Fig. 5: Signal bias of SSTR2 induced by octreotide and paltusotine.

a, b The effects of SSTR2 N276^6.55A mutation on cAMP inhibition (a) and β-arrestin recruitment (b) induced by octreotide. Data represent mean ± SEM from three independent experiments. c, d The effects of SSTR2 N276^6.55A mutation on cAMP inhibition (c) and β-arrestin recruitment (d) induced by paltusotine. Data represent mean ± SEM from three independent experiments. e, f The effects of SSTR2 F294^7.35A mutation on cAMP inhibition (e) and β-arrestin recruitment (f) induced by octreotide. Data represent mean ± SEM from three independent experiments. g, h The effects of SSTR2 F294^7.35A mutation on cAMP inhibition on cAMP inhibition (g) and β-arrestin recruitment (h) induced by paltusotine. Data represent mean ± SEM from three independent experiments. i, j Bias factors of the substitution of the microswitch residues in SSTR2 relative to wild-type induced by octreotide (i) and paltusotine (j). Statistical differences between wild-type and mutants were determined by one-way of variance ANOVA with Dunnett’s test. *P  < 0.033, **P < 0.02; ***P < 0.001; n.d., not detected. Octreotide (P = 0.022, 0.012, <0.001, 0.012, n.d., n.d., from top to bottom). Paltusotine (P = 0.002, <0.001, <0.001, n.d., n.d., n.d., from top to bottom). Data represent mean ± SEM from three independent experiments. k Residues that markedly affect β-arrestin signaling of SSTR2 are shown in sphere sticks. Residues involved in both octreotide- and paltusotine-induced arrestin recruitment are colored in light pink; residues mainly affect the octreotide-induced β-arrestin recruitment are colored in cyan; residues mainly affect the paltusotine-induced β-arrestin recruitment are colored in lime green; residues that mainly affect Gi protein signaling are colored in bright orange.