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Structure of alpha6 beta3 delta GABA(A) receptors and their lack of ethanol sensitivity.

  • Baur R Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
  • Kaur KH
  • Sigel E
  • 2009-09-22
Published in:
  • Journal of neurochemistry. - 2009
Animals
Anti-Anxiety Agents
Biophysical Phenomena
Central Nervous System Depressants
Desoxycorticosterone
Dose-Response Relationship, Drug
Drug Interactions
Electric Stimulation
Ethanol
GABA Agonists
Isoxazoles
Membrane Potentials
Oocytes
Patch-Clamp Techniques
Protein Subunits
Receptors, GABA-A
Transfection
Xenopus
gamma-Aminobutyric Acid
English Delta (delta) subunit containing GABA(A) receptors are expressed extra-synaptically and mediate tonic inhibition. In cerebellar granule cells, they often form a receptor together with alpha(6) subunits. We were interested to determine the architecture of these receptors. We predefined the subunit arrangement of 24 different GABA(A) receptor pentamers by subunit concatenation. These receptors (composed of alpha(6), beta(3) and delta subunits) were expressed in Xenopus oocytes and their electrophysiological properties analyzed. Currents elicited in response to GABA were determined in presence and absence of 3alpha, 21-dihydroxy-5alpha-pregnan-20-one and to 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol. alpha(6)-beta(3)-alpha(6)/delta receptors showed a substantial response to GABA alone. Three receptors, beta(3)-alpha(6)-delta/alpha(6)-beta(3), alpha(6)-beta(3)-alpha(6)/beta(3)-delta and beta(3)-delta-beta(3)/alpha(6)-beta(3), were only uncovered in the combined presence of the neurosteroid 3alpha, 21-dihydroxy-5alpha-pregnan-20-one with GABA. All four receptors were activated by 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol. None of the functional receptors was modulated by physiological concentrations (up to 30 mM) of ethanol. GABA concentration response curves indicated that the delta subunit can contribute to the formation of an agonist site. We conclude from the investigated receptors that the delta subunit can assume multiple positions in a receptor pentamer composed of alpha(6), beta(3) and delta subunits.
Language
  • English
Open access status
bronze
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https://sonar.ch/global/documents/1233
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