Table 1.
Summary of in vitro and/or in vivo results on published glucagon receptor missense variants and the present study
| Receptor variant | Reference | Binding |
Signaling |
Clinical phenotype | ||
|---|---|---|---|---|---|---|
| Experimental setup and cell type | Results | Experimental setup and cell type | Results | |||
| G40ECDS | Present study | [125I]glucagon for 3 h at 4 °C (transient COS-7 cells) | Similar KD and similar Bmax | cAMP accumulation 30-min stimulation (transient COS-7 cells) |
Similar EC50 and Emax | |
| Siani et al. (27) | Central adiposity in men; 37 individuals (total 985); heterozygous | |||||
| Hager et al. (31) | [125I]glucagon for 2 h at room temperature (stable BHK cells) | 3.0-fold lower KD, similar Bmax | Non-insulin-dependent diabetes; 13 individuals (total 1218); heterozygous | |||
| Mukund et al. (82) | [125I]glucagon (stable HEK 293) | Similar KD and Bmax | CRE-luciferase (stable HEK 293) | 4.7-fold lower EC50 | ||
| Hansen et al. (83) | [125I]glucagon (stable BHK cells/RIN cells) | 3.5- to 6.1-fold lower KD, similar Bmax | cAMP accumulation (stable BHK cells/RIN cells) | 2.5- to 4-fold lower pEC50 and lower Emax | ||
| Lin et al. (30) | [125I]glucagon for 3 h at room temperature (transient CHO-K1 cells) | Similar KD, 1.5-fold lower Bmax | TR-FRET cAMP accumulation 40-min stimulation (transient CHO-K1 cells) |
Similar EC50 and Emax | ||
| D63ECDN | Present study | [125I]glucagon for 3 h at 4 °C (transient COS-7 cells) | Increased KD but very low Bmax | cAMP accumulation 30-min stimulation (transient COS-7 cells) |
219.2-fold lower EC50 and lower Emax | |
| Gild et al. (33) | Hyperglucagonemia and Mahvash disease; 1 individual homozygous | |||||
| P86ECDS | Present study | [125I]glucagon for 3 h at 4 °C (transient COS-7 cells) | Similar KD, 20-fold lower Bmax | cAMP accumulation 30-min stimulation (transient COS-7 cells) |
18.6-fold lower EC50, similar Emax | |
| Zhou et al. (28) | [125I]glucagon for 1 h at 37 °C (transient HEK 293 cells) | 29-fold lower Bmax | LANCE cAMP accumulation 60-min stimulation (transient HEK 293 cells) |
9.9-fold lower EC50, similar Emax | Hyperglucagonemia and ɑ-cell hyperplasia; 1 individual; homozygous | |
| Siu et al. (40) | [125I]glucagon for 2 h at room temperature (transient CHO-K1 cells) | No binding observed | ||||
| R2253.30H | Present study | [125I]glucagon for 3 h at 4 °C (transient COS-7 cells) | Similar KD, 20-fold lower Bmax | cAMP accumulation 30-min stimulation (transient COS-7 cells) |
86.4-fold lower EC50, slightly lower Emax | |
| Lin et al. (30) | [125I]glucagon for 3 h at room temperature (transient CHO-K1 cells) | No binding observed | TR-FRET cAMP accumulation 40-min stimulation (transient CHO-K1 cells) |
>10-fold lower EC50, similar Emax | ||
| R2253.30H-V3686.59M | Sipos et al. (29) | ɑ-Cell hyperplasia; 1 individual; homozygous | ||||
| V3686.59M | Present study | [125I]glucagon for 3 h at 4 °C (transient COS-7 cells) | Similar KD, 3.3-fold lower Bmax | cAMP accumulation 30-min stimulation (transient COS-7 cells) |
Weak activation | |
| Lin et al. (30) | [125I]glucagon for 3 h at room temperature (transient CHO-K1 cells/liver cell membranes of mice) | Similar KD, 1.9-fold lower Bmax/similar KD, 4.0-fold lower Bmax | TR-FRET cAMP accumulation 40-min stimulation (transient CHO-K1 cells/liver cell membranes of mice) |
2.5-fold lower EC50, similar Emax/9.5-fold lower EC50, similar Emax | Hyperglucagonemia and ɑ-cell hyperplasia (mice; homozygous) | |
Within each experiment, the receptor variant is compared with the wildtype glucagon receptor. Ligand stimulations were performed with glucagon.