Adenosine modulates neurotransmission through inhibitory adenosine A₁ receptors (A₁Rs) and stimulatory A_2A receptors (A_2ARs). 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 (G279^7.44S) within the transmembrane helix (TM) 7 of A₁R (A₁R^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 A₁R and the A₁R-A_2AR heteromer. Our results revealed that the G279^7.44S mutation does not alter A₁R 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, A₁R^G279S weakened the ability of A₁R to heteromerize with A_2AR, as shown in a NanoBiT assay, which led to the disappearance of the heteromerization-dependent negative allosteric modulation that A₁R imposes on the constitutive activity and agonist-induced activation of the A_2AR. Molecular dynamic simulations allowed to propose an indirect mechanism by which the G279^7.44S mutation in TM 7 of A₁R weakens the TM 5/6 interface of the A₁R-A_2AR 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_2AR not forming heteromers with A₁R could represent a main pathogenetic mechanism of the EOPD associated with the G279^7.44S ADORA1 mutation.