Molecular Pharmacology, Vol 18, 199-209, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

-Adrenergic-Sensitive Adenylate Cyclase in Choroid Plexus: Properties and Cellular Localization

¹ Departments of Neurology and Pharmacology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114

Because of physiological evidence suggesting the possibility of adrenergic regulation of choroid plexus secretion, a detailed study was undertaken to identify, characterize, and localize -adrenergic-stimulated adenylate cyclase in broken cell preparations of cat choroid plexus. The enzyme was GTP (EC₅₀ = 2 x 10^-6 M)-but not calcium-dependent and was activated by low concentrations of isoproterenol (K_a = 1.4 x 10^-7 M). Isoproterenol, in the presence of Mg²⁺, increased the maximal reaction velocity without altering the K_m for ATP. The optimal ratio of added Mg²⁺/ATP was 4-8/1. Mn²⁺ and, to a lesser extent, Co²⁺ (but not Cu²⁺) could also support enzyme activity. Among receptor agonists, isoproterenol was most potent, followed in order by epinephrine (K_a = 1.6 x l0^-6 M), norepinephrine (K_a = 2.5 x 10^-5 M), phenylephrine (K_a > 2.5 x l0^-5 M), and dopamine (K_a = 2 x 10^-4 M). Isoproterenol activation was blocked by low concentrations of (±)-propranolol (K_i = 2.7 x 10^-9 M) but only by higher concentrations of (+)-propranolol (K_i = 3 x 10^-6 M), fluphenazine (K_i = 1.2 x 10^-7 M), or phentolamine (K_i > l0^-3 M). Among the more selective -adrenergic agents, the relatively ₂-selective agonists, zinterol (K_a = 2.3 x 10^-8 M) and OPC 2009 (K_a = 1.3 x 10^-7 M), were much more potent and effective than the ₁-selective agonist, prenalterol. Salbutamol, terbutaline, and orciprenaline were of intermediate potency and, along with zinterol, acted as partial agonists. Among several antagonists (IPS 339, H35/25, butoxamine, metoprolol, p-oxyprenolol, atenolol, and practolol), the calculated inhibitory constants correlated well with those obtained for the same agents in blocking isoproterenol-stimulated adenylate cyclase and IHYP binding in lung. Both agonist and antagonist data indicated that the majority of the adenylate cyclase-associated receptors in choroid plexus were ₂. Anatomical studies indicated that -adrenergic-sensitive adenylate cyclase activity was greater in fourth ventricle than lateral ventricle choroid plexus. Cell separation experiments, utilizing several different procedures, consistently demonstrated substantial enrichment of hormone sensitivity in fractions enriched in epithelial as compared with vascular elements. The results suggest a possible ₂-adrenergic regulation of choroid plexus secretory epithelium.

Note:
ACKNOWLEDGMENT I thank E. J. Hunnicutt, Jr., for expert technical assistance.

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