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Cancer-Related Somatic Mutations in Transmembrane Helices Alter Adenosine A1 Receptor Pharmacology
Xuesong Wang1, Willem Jespers1, Kim A N Wolff1
1Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
Abstract:
Overexpression of the adenosine A1 receptor (A1AR) has been detected in various cancer cell lines. However, the role of A1AR in tumor development is still unclear. Thirteen A1AR mutations were identified in the Cancer Genome Atlas from cancer patient samples. We have investigated the pharmacology of the mutations located at the 7-transmembrane domain using a yeast system. Concentration-growth curves were obtained with the full agonist CPA and compared to the wild type hA1AR. H78L3.23 and S246T6.47 showed increased constitutive activity, while only the constitutive activity of S246T6.47 could be reduced to wild type levels by the inverse agonist DPCPX. Decreased constitutive activity was observed on five mutant receptors, among which A52V2.47 and W188C5.46 showed a diminished potency for CPA. Lastly, a complete loss of activation was observed in five mutant receptors. A selection of mutations was also investigated in a mammalian system, showing comparable effects on receptor activation as in the yeast system, except for residues pointing toward the membrane. Taken together, this study will enrich the view of the receptor structure and function of A1AR, enlightening the consequences of these mutations in cancer. Ultimately, this may provide an opportunity for precision medicine for cancer patients with pathological phenotypes involving these mutations.
Insights
Adenosine A1 receptor (A1AR) mutations found in cancer impact its function. This study characterizes these mutations, offering insights for precision cancer medicine.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Adenosine A1 receptor (A1AR) overexpression is observed in cancer cells, but its role in tumor development remains unclear.
- Thirteen A1AR mutations were identified in The Cancer Genome Atlas (TCGA) database from patient samples.
- Understanding A1AR mutation effects is crucial for cancer research.
Purpose of the Study:
- To investigate the pharmacological effects of A1AR mutations located in the 7-transmembrane domain.
- To compare the function of mutant A1ARs to the wild-type receptor.
- To elucidate the impact of A1AR mutations on cancer development and explore potential therapeutic strategies.
Main Methods:
- Utilized a yeast expression system to study A1AR mutations.
- Performed concentration-growth curve assays with the agonist CPA.
- Investigated receptor activity in a mammalian system for selected mutations.
Main Results:
- H78L3.23 and S246T6.47 mutations exhibited increased constitutive activity.
- S246T6.47 constitutive activity was normalized by the inverse agonist DPCPX.
- Five mutants showed decreased constitutive activity, with A52V2.47 and W188C5.46 displaying reduced CPA potency.
- Five mutants demonstrated a complete loss of activation.
- Mammalian system results largely corroborated yeast system findings, with exceptions for membrane-facing residues.
Conclusions:
- Characterized the functional impact of various A1AR mutations, revealing altered constitutive activity and agonist responsiveness.
- Demonstrated the utility of yeast and mammalian systems for studying GPCR mutations.
- Findings contribute to understanding A1AR structure-function relationships and their implications in cancer, potentially paving the way for precision medicine approaches.
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