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Cancer-related somatic mutations alter adenosine A1 receptor pharmacology-A focus on mutations in the loops and
Xuesong Wang1, Willem Jespers1, Just J de Waal1
1Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden, the Netherlands.
Abstract:
G protein-coupled receptors (GPCRs) are known to be involved in tumor progression and metastasis. The adenosine A1 receptor (A1 AR) has been detected to be over-expressed in various cancer cell lines. However, the role of A1 AR in tumor development is not yet well characterized. A series of A1 AR mutations were identified in the Cancer Genome Atlas from cancer patient samples. In this study, we have investigated the pharmacology of mutations located outside of the 7-transmembrane domain by using a "single-GPCR-one-G protein" yeast system. Concentration-growth curves were obtained with the full agonist CPA for 12 mutant receptors and compared to the wild-type hA1 AR. Most mutations located at the extracellular loops (EL) reduced the levels of constitutive activity of the receptor and agonist potency. For mutants at the intracellular loops (ILs) of the receptor, an increased constitutive activity was found for mutant receptor L211R5.69 , while a decreased constitutive activity and agonist response were found for mutant receptor L113F34.51 . Lastly, mutations identified on the C-terminus did not significantly influence the pharmacological function of the receptor. A selection of mutations was also investigated in a mammalian system. Overall, similar effects on receptor activation compared to the yeast system were found with mutations located at the EL, but some contradictory effects were observed for mutations located at the IL. Taken together, this study will enrich the insight of A1 AR structure and function, enlightening the consequences of these mutations in cancer. Ultimately, this may provide potential precision medicine in cancer treatment.
Insights
Investigating adenosine A1 receptor (A1 AR) mutations in cancer reveals how extracellular loop changes impact receptor activity. Intracellular loop mutations show varied effects, offering insights for precision cancer medicine.
Area of Science:
- Molecular Biology
- Pharmacology
- Oncology
Background:
- G protein-coupled receptors (GPCRs), including the adenosine A1 receptor (A1 AR), are implicated in cancer progression.
- A1 AR is over-expressed in various cancer cell lines, but its precise role in tumor development remains unclear.
- Cancer Genome Atlas data revealed A1 AR mutations in patient samples, necessitating functional characterization.
Purpose of the Study:
- To investigate the pharmacological impact of A1 AR mutations outside the 7-transmembrane domain.
- To understand how specific A1 AR mutations affect receptor activity and agonist response.
- To explore the potential of A1 AR mutations as targets for precision cancer therapy.
Main Methods:
- Utilized a "single-GPCR-one-G protein" yeast system to assess the pharmacology of 12 A1 AR mutants.
- Compared concentration-growth curves of mutant receptors with wild-type hA1 AR using the agonist CPA.
- Validated selected mutations in a mammalian system to confirm findings.
Main Results:
- Mutations in extracellular loops (EL) generally reduced constitutive activity and agonist potency.
- Intracellular loop (IL) mutants exhibited varied effects: L211R5.69 showed increased constitutive activity, while L113F34.51 displayed decreased activity and response.
- C-terminal mutations had minimal impact on A1 AR pharmacological function; yeast and mammalian system results largely agreed for EL mutations but showed discrepancies for IL mutations.
Conclusions:
- This study elucidates the structure-function relationship of A1 AR, detailing the consequences of specific mutations.
- Findings highlight how A1 AR mutations, particularly in EL and IL regions, modulate receptor activity.
- Understanding these mutations provides a basis for developing targeted precision medicine strategies for cancer treatment.
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