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Activity-restoring mutations in the histamine H3 receptor increase constitutive activity and reduce structural
Ami Nakajima1, Hiroto Kaneko1, Kosuke Oyama1
1Department of Biological Science and Technology, Tokyo University of Science, Tokyo, Japan.
Protein Science : a Publication of the Protein Society
|December 22, 2025
Summary
Specific mutations enhance constitutive activity of the histamine H3 receptor (H3R) by destabilizing its structure. These findings reveal a link between structural instability and GPCR activation.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- The histamine H3 receptor (H3R), a G protein-coupled receptor (GPCR), regulates neurotransmitter release.
- Understanding the functional roles of specific residues in H3R activation is crucial.
- Previous studies identified mutations restoring yeast signaling, but their mechanism remained unclear.
Purpose of the Study:
- To investigate the functional roles of specific H3R residues.
- To elucidate the mechanism by which identified mutations enhance receptor activity.
- To explore the relationship between structural stability and constitutive activation in H3R.
Main Methods:
- Site-directed mutagenesis of H3R and H1R.
- Functional assays in yeast and mammalian cells.
- Radioligand binding assays and Fast-label Free-field ElectroChemical Scanning (FSEC) analyses.
Main Results:
- Identified mutations (L73M, F193S, S359Y, C415R) enhance constitutive activity of H3R.
- Mutations act cooperatively to shift the conformational equilibrium toward the active state.
- Increased constitutive activity correlates with reduced structural stability and minimal changes in histamine affinity.
Conclusions:
- Structural destabilization is closely linked to constitutive activation of H3R.
- The functional consequences of these mutations are receptor-dependent.
- GPCR activation is a complex process involving conformational modulation and structural stability.
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