Molecular Pharmacology, Vol 16, 790-804, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Adenosine-Sensitive Adenylate Cyclase in Rat Brain Homogenates: Kinetic Characteristics, Specificity, Topographical, Subcellular and Cellular Distribution

¹ Laboratoire de Physiologie Cellulaire and Groupe NB, Institut National de la Santé et de la Recherche Médicale U 114 Collège de France, 75231 Paris, France

Two adenosine receptor sites have been detected in striatal homogenates. One triggered the stimulation and the other the inhibition of the adenylate cyclase. They clearly had different chemical specificity toward adenosine analogues. In particular, N6 derivatives of adenosine were full agonists on the stimulatory site and had no affinity for the inhibitory site. Adenosine stimulation of the adenylate cyclase in striatal homogenates had characteristics similar to those of other neurotransmitter-sensitive adenylate cyclases: 1— Adenosine increased the maximal reaction velocity of adenylate cyclase without altering the K_m (18 µM) for its substrate Mg-ATP. 2—Increasing the concentration of free Mg²⁺ increased the adenylate cyclase activity with characteristics suggesting the existence of an allosteric site for Mg²⁺ 3—Adenosine increased the apparent affinity of the Mg²⁺ allosteric site. 4—GTP was required in order to obtain optimal stimulation. 5—The highest total and specific adenosine-sensitive adenylate cyclase activities were observed in fractions enriched in nerve endings while the activity of this enzyme was very low in cytosol and myelin fractions. Adenosine-sensitive adenylate cyclase was found in homogenates of striatum, nucleus accumbens, globus pallidus, tuberculum olfactorium, olfactory bulb and posterior cerebellar cortex but not in homogenates of frontal and parietal cerebral cortex, anterior and central cerebellar cortex, substantia nigra, ventral tegmental area, hippocampus and hypothalamus. The topographical distribution of the adenosine sensitive adenylate cyclase was also heterogeneous within the stniatum. On the contrary the specific [³H]adenosine uptake was similar in brain areas whether or not they contained an adenosine-sensitive adenylate cyclase. The adenosine-sensitive adenylate cyclase did not disappear after a complete degeneration of presynaptic dopaminergic terminals. Furthermore, the near complete disappearance of the basal, dopamine and adenosine-sensitive adenylate cyclases, after kainic acid injection into striatum, indicated that these enzymes are not located on glial cells, axons or nerve terminals of extrinsic neurons but rather on neurons having their cell bodies within this structure.

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