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. 1995 Sep;116(2):1875–1881. doi: 10.1111/j.1476-5381.1995.tb16676.x

Pharmacological modulation of adrenal medullary GABAA receptor: consistent with its subunit composition.

M Parramón 1, M P González 1, M J Oset-Gasque 1
PMCID: PMC1909111  PMID: 8528573

Abstract

1. Muscimol, the specific GABAA receptor agonist, increased the secretion of catecholamines by chromaffin cells with an EC50 of 2.9 +/- 0.4 microM. 2. GABAA receptors of these cells were modulated by the same drugs which modulate GABAA receptors in brain tissue. 3. Benzodiazepines enhanced muscimol-evoked catecholamine secretion by between 20 and 80%. This effect seems to be mediated by binding to a central type of benzodiazepine receptor because it was completely blocked by the specific antagonist, Ro 15 1788. This antagonist was able to displace [3H]-flunitrazepam binding with an EC50 of 0.26 +/- 0.05 nM. 4. beta-Carbolines weakly inhibited muscimol-induced catecholamine secretion and were able to displace [3H]-flunitrazepam binding with an EC50 between 0.2 and 0.9 nM, depending on the beta-carboline used. 5. Pregnanolone and related neuroactive steroids enhanced muscimol-evoked catecholamine secretion by up to 87%, in a dose-dependent fashion. In contrast pregnenolone weakly inhibited muscimol-evoked catecholamine secretion. 6. Zn2+ did not affect GABAA receptor-induced catecholamine secretion. 7. These pharmacological results are absolutely concordant with the theoretical properties given by the GABAA receptor subunit composition of bovine adrenal medulla -alpha 1, alpha 4, beta 1-3, gamma 2-previously characterized by Western blot analysis.

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Selected References

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  1. Bader M. F., Ciesielski-Treska J., Thierse D., Hesketh J. E., Aunis D. Immunocytochemical study of microtubules in chromaffin cells in culture and evidence that tubulin is not an integral protein of the chromaffin granule membrane. J Neurochem. 1981 Oct;37(4):917–933. doi: 10.1111/j.1471-4159.1981.tb04479.x. [DOI] [PubMed] [Google Scholar]
  2. Casalotti S. O., Stephenson F. A., Barnard E. A. Separate subunits for agonist and benzodiazepine binding in the gamma-aminobutyric acidA receptor oligomer. J Biol Chem. 1986 Nov 15;261(32):15013–15016. [PubMed] [Google Scholar]
  3. Castro E., Oset-Gasque M. J., Cañadas S., Gimenez G., González M. P. GABAA and GABAB sites in bovine adrenal medulla membranes. J Neurosci Res. 1988;20(2):241–245. doi: 10.1002/jnr.490200213. [DOI] [PubMed] [Google Scholar]
  4. Castro E., Oset-Gasque M. J., González M. P. GABAA and GABAB receptors are functionally active in the regulation of catecholamine secretion by bovine chromaffin cells. J Neurosci Res. 1989 Jul;23(3):290–296. doi: 10.1002/jnr.490230307. [DOI] [PubMed] [Google Scholar]
  5. Cottrell G. A., Lambert J. J., Peters J. A. Modulation of GABAA receptor activity by alphaxalone. Br J Pharmacol. 1987 Mar;90(3):491–500. doi: 10.1111/j.1476-5381.1987.tb11198.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Duggan M. J., Stephenson F. A. Benzodiazepine binding site heterogeneity in the purified GABAA receptor. Eur J Pharmacol. 1988 Sep 23;154(3):293–298. doi: 10.1016/0014-2999(88)90204-x. [DOI] [PubMed] [Google Scholar]
  7. Edgar P. P., Schwartz R. D. Functionally relevant gamma-aminobutyric acidA receptors: equivalence between receptor affinity (Kd) and potency (EC50)? Mol Pharmacol. 1992 Jun;41(6):1124–1129. [PubMed] [Google Scholar]
  8. Fiszman M. L., Novotny E. A., Lange G. D., Barker J. L. Embryonic and early postnatal hippocampal cells respond to nanomolar concentrations of muscimol. Brain Res Dev Brain Res. 1990 May 1;53(2):186–193. doi: 10.1016/0165-3806(90)90005-j. [DOI] [PubMed] [Google Scholar]
  9. Gonzalez M. P., Oset-Gasque M. J., Castro E., Bugeda J., Arce C., Parramon M. Mechanism through which GABAA receptor modulates catecholamine secretion from bovine chromaffin cells. Neuroscience. 1992;47(2):487–494. doi: 10.1016/0306-4522(92)90263-2. [DOI] [PubMed] [Google Scholar]
  10. Grigorenko E. V., Yeh H. H. Expression profiling of GABAA receptor beta-subunits in the rat retina. Vis Neurosci. 1994 Mar-Apr;11(2):379–387. doi: 10.1017/s0952523800001723. [DOI] [PubMed] [Google Scholar]
  11. Harrison N. L., Lambert N. A. Modification of GABAA receptor function by an analog of cyclic AMP. Neurosci Lett. 1989 Oct 23;105(1-2):137–142. doi: 10.1016/0304-3940(89)90025-6. [DOI] [PubMed] [Google Scholar]
  12. Kataoka Y., Gutman Y., Guidotti A., Panula P., Wroblewski J., Cosenza-Murphy D., Wu J. Y., Costa E. Intrinsic GABAergic system of adrenal chromaffin cells. Proc Natl Acad Sci U S A. 1984 May;81(10):3218–3222. doi: 10.1073/pnas.81.10.3218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kitayama S., Morita K., Dohi T., Tsujimoto A. Benzodiazepines facilitate the stimulatory action of gamma-aminobutyric acid (GABA) on basal and veratridine-evoked catecholamine release from cultured bovine adrenal chromaffin cells. Arch Int Pharmacodyn Ther. 1989 Jul-Aug;300:254–264. [PubMed] [Google Scholar]
  14. Leidenheimer N. J., Browning M. D., Harris R. A. GABAA receptor phosphorylation: multiple sites, actions and artifacts. Trends Pharmacol Sci. 1991 Mar;12(3):84–87. doi: 10.1016/0165-6147(91)90509-q. [DOI] [PubMed] [Google Scholar]
  15. Levitan E. S., Schofield P. R., Burt D. R., Rhee L. M., Wisden W., Köhler M., Fujita N., Rodriguez H. F., Stephenson A., Darlison M. G. Structural and functional basis for GABAA receptor heterogeneity. Nature. 1988 Sep 1;335(6185):76–79. doi: 10.1038/335076a0. [DOI] [PubMed] [Google Scholar]
  16. Lin L. H., Chen L. L., Zirrolli J. A., Harris R. A. General anesthetics potentiate gamma-aminobutyric acid actions on gamma-aminobutyric acidA receptors expressed by Xenopus oocytes: lack of involvement of intracellular calcium. J Pharmacol Exp Ther. 1992 Nov;263(2):569–578. [PubMed] [Google Scholar]
  17. Lüddens H., Wisden W. Function and pharmacology of multiple GABAA receptor subunits. Trends Pharmacol Sci. 1991 Feb;12(2):49–51. doi: 10.1016/0165-6147(91)90495-e. [DOI] [PubMed] [Google Scholar]
  18. McEwen B. S. Non-genomic and genomic effects of steroids on neural activity. Trends Pharmacol Sci. 1991 Apr;12(4):141–147. doi: 10.1016/0165-6147(91)90531-v. [DOI] [PubMed] [Google Scholar]
  19. Ohara-Imaizumi M., Nakazawa K., Obama T., Fujimori K., Takanaka A., Inoue K. Inhibitory action of peripheral-type benzodiazepines on dopamine release from PC12 pheochromocytoma cells. J Pharmacol Exp Ther. 1991 Nov;259(2):484–489. [PubMed] [Google Scholar]
  20. Oset-Gasque M. J., Parramón M., González M. P. GABAB receptors modulate catecholamine secretion in chromaffin cells by a mechanism involving cyclic AMP formation. Br J Pharmacol. 1993 Dec;110(4):1586–1592. doi: 10.1111/j.1476-5381.1993.tb14005.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Parramón M., Oset-Gasque M. J., Gonzalez M. P., Stephenson F. A. Identification of GABAA receptor subunits expressed in bovine adrenal medulla. Neurosci Lett. 1994 Feb 28;168(1-2):243–246. doi: 10.1016/0304-3940(94)90460-x. [DOI] [PubMed] [Google Scholar]
  22. Persohn E., Malherbe P., Richards J. G. Comparative molecular neuroanatomy of cloned GABAA receptor subunits in the rat CNS. J Comp Neurol. 1992 Dec 8;326(2):193–216. doi: 10.1002/cne.903260204. [DOI] [PubMed] [Google Scholar]
  23. Peters J. A., Kirkness E. F., Callachan H., Lambert J. J., Turner A. J. Modulation of the GABAA receptor by depressant barbiturates and pregnane steroids. Br J Pharmacol. 1988 Aug;94(4):1257–1269. doi: 10.1111/j.1476-5381.1988.tb11646.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Peters J. A., Lambert J. J., Cottrell G. A. An electrophysiological investigation of the characteristics and function of GABAA receptors on bovine adrenomedullary chromaffin cells. Pflugers Arch. 1989 Oct;415(1):95–103. doi: 10.1007/BF00373146. [DOI] [PubMed] [Google Scholar]
  25. Pritchett D. B., Sontheimer H., Shivers B. D., Ymer S., Kettenmann H., Schofield P. R., Seeburg P. H. Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature. 1989 Apr 13;338(6216):582–585. doi: 10.1038/338582a0. [DOI] [PubMed] [Google Scholar]
  26. Ruano D., Khan Z., De Blas A. L., Machado A., Vitorica J. Molecular heterogeneity of the type I GABAA/benzodiazepine receptor complex. Eur J Pharmacol. 1994 Mar 15;267(1):123–128. doi: 10.1016/0922-4106(94)90233-x. [DOI] [PubMed] [Google Scholar]
  27. Schofield P. R. The GABAA receptor: molecular biology reveals a complex picture. Trends Pharmacol Sci. 1989 Dec;10(12):476–478. doi: 10.1016/0165-6147(89)90041-2. [DOI] [PubMed] [Google Scholar]
  28. Sieghart W. GABAA receptors: ligand-gated Cl- ion channels modulated by multiple drug-binding sites. Trends Pharmacol Sci. 1992 Dec;13(12):446–450. doi: 10.1016/0165-6147(92)90142-s. [DOI] [PubMed] [Google Scholar]
  29. Sieghart W. Multiplicity of GABAA--benzodiazepine receptors. Trends Pharmacol Sci. 1989 Oct;10(10):407–411. doi: 10.1016/0165-6147(89)90189-2. [DOI] [PubMed] [Google Scholar]
  30. Sigel E., Baur R., Trube G., Möhler H., Malherbe P. The effect of subunit composition of rat brain GABAA receptors on channel function. Neuron. 1990 Nov;5(5):703–711. doi: 10.1016/0896-6273(90)90224-4. [DOI] [PubMed] [Google Scholar]
  31. Sigel E., Stephenson F. A., Mamalaki C., Barnard E. A. A gamma-aminobutyric acid/benzodiazepine receptor complex of bovine cerebral cortex. J Biol Chem. 1983 Jun 10;258(11):6965–6971. [PubMed] [Google Scholar]
  32. Smart T. G., Moss S. J., Xie X., Huganir R. L. GABAA receptors are differentially sensitive to zinc: dependence on subunit composition. Br J Pharmacol. 1991 Aug;103(4):1837–1839. doi: 10.1111/j.1476-5381.1991.tb12337.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Steiger A., Trachsel L., Guldner J., Hemmeter U., Rothe B., Rupprecht R., Vedder H., Holsboer F. Neurosteroid pregnenolone induces sleep-EEG changes in man compatible with inverse agonistic GABAA-receptor modulation. Brain Res. 1993 Jul 2;615(2):267–274. doi: 10.1016/0006-8993(93)90037-n. [DOI] [PubMed] [Google Scholar]
  34. Stephenson F. A., Watkins A. E., Olsen R. W. Physicochemical characterization of detergent-solubilized gamma-aminobutyric acid and benzodiazepine receptor proteins from bovine brain. Eur J Biochem. 1982 Apr 1;123(2):291–298. doi: 10.1111/j.1432-1033.1982.tb19766.x. [DOI] [PubMed] [Google Scholar]
  35. Tseng Y. T., Wellman S. E., Ho I. K. In situ hybridization evidence of differential modulation by pentobarbital of GABAA receptor alpha 1- and beta 3-subunit mRNAs. J Neurochem. 1994 Jul;63(1):301–309. doi: 10.1046/j.1471-4159.1994.63010301.x. [DOI] [PubMed] [Google Scholar]
  36. Verdoorn T. A., Draguhn A., Ymer S., Seeburg P. H., Sakmann B. Functional properties of recombinant rat GABAA receptors depend upon subunit composition. Neuron. 1990 Jun;4(6):919–928. doi: 10.1016/0896-6273(90)90145-6. [DOI] [PubMed] [Google Scholar]
  37. Verdoorn T. A. Formation of heteromeric gamma-aminobutyric acid type A receptors containing two different alpha subunits. Mol Pharmacol. 1994 Mar;45(3):475–480. [PubMed] [Google Scholar]
  38. Wafford K. A., Whiting P. J., Kemp J. A. Differences in affinity and efficacy of benzodiazepine receptor ligands at recombinant gamma-aminobutyric acidA receptor subtypes. Mol Pharmacol. 1993 Feb;43(2):240–244. [PubMed] [Google Scholar]
  39. Ymer S., Schofield P. R., Draguhn A., Werner P., Köhler M., Seeburg P. H. GABAA receptor beta subunit heterogeneity: functional expression of cloned cDNAs. EMBO J. 1989 Jun;8(6):1665–1670. doi: 10.1002/j.1460-2075.1989.tb03557.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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