The effect of cancer-associated mutations on ligand binding and receptor function - A case for the 5-HT_2C receptor

Area of Science:

• Pharmacology
• Molecular Biology
• Oncology

Background:

• The serotonin 5-HT_2C receptor, a G protein-coupled receptor (GPCR), is primarily found in the central nervous system.
• It plays roles in mood, appetite, and reproduction, and is a potential target for cancer therapy.
• Cancer-associated mutations in this receptor may affect its normal function and response to drugs.

Purpose of the Study:

• To investigate how patient-derived mutations in the serotonin 5-HT_2C receptor affect its binding to ligands and its overall functionality.
• To analyze the impact of specific mutations on receptor activity and signaling pathways relevant to cancer.

Main Methods:

• Filtered sequencing data from the Genomic Data Commons (GDC) to identify 12 relevant 5-HT_2C receptor mutations from various cancer types.
• Assessed ligand binding affinity for serotonin (5-HT) and mesulergine using mutation analysis.
• Utilized calcium-flux assays to evaluate receptor functionality and potency changes.

Main Results:

• Mutations L209H^ECL2 and F328S^6.52 in the binding pocket significantly reduced the affinity for serotonin and mesulergine.
• The F328S^6.52 mutation decreased serotonin potency while potentially increasing efficacy; E306K^6.30 and E306A^6.30 mutations increased serotonin affinity but decreased efficacy, possibly by disrupting ionic interactions.
• Mutation P365H^7.50 drastically reduced receptor expression, hindering further analysis.

Conclusions:

• Cancer-associated mutations in the serotonin 5-HT_2C receptor exhibit varied effects on ligand binding and receptor function.
• These mutations can alter serotonin signaling in tumor cells and influence the effectiveness of targeted cancer therapies.
• Understanding these mutation-specific effects is crucial for developing effective therapeutic strategies.