4.5 Article

Functional Impact of the G279S Substitution in the Adenosine A1-Receptor (A1R-G279S7.44), a Mutation Associated with Parkinson's Disease

期刊

MOLECULAR PHARMACOLOGY
卷 98, 期 3, 页码 250-266

出版社

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/molpharm.120.000003

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资金

  1. doctoral program Cell Communication in Health and Disease
  2. Austrian Science Fund/FWF [W1205]
  3. Medical University of Vienna
  4. Austrian Science Fund (FWF) [W1205] Funding Source: Austrian Science Fund (FWF)

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In medium-size, spiny striatal neurons of the direct pathway, dopamine and adenosine A(1)-receptors are coexpressed and are mutually antagonistic. Recently, a mutation in the gene encoding the A(1)-receptor (A(1)R), A(1)R-G279S(7.44), was identified in an Iranian family: two affected offspring suffered from early-onset L-DOPA-responsive Parkinson's disease. The link between the mutation and the phenotype is unclear. Here, we explored the functional consequence of the G279S substitution on the activity of the A(1)-receptor after heterologous expression in HEK293 cells. The mutation did not affect surface expression and ligand binding but changed the susceptibility to heat denaturation: the thermodynamic stability of A(1)R-G279S(7.44) was enhanced by about 2 and 8 K when compared with wildtype A(1-)receptor and A(1)R-Y288A(7.53) (a folding-deficient variant used as a reference), respectively. In contrast, the kinetic stability was reduced, indicating a lower energy barrier for conformational transitions in A(1)R-G279S(7.44) (73 +/- 23 kJ/mol) than in wild-type A(1)R (135 +/- 4 kJ/mol) or in A(1)R-Y288A(7.53) (184 +/- 24 kJ/mol). Consistent with this lower energy barrier, A(1)R-G279S(7.44) was more effective in promoting guanine nucleotide exchange than wild-type A(1)R. We detected similar levels of complexes formed between D-1-receptors and wild-type A(1)R or A(1)R-G279S(7.44) by coimmunoprecipitation and bioluminescence resonance energy transfer. However, lower concentrations of agonist were required for half-maximum inhibition of dopamine-induced cAMP accumulation in cells coexpressing D-1-receptor and A(1)R-G279S(7.44) than in those coexpressing wild-type A(1)R. These observations predict enhanced inhibition of dopaminergic signaling by A(1)R-G279S(7.44) in vivo, consistent with a pathogenic role in Parkinson's disease. SIGNIFICANCE STATEMENT Parkinson's disease is caused by a loss of dopaminergic input from the substantia nigra to the caudate nucleus and the putamen. Activation of the adenosine A(1)-receptor antagonizes responses elicited by dopamine D-1-receptor. We show that this activity is more pronounced in a mutant version of the A(1)-receptor (A(1)R-G279S(7.44)), which was identified in individuals suffering from early-onset Parkinson's disease.

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