What question did this study set out to answer?

This research examines how different variants of RIC8B influence olfactory receptor responses through cAMP production.

February 12, 2026

Structural and Functional Analysis of RIC8B Variants Regulating Olfactory Receptor Responses

Key Points

This research examines how different variants of RIC8B influence olfactory receptor responses through cAMP production.
Evaluated five RIC8B variants for their chaperone activity.
Co-expressed variants with olfactory receptors in HEK293T cells.
Measured odorant-induced cAMP production as a functional readout.
Utilized AlphaFold3 for complex structure prediction of variants with Gαs.
Variant 4 consistently suppressed cAMP responses in olfactory receptors.
Variant 1 established hydrogen bonds with Gαs via its Cradle Loop Helix.
Variant 4's lack of the Cradle Loop Helix may prevent stable binding with Gαs.

Abstract

Abstract Resistance to inhibitors of cholinesterase 8B (RIC8B) functions as a chaperone and guanine nucleotide exchange factor for Gαs/olf. We focused on RIC8B variant 1 (v1), which is abundantly expressed at the mRNA level, and variant 4 (v4), which lacks the C-terminal Cradle Loop Helix (CLH) domain. Together with three closely related variants (v2, v3, and v10), we evaluated five variants for chaperone activity. HEK293T cells were co-expressed with olfactory receptors (ORs), and odorant-induced cAMP production was used as a functional readout. Among the variants tested, only v4 consistently suppressed cAMP responses. AlphaFold3-based complex structure prediction indicated that v1 forms multiple hydrogen bonds with Gαs via its CLH domain, whereas v4 failed to establish these interactions. This suggests that v4 may be unable to stably adopt the proper binding conformation with Gαs, potentially resulting in improperly folded Gαs that exert a dominant-negative effect on OR responses.

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