CHRONIC EXPOSURE TO ADENOSINE RECEPTOR AGONISTS AND ANTAGONISTS RECIPROCALLY REGULATES THE A(1) ADENOSINE RECEPTOR-ADENYLYL CYCLASE SYSTEM IN CEREBELLAR GRANULE CELLS

Chronic treatment with the adenosine receptor antagonist caffeine evok es an up-regulation of A(1) adenosine receptors and increased coupling of the receptor to G proteins in rat brain membranes. However, chroni c agonist exposure has not been explored. Primary cultures of cerebell ar granule cells were exposed chronically to A(1) adenosine receptor a gonists and antagonists. Exposure to the A(1) adenosine receptor agoni st N-6-cyclopentyladenosine resulted in (1) a time- and concentration- dependent reduction in the density of receptors labeled by 1,3-[H-3]di propyl-8-cyclopentylxanthine, (2) an enhanced ability of guanyl nucleo tides to decrease the fraction of A(1) adenosine receptor sites displa ying high affinity for 2-chloroadenosine, and (3) a functional uncoupl ing of receptors from adenylyl cyclase (EC 4.6.1.1). The adenosine ant agonists caffeine and 8-p-sulfophenyltheophylline produced alterations in A(1) adenosine receptor homeostasis that were antipodal to those a ssociated with agonist treatment. Antagonist exposure (1) increased th e density of A(1) adenosine receptors in cerebellar granule cell membr anes, (2) blunted the effect of guanyl nucleotides on receptor couplin g to G proteins, and (3) increased the functional coupling of receptor s to adenylyl cyclase inhibition. Forskolin treatment of cerebellar gr anule cells did not affect receptor density, suggesting that cyclic AM P is not involved in the regulation of A(1) adenosine receptor express ion.