A₁ and A₃ adenosine receptors alter glutathione status in an organ-specific manner and influence the changes after inhibition of γ-glutamylcysteine ligase

Abstract

Adenosine levels are increased in stress and act as anti-oxidant and anti-inflammatory mediators by binding to 4 G-protein-coupled receptors. Using genetically modified mice lacking A₁ and A₃ adenosine receptors, treated with ip buthionine-[S,R]-sulphoximine injections to inhibit γ-glutamylcysteine ligase, the question was addressed whether these receptors modulate the responses to the stress related to altered glutathione levels. This study determined organ glutathione levels and expression of two sub-units of γ-glutamylcysteine ligase and the cationic x_c-transporter and found that deletion of one or both adenosine receptors influenced the responses in an organ-specific manner. The lack of A₁ and A₃ adenosine receptors is related to decreased basal glutathione content and down-regulation of γ-glutamylcysteine ligase sub-units in several organs. Moreover, responses to buthionine-[S,R]-sulphoximine were different. For example, the lack of A₃ adenosine receptors, or their blockade of A₃ by MRS 1191, caused a marked increase in gene expression, which was not observed in mice lacking both A₁ and A₃ receptors. The results indicate that A₁ and A₃ adenosine receptors play a role in antioxidant responses and their role differs in an organ-specific way.

• A1/A3/A1A3 knockout mice
• organ GSH levels
• γ-glutamylcysteine ligase catalytic/modulator sub-units
• x_c⁻ cysstine transport system
• Nrf2