Non Animal Testing Database

Effect of adenosine A1 receptor mutation in Parkinson´s disease studied in human cells

October 2022
National Institutes of Health, Baltimore, USA(1)
Universitat Autònoma Barcelona, Barcelona, Spain(2)
University of Barcelona, L’Hospitalet de Llobregat, Spain(3)
An autosomal-recessive mutation within the adenosine A1 receptor (A1R) is associated with the development of early-onset Parkinson’s disease. In this study, the impact of this mutation on the structure and function of A1R and its heteromerization with the adenosine A2A receptor (A2AR) was investigated. Human embryonic kidney (HEK) cells were transfected with A1R (wild type and mutated receptor), as well as with human A2AR. It was shown, that the mutation does not alter A1R expression, ligand binding, constitutive activity or coupling to transducer proteins. However, the mutation weakened the ability of A1R to heteromerize with A2AR, which led to the disappearance of the heteromerization-dependent negative modulation that A1R imposes on the activity of A2AR. Molecular dynamic simulations allowed the researchers to propose an indirect mechanism by which the mutation weakens the interface of the A1R-A2AR heteromer. Therefore, it is demonstrated that the mutation is associated with dysfunction of adenosine receptor heteromerization, which can represent a novel target for the treatment of early-onset Parkinson’s disease.
The ADORA1 mutation linked to early-onset Parkinson’s disease alters adenosine A1-A2A receptor heteromer formation and function
Sergi Ferré(1), Leonardo Pardo(2), Francisco Ciruela(3)
Added on: 11-15-2022
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