.14* (4.47) | >1000 nM*** | 7.31 ± 0.11**(49.0) | N.D. | N.D. | N.D. | N.D. | N.D. |
| I125F | 8.57 ± 0.13 (2.69) | 7.77 ± 0.03 (17.0) | 8.04 ± 0.10*(9.12) | 9.33 ± 0.14* (0.468) | N.D. | 7.95 ± 0.08*** (11.2) | 6.12 ± 0.12 (759) | 6.90 ± 0.25 (126) |
| I137T | 8.51 ± 0.15 (3.09) | 7.70 ± 0.05 (20.0) | 8.26 ± 0.16* (5.50) | 8.75 ± 0.29* (1.78) | 7.83 ± 0.12* (14.8) | N.D. | N.D. | N.D. |
| F184M | 8.88 ± 0.18 (1.32) | 8.16 ± 0.14 (6.92) | 8.49 ± 0.09 (3.24) | 9.18 ± 0.20 (0.661) | 7.95 ± 0.25 (11.2) | N.D. | N.D. | N.D. |
| F261A | 8.83 ± 0.14 (1.48) | 6.93 ± 0.14**(117) | 7.09 ± 0.14**(81.3) | N.D. | N.D. | N.D. | N.D. | N.D. |
| F284A | 8.85 ± 0.10 (1.41) | 7.02 ± 0.01*** (95.5) | 7.57 ± 0.20** (26.9) | 9.19 ± 0.13* (0.646) | 7.11 ± 0.15** (77.6) | N.D. | N.D. | N.D. |
| MC3R | 8.68 ± 0.10 (2.09) | 8.00 ± 0.07 (10.0) | 6.45 ± 0.22 (355) | 8.62 ± 0.01 (2.40) | 8.22 ± 0.05 (6.03) | 6.80 ± 0.05 (158) | 7.04 ± 0.14 (91.2) | 9.20 ± 0.15 (0.631) |
| F157I | 9.16 ± 0.21 (0.692) | 8.49 ± 0.08* (3.24) | 6.74 ± 0.14 (182) | 9.26 ± 0.18* (0.550) | N.D. | 7.61 ± 0.18** (24.5) | 7.49 ± 0.11 (32.4) | 9.06 ± 0.03 (0.871) |
Agonist-stimulation of cAMP accumulation was determined as described under Materials and Methods, and potency (EC50) values were determined. Potency values are expressed aspEC50 ± S.E.M (EC50 nM) (n= 3–6). The asterisk (*) indicates that D122A, I125F, I137T, F184M, F261A, or F284A exhibit a significantly different functional potency to the wild-type MC4 receptor or that F157I exhibits a significantly different functional potency to the wild-type MC3 receptor (* p < 0.05,** p < 0.01,*** p < 0.005, Student's ttest).
N.D., not determined.