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Published on: August 16, 2018
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Amylin receptor subunit interactions are modulated by agonists and determine signaling
Sandra E Gostynska1, Jordan A Karim1, Bailee E Ford1
1Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK. 73104. USA.
Biorxiv : the Preprint Server for Biology
|October 17, 2024
Summary
Amylin receptors (AMYRs) are crucial for metabolic regulation. This study reveals how AMYR subunit interactions dynamically change with agonists, impacting cAMP signaling and offering new therapeutic targets for diabetes and obesity.
Area of Science:
- Biochemistry
- Molecular Pharmacology
- Endocrinology
Background:
- Three amylin receptors (AMYRs) mediate the metabolic actions of amylin, a peptide hormone.
- AMYRs are heterodimers of calcitonin receptor (CTR) and RAMP1, RAMP2, or RAMP3, influencing amylin potency.
- Understanding AMYR subunit interactions is key to their role in signaling.
Purpose of the Study:
- To investigate the distinct basal subunit equilibriums of AMYRs.
- To determine how peptide agonists modulate these equilibriums and affect cAMP signaling.
- To elucidate the role of subunit interaction dynamics in heteromeric G protein-coupled receptor (GPCR) signaling.
Main Methods:
- Development of a novel biochemical assay to resolve AMYR heterodimers and free subunits.
- Analysis of subunit association and dissociation in response to various peptide agonists (rat amylin, αCGRP, human and salmon calcitonin).
- Assessment of changes in live cell membranes, G protein coupling, and cAMP signaling.
Main Results:
- AMY1R and AMY2R equilibriums favored free CTR and RAMP1/2, with agonists promoting association.
- AMY3R exhibited a more stable CTR-RAMP3 interface, with agonists promoting dissociation.
- Agonist-induced changes in subunit association correlated with altered G protein coupling and cAMP signaling phenotypes.
Conclusions:
- AMYR basal subunit equilibriums are distinct and modulated by agonists.
- Subunit interaction dynamics directly influence AMYR signaling outcomes.
- These findings reveal a novel mechanism for regulating heteromeric GPCR signaling through subunit interplay.
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