Adenosine modulates neurotransmission through inhibitory adenosine A ₁ receptors (A ₁ Rs) and stimulatory A _2A receptors (A _2A Rs). These G protein-coupled receptors are involved in motor function and related to neurodegenerative diseases such as Parkinson’s disease (PD). An autosomal-recessive mutation (G279 ^7.44 S) within the transmembrane helix (TM) 7 of A ₁ R (A ₁ R ^G279S ) has been associated with the development of early onset PD (EOPD). Here, we aimed at investigating the impact of this mutation on the structure and function of the A ₁ R and the A ₁ R-A _2A R heteromer. Our results revealed that the G279 ^7.44 S mutation does not alter A ₁ R expression, ligand binding, constitutive activity or coupling to transducer proteins (G _αi , G _αq , G _α12/13 , G _αs , β-arrestin2 and GRK2) in transfected HEK-293 T cells. However, A ₁ R ^G279S weakened the ability of A ₁ R to heteromerize with A _2A R, as shown in a NanoBiT assay, which led to the disappearance of the heteromerization-dependent negative allosteric modulation that A ₁ R imposes on the constitutive activity and agonist-induced activation of the A _2A R. Molecular dynamic simulations allowed to propose an indirect mechanism by which the G279 ^7.44 S mutation in TM 7 of A ₁ R weakens the TM 5/6 interface of the A ₁ R-A _2A R heteromer. Therefore, it is demonstrated that a PD linked ADORA1 mutation is associated with dysfunction of adenosine receptor heteromerization. We postulate that a hyperglutamatergic state secondary to increased constitutive activity and sensitivity to adenosine of A _2A R not forming heteromers with A ₁ R could represent a main pathogenetic mechanism of the EOPD associated with the G279 ^7.44 S ADORA1 mutation.