Agonist function of the recombinant alpha 4 beta 3 delta GABAA receptor is dependent on the human and rat variants of the alpha 4-subunit
2010 (English)In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 37, no 7, 662-669 p.Article in journal (Refereed) Published
1. It is known that the alpha(4)-subunit is likely to occur in the brain predominantly in alpha(4)beta(3)delta receptors at extrasynaptic sites. Recent studies have revealed that the alpha(1)-, alpha(4)-, gamma(2)- and delta-subunits may colocalize extrasynaptically in dentate granule cells of the hippocampus. In the present study, we characterized a series of recombinant GABA(A) receptors containing human (H) and rat (R) alpha(1)/alpha(4)-, beta(2)/beta(3)- and gamma(2S)/delta-subunits in Xenopus oocytes using the two-electrode voltage-clamp technique. 2. Both H alpha(1)beta(3)delta and H alpha(4)beta(3)gamma(2S) receptors were sensitive to activation by GABA and pentobarbital. Contrary to earlier findings that the alpha(4)beta(3)delta combination was more sensitive to agonist action than the alpha(4)beta(3)gamma(2S) receptor, we observed extremely small GABA- and pentobarbital-activated currents at the wild-type H alpha(4)beta(3)delta receptor. However, GABA and pentobarbital activated the wild-type R alpha(4)beta(3)delta receptor with high potency (EC(50) = 0.5 +/- 0.7 and 294 +/- 5 micromol/L, respectively). 3. Substituting the H alpha(4) subunit with R alpha(4) conferred a significant increase in activation on the GABA and pentobarbital site in terms of reduced EC(50) and increased I(max). When the H alpha(4) subunit was combined with the R beta(3) and R delta subunit in a heteropentameric form, the amplitude of GABA- and pentobarbital-activated currents increased significantly compared with the wild-type H alpha(4)beta(3)delta receptor. 4. Thus, the results indicate that the R alpha(4)beta(3)delta, H alpha(1)beta(3)delta and H alpha(4)beta(3)gamma(2S) combinations may contribute to functions of extrasynaptic GABA(A) receptors. The presence of the R alpha(4) subunit at recombinant GABA(A) receptors containing the delta-subunit is a strong determinant of agonist action. The recombinant H alpha(4)beta(3)delta receptor is a less sensitive subunit composition in terms of agonist activation.
Place, publisher, year, edition, pages
Blackwell Publishing, 2010. Vol. 37, no 7, 662-669 p.
α4-subunit, β3-subunit, δ-subunit, GABA, GABAA
Obstetrics, Gynecology and Reproductive Medicine
IdentifiersURN: urn:nbn:se:umu:diva-36800DOI: 10.1111/j.1440-1681.2010.05374.xISI: 000278917600004PubMedID: 20337660OAI: oai:DiVA.org:umu-36800DiVA: diva2:356367