Histaminergic pharmacology of homo-oligomeric 尾3 纬-aminobutyric acid type A receptors characterized by surface plasmon resonance biosensor technology

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• 作者：Christian Seeger^a ; ^b ; Tony Christopeit^b ; Karoline Fuchs^c ; Katharina Grote^c ; Werner Sieghart^c ; U. Helena Danielson^a ; ^b ; ^{helena.danielson@biorg.uu.se}
• 关键词：GABA ; 纬-aminobutyric acid ; GABAA receptors ; GABA type A receptors ; SPR ; surface plasmon resonance
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：1 August, 2012
• 卷：84
• 期：3
• 页码：341-351
• 文件大小：1184 K

摘要

A surface plasmon resonance biosensor assay was established for studying the interactions of 51 histaminergic and 15 GABAergic ligands with homo-oligomeric 尾3 GABA_A receptors. Detergent solubilized receptors were successfully immobilized via affinity-capture on biosensor surfaces. The interaction kinetics of both histaminergic and GABAergic ligands were very rapid but affinities could be determined by steady-state analysis. Binding of several GABAergic ligands was observed, in agreement with previous data. Histamine and 16 histaminergic ligands were detected to directly bind to 尾3 GABA_A receptors with micromolar affinity (K_D < 300 渭M), thus extending previous evidence that 尾3 GABA_A receptors can interact with histaminergic ligands. Histamine exhibited an affinity for these receptors comparable to that for human histamine type 1 (H1) or type 2 (H2) receptors. Furthermore, 13 of these histaminergic ligands appeared to compete with histamine. The discovery that H2, H3 and H4 receptor ligands interact with 尾3 receptors indicates a unique histaminergic pharmacology of these receptors. Due to their low affinity for the homo-pentameric 尾3 receptors these histaminergic drugs are not expected to modulate these receptors at clinically relevant concentrations. The results support the use of the new biosensor assay for the identification of drugs interacting with full length receptors and for fragment-based drug discovery of high affinity ligands for 尾3 receptors. Drugs with high affinity and selectivity for these receptors can be used to clarify the question whether 尾3 receptors do exist in the brain, and provide new avenues for the development of therapeutically active compounds targeting this novel histamine binding site.