Major differences in CNS sulfonylurea receptor distribution between the rat (newborn, adult) and turtle.
Our previous results have shown that KATP channels play an important role in K+ efflux and extracellular K+ accumulation in the rat brain, and this role was quantitatively more important in the adult than in the newborn brain. The purpose of this study was to localize by autoradiographic techniques the binding sites of glibenclamide, a potent sulfonylurea ligand that targets KATP channels, in the adult and newborn rat central nervous system (CNS). Since the adult turtle is resistant to anoxia, we also compared the rat to the turtle brain sulfonylurea receptor distribution. In all three animal groups (newborn rat, adult rat, adult turtle), specific glibenclamide binding was saturable. Scatchard plots were curvilinear in the rat, thus suggesting that glibenclamide binds to two types of sites, i.e., high and low affinity sites. Scatchard analysis on turtle brain tissue showed evidence of one binding site only. We also found that the distribution of glibenclamide binding sites was heterogeneous in the adult rat CNS with a higher density in rostral than in caudal regions. The highest binding densities were seen in the cortex, hippocampus, cerebellum, substantia nigra, and a few thalamic nuclei; intermediate densities were observed in the basal ganglia, septum, thalamus, and the hypoglossal nucleus. There was a low density in most areas of the hypothalamus, midbrain, brainstem, and spinal cord. Compared with the adult rat, the newborn had a very homogeneous distribution of binding sites and densities were very low throughout the CNS; the level of binding density was even lower in some regions undetectable in the adult turtle. Our results indicate that (1) there are high and low affinity sulfonylurea receptors in the rat CNS, (2) there is a striking heterogeneity in the distribution and density of sulfonylurea receptors in the adult rat CNS and this is in sharp contrast to the homogeneous distribution and low density in both newborn rat and adult turtle; (3) sulfonylurea receptors increase in number postnatally in the rat since binding density increases and the Kd in the newborn rat is similar to that in the adult rat. We speculate that KATP channels and sulfonylurea receptors are poorly developed in the turtle and develop mostly after birth in the rat, reaching highest density in adulthood.
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Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06510.
Haddad
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D018528:ATP-Binding Cassette Transporters; D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D001345:Autoradiography; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D005905:Glyburide / Q000378:metabolism*; D007700:Kinetics; D009928:Organ Specificity; D010802:Phylogeny; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D011919:Rats, Inbred Strains / Q000378:metabolism*; D011955:Receptors, Drug / Q000032:analysis / Q000378:metabolism*; D013116:Spinal Cord / Q000254:growth & development / Q000378:metabolism*; D064233:Sulfonylurea Receptors; D014316:Tritium; D014426:Turtles / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014316:Tritium; D005905:Glyburide