Roles of adenosine A(1) receptors in the regulation of SFK activity in the rat forebrain

Adenosine A(1) receptors are widely expressed in the mammalian brain. Through interacting with G(αi/o)‐coupled A(1) receptors, the neuromodulator adenosine modulates a variety of cellular and synaptic activities. To determine the linkage from A(1) receptors to a key intracellular signaling pathway, we investigated the impact of blocking A(1) receptors on a subfamily of nonreceptor tyrosine kinases, that is, the Src family kinase (SFK), in different rat brain regions in vivo. We found that pharmacological blockade of A(1) receptors by a single systemic injection of the A(1) selective antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX) induced an increase in autophosphorylation of SFKs at a consensus activation site, tyrosine 416 (Y416), in the two subdivisions of the striatum, the caudate putamen and nucleus accumbens. DPCPX also increased SFK Y416 phosphorylation in the medial prefrontal cortex (mPFC) but not the hippocampus. The DPCPX‐induced Y416 phosphorylation was time dependent and reversible. In immunopurified Fyn and Src proteins from the striatum, DPCPX elevated SFK Y416 phosphorylation and tyrosine kinase activity in Fyn but not in Src proteins. In the mPFC, DPCPX enhanced Y416 phosphorylation and tyrosine kinase activity in both Fyn and Src immunoprecipitates. DPCPX had no effect on expression of total Fyn and Src proteins in the striatum, mPFC, and hippocampus. These results demonstrate a tonic inhibitory linkage from A(1) receptors to SFKs in the striatum and mPFC. Blocking this inhibitory tone could significantly enhance constitutive SFK Y416 phosphorylation in the rat brain in a region‐ and time‐dependent manner.