The N-terminal acidic residue of the cytosolic helix 8 of an odorant receptor is responsible for different response dynamics via G-protein

•Residues responsible for improved Ca2+ response dynamics by Gα15_olf are unknown.•We analyzed Ca2+ responses of mutated mOR-S6 helix 8 and created a homology model.•The N-terminal hydrophobic core of helix 8/TM1−2 is important for Gα activation.•Mutations of the second residue of helix 8 eliminated different response dynamics.•The second and fifth residues are responsible for improved responses by Gα15_olf. We previously observed highly rapid and robust response of murine olfactory receptor S6 (mOR-S6) with chimeric Gα15_olf, compared to Gα15. To identify residues responsible for this difference in response, mutations of the cytosolic helix 8 were analyzed in a heterologous functional expression system. The N-terminal hydrophobic core between helix 8 and TM1–2 of mOR-S6 is important for activation of both Gα15_olf and Gα15. Point mutation of a helix 8 N-terminal acidic residue eliminated the differences in response dynamics via Gα. This result suggests that an N-terminal acidic residue of helix 8 is responsible for rapid response via Gα15_olf.