Wafford K A, Thompson S A, Thomas D, Sikela J, Wilcox A S, Whiting P J
Merck Sharp & Dohme Research Laboratories, Harlow, Essex, UK.
Mol Pharmacol. 1996 Sep;50(3):670-8.
The alpha subunits are an important determinant of the pharmacology of gamma-aminobutyric acidA (GABAA) receptors with respect to agonists, antagonists, and modulatory compounds, particularly the benzodiazepines. The alpha 4 subunit is the least abundant subunit in the brain and the most similar in deduced primary amino acid sequence to the alpha 6 subunit. We demonstrate that the human alpha 4 subunit forms a functional receptor when expressed with beta gamma 2, demonstrating some properties similar to alpha 6 beta gamma 2 and some properties more akin to alpha 1 beta gamma 2. It also exhibited some properties that were unlike any other alpha subunit-containing receptor. GABA affinity seemed to be identical to that of the alpha 1 beta 1 gamma 2 receptor; however, the partial agonists 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol and piperidine-4-sulfonic acid showed lower efficacy than at either alpha 1 beta 1 gamma 2 or alpha 6 beta 1 gamma 2. Benzodiazepine pharmacology of alpha 4-containing receptors was similar to that of alpha 6-containing receptors with the exception of dimethoxy-4-ethyl-beta-carboline-3-carboxylate, which behaved as a partial inverse agonist. Pentobarbital potentiated alpha 4 beta 1 gamma 2 receptor GABA responses to a level comparable with alpha 6 beta 1 gamma 2 (approximately 700% of EC20); however, unlike alpha 6 beta 1 gamma 2 receptors, it did not elicit any direct activation of the receptor. Propofol also potentiated alpha 4 beta 1 gamma 2 GABA responses but to a level more comparable to that of alpha 1 beta 1 gamma 2, suggesting that these compounds act via different sites. Unlike other subunit combinations, propofol did not elicit a direct activation of the receptor. These results suggest that the mechanism for direct activation of the GABAA receptor by pentobarbital and propofol is absent on alpha 4-containing receptors. Furosemide, which non-competitively inhibits the GABAA receptor, showed 700-fold selectivity for alpha 6 beta 3 gamma 2 receptors over alpha 1-, alpha 2-, alpha 3-, and alpha 5-containing receptors and exhibited selectivity for alpha 4 beta 3 gamma 2 receptors (> 50-fold). These experiments reveal a unique pharmacology for alpha 4-containing receptors with some similarities to both alpha 6- and alpha 1-containing receptors.
就激动剂、拮抗剂和调节性化合物（特别是苯二氮䓬类药物）而言，α亚基是γ-氨基丁酸A（GABAA）受体药理学的重要决定因素。α4亚基是大脑中含量最少的亚基，在推导的一级氨基酸序列上与α6亚基最为相似。我们证明，人α4亚基与βγ2一起表达时可形成功能性受体，表现出一些与α6βγ2相似的特性，以及一些更类似于α1βγ2的特性。它还表现出一些不同于任何其他含α亚基受体的特性。GABA亲和力似乎与α1β1γ2受体相同；然而，部分激动剂4,5,6,7-四氢异恶唑并-[5,4-c]吡啶-3-醇和哌啶-4-磺酸在α4β1γ2上的效力低于在α1β1γ2或α6β1γ2上的效力。含α4受体的苯二氮䓬类药理学与含α6受体的相似，但4-乙基-二甲氧基-β-咔啉-3-羧酸酯除外，它表现为部分反向激动剂。戊巴比妥增强α4β1γ2受体的GABA反应至与α6β1γ2相当的水平（约为EC20的700%）；然而，与α6β1γ2受体不同，它不会引起受体的任何直接激活。丙泊酚也增强α4β1γ2的GABA反应，但至与α1β1γ2更相当的水平，表明这些化合物通过不同位点起作用。与其他亚基组合不同，丙泊酚不会引起受体的直接激活。这些结果表明，戊巴比妥和丙泊酚对含α4受体不存在直接激活GABAA受体的机制。呋塞米非竞争性抑制GABAA受体，对含α6β3γ2受体相对于含α1、α2、α3和α5亚基的受体表现出700倍的选择性，对α4β3γ2受体也表现出选择性（>50倍）。这些实验揭示了含α4受体独特的药理学特性，与含α6和含α1受体均有一些相似之处。
