TABLE 1.
Transducer-specific molecular efficacies of AT1R ligands for Gq and βarr2 signaling pathways
| Ligand | Peptide sequencea | AT1R-Gq |
AT1R-βarr2 |
||||||
|---|---|---|---|---|---|---|---|---|---|
| LogαGq (mean ± S.E.)b | αGqb | ΔΔG (mean ± S.E.)c | Δ Integral (mean ± S.E.)d | Log αβarr2 (mean ± S.E.)b | αβarr2b | ΔΔG (mean ± S.E.)c | Δ Integral (mean ± S.E.)d | ||
| AngIIe,f | Asp-Arg-Val-Tyr-Ile-His-Pro-Phe | 1.63 ± 0.02 | 43.0 | −3.76 ± 0.05 | 0.69 ± 0.01 | 1.47 ± 0.03 | 29.6 | −3.39 ± 0.07 | 0.59 ± 0.02 |
| SIIe,f | Sar-Arg-Val-Ile-Ile-His-Pro-Ile | 0.57 ± 0.07 | 3.7 | −1.31 ± 0.16 | 0.20 ± 0.02 | 0.77 ± 0.03 | 5.9 | −1.77 ± 0.06 | 0.30 ± 0.01 |
| TRV120023 | Sar-Arg-Val-Tyr-Lys-His-Pro-Ala | 0.28 ± 0.04 | 1.9 | −0.64 ± 0.08 | 0.10 ± 0.01 | 1.14 ± 0.08 | 13.8 | −2.63 ± 0.18 | 0.44 ± 0.02 |
| TRV120026 | Sar-Arg-Val-Tyr-Tyr-His-Pro-NH2 | 0.20 ± 0.02 | 1.6 | −0.45 ± 0.06 | 0.08 ± 0.01 | 1.26 ± 0.08 | 18.1 | −2.90 ± 0.19 | 0.52 ± 0.03 |
| TRV120034 | N-Methyl-l-Ala-Arg-Val-Tyr-Ile-His-Pro-Ala | 0.35 ± 0.08 | 2.3 | −0.81 ± 0.19 | 0.14 ± 0.03 | 1.11 ± 0.04 | 13.0 | −2.56 ± 0.10 | 0.43 ± 0.02 |
| TRV120044 | N-Methyl-l-Ala-Arg-Val-Tyr-Ile-His-Pro-d-Ala | 0.17 ± 0.06 | 1.5 | −0.40 ± 0.13 | 0.07 ± 0.02 | 1.11 ± 0.16 | 12.8 | −2.55 ± 0.36 | 0.43 ± 0.09 |
| TRV120045f | N-Methyl-d-Ala-Arg-Val-Tyr-Ile-His-Pro-Ala | 0.54 ± 0.11 | 3.5 | −1.24 ±0.25 | 0.19 ± 0.03 | 1.09 ± 0.08 | 12.3 | −2.51 ± 0.19 | 0.44 ± 0.04 |
| TRV120055 | Gly-Val-Tyr-Ile-His-Pro-Phe | 2.62 ± 0.02 | 412.7 | −6.02 ± 0.06 | 0.93 ± 0.03 | 1.51 ± 0.02 | 32.3 | −3.48 ± 0.06 | 0.57 ± 0.02 |
| TRV120056 | Asp-Arg-Gly-Val-Tyr-Ile-His-Pro-Phe | 2.59 ± 0.04 | 391.7 | −5.97 ± 0.10 | 0.91 ± 0.03 | 1.35 ± 0.09 | 22.3 | −3.10 ± 0.20 | 0.54 ± 0.04 |
| Telmisartane | −0.02 ± 0.05 | 1.0 | 0.04 ± 0.10 | 0.00 ± 0.01 | −0.12 ± 0.01 | 0.8 | 0.28 ± 0.01 | −0.04 ± 0.00 | |
a Peptide sequences are corrected from a previous report (17).
b Molecular efficacies for activating Gq(αGq) and βarr2(αβarr2) in vitro. Calculated from KLo/KHi affinity shifts at AT1R-Gq and AT1R-βarr2 fusion proteins, respectively (see “Experimental Procedures”).
c Difference of free-energy changes expressed as RT units. Provides overall physical measure of ligand molecular efficacy for activating Gq and βarr2 (see “Experimental Procedures”).
d The area bounded by unfused and transducer-fused curves. Provides a model-free quantification of ligand molecular efficacy for activating Gq and βarr2 (see “Experimental Procedures”).
e Small differences between log αGq and logαβarr2 were significantly different according to two-way ANOVA and Bonferroni post-tests, p < 0.05. The antagonist telmisartan failed to reach statistical significance by the same test; p > 0.05.
f The bias factors of both TRV120045 and SII were significantly different from that of the antagonist telmisartan which lacked molecular efficacy at either transducer (p < 0.05 by one-way ANOVA and Tukey-Kramer post-tests). By this criterion, AngII is balanced (p > 0.05 by one-way ANOVA and Tukey-Kramer post-tests).