TABLE 3.
Effects of naturally occurring human GLP-1R polymorphisms on agonist signaling via cAMP
Data were analyzed using a three-parameter logistic equation as defined in eq. 1. pEC50 values represent the negative logarithm of the concentration of agonist that produces half the maximal response. Emax represents the maximal response normalized to the response elicited by that of 100 nM forskolin. All values are mean ± S.E.M. of four to ten independent experiments, conducted in duplicate. Data were analyzed with one-way analysis of variance and Dunnett's post test.
| cAMP Accumulation |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| pEC50 |
Emax |
|||||||||
| GLP-1 (1–36)NH2 | GLP-1 (7–36)NH2 | Exendin-4 | Oxyntomodulin | Compound 2a | GLP-1 (1–36)NH2 | GLP-1 (7–36)NH2 | Exendin-4 | Oxyntomodulin | Compound 2b | |
| Wild type | 6.8 ± 0.2 | 10.2 ± 0.2 | 10.7 ± 0.1 | 8.7 ± 0.1 | 5.5 ± 0.1 | 270 ± 36 | 343 ± 21 | 299 ± 9 | 368 ± 9 | 254 ± 44 |
| Leu7 | 7.1 ± 0.2 | 10.5 ± 0.2 | 10.4 ± 0.2 | 8.5 ± 0.1 | 5.6 ± 0.1 | 217 ± 18 | 294 ± 18 | 277 ± 14 | 283 ± 13* | 242 ± 50 |
| Lys20 | 7.3 ± 0.2 | 10.3 ± 0.2 | 10.6 ± 0.2 | 8.5 ± 0.2 | 5.6 ± 0.1 | 244 ± 26 | 339 ± 19 | 249 ± 12 | 279 ± 18* | 200 ± 26 |
| His44 | 7.1 ± 0.2 | 10.4 ± 0.2 | 10.4 ± 0.2 | 8.3 ± 0.1 | 5.7 ± 0.1 | 244 ± 27 | 321 ± 18 | 302 ± 16 | 322 ± 17 | 291 ± 46 |
| Gln131 | 7.4 ± 0.3 | 10.4 ± 0.2 | 10.6 ± 0.2 | 8.3 ± 0.2 | 5.6 ± 0.1 | 209 ± 31 | 322 ± 21 | 253 ± 15 | 271 ± 14* | 225 ± 35 |
| Met149 | N.D. | 8.0 ± 0.3* | 8.4 ± 0.1* | N.D. | 5.5 ± 0.1 | N.D. | N.D. | 223 ± 13 | N.D. | 217 ± 24 |
| Ser168 | 6.9 ± 0.2 | 10.5 ± 0.2 | 10.4 ± 0.2 | 8.3 ± 0.2 | 5.8 ± 0.1 | 314 ± 33 | 320 ± 17 | 242 ± 11 | 273 ± 14* | 283 ± 13 |
| Leu260 | 6.9 ± 0.2 | 10.4 ± 0.3 | 10.5 ± 0.2 | 8.4 ± 0.1 | 5.3 ± 0.1 | 297 ± 28 | 291 ± 21 | 290 ± 13 | 302 ± 12 | 184 ± 30 |
| Thr316 | 7.2 ± 0.2 | 10.5 ± 0.3 | 10.5 ± 0.4 | 8.7 ± 0.3 | 5.3 ± 0.1 | 304 ± 33 | 228 ± 16* | 301 ± 30 | 277 ± 22* | 182 ± 18 |
| Cys333 | 6.9 ± 0.2 | 10.2 ± 0.3 | 10.2 ± 0.2 | 8.2 ± 0.2 | N.D. | 259 ± 24 | 331 ± 26 | 257 ± 12 | 288 ± 16 | 46 ± 8* |
| Gln421 | 6.7 ± 0.2 | 10.1 ± 0.2 | 10.3 ± 0.2 | 8.1 ± 0.1 | 5.6 ± 0.1 | 242 ± 23 | 275 ± 15 | 267 ± 13 | 332 ± 15 | 236 ± 45 |
N.D., data unable to be experimentally defined or with incomplete curves.
For estimation of pEC50 values, Emax was set to ≤300% of the 100 nM forskolin response.
Compound 2 response at 10−5 M.
Statistically significant at p < 0.05.