Scherer R W, Ferkany J W, Enna S J
Nova Pharmaceutical Corporation, Baltimore, MD 21224-2788.
Brain Res Bull. 1988 Sep;21(3):439-43. doi: 10.1016/0361-9230(88)90156-6.
Activation of GABAB receptors augments neurotransmitter-stimulated cyclic AMP accumulation while inhibiting forskolin-mediated second messenger production. Previous studies have revealed that GABAB receptors are associated with a pertussis toxin sensitive G protein, such as Gi. While such a linkage is consistent with the finding that GABAB receptor activation inhibits forskolin-mediated second messenger accumulation, it fails to explain how GABAB agonists are capable of augmenting receptor-mediated cyclic AMP production. The present experiments were undertaken to explore the possible existence of pharmacologically distinct GABAB receptors in an attempt to explain this apparent discrepancy. For the study, a variety of agents were examined for their ability to inhibit GABAB binding to brain membranes and to modify isoproterenol- or forskolin-stimulated second messenger production in rat brain slices. Of the compounds studied, only 3-aminopropylphosphonic acid and 4-aminobutylphosphonic acid were found to inhibit GABAB binding. However, 4-aminobutylphosphonic acid failed to influence either isoproterenol- or forskolin-stimulated cyclic AMP production. On the other hand, while 3-aminopropylphosphonic acid also failed to affect isoproterenol-stimulated second messenger accumulation, it inhibited the forskolin-mediated response. Given this finding, and the fact that some of the agents tested are known to influence GABAB receptor function in other systems, the results indicate a multiplicity of pharmacologically distinct GABAB receptor recognition sites. This discovery paves the way for the development of more selective GABAB receptor agonists and antagonists possessing different therapeutic potentials.
GABAB受体的激活增强了神经递质刺激的环磷酸腺苷（cAMP）积累，同时抑制了福斯高林介导的第二信使生成。先前的研究表明，GABAB受体与一种对百日咳毒素敏感的G蛋白相关，比如Gi蛋白。虽然这种联系与GABAB受体激活抑制福斯高林介导的第二信使积累这一发现相符，但它无法解释GABAB激动剂如何能够增强受体介导的环磷酸腺苷生成。进行本实验是为了探索药理学上不同的GABAB受体的可能存在，以试图解释这一明显的差异。在该研究中，检测了多种药物抑制GABAB与脑膜结合以及改变异丙肾上腺素或福斯高林刺激的大鼠脑片第二信使生成的能力。在所研究的化合物中，仅发现3-氨基丙基膦酸和4-氨基丁基膦酸能抑制GABAB结合。然而，4-氨基丁基膦酸未能影响异丙肾上腺素或福斯高林刺激的环磷酸腺苷生成。另一方面，虽然3-氨基丙基膦酸也未能影响异丙肾上腺素刺激的第二信使积累，但它抑制了福斯高林介导的反应。鉴于这一发现，以及一些测试药物已知会在其他系统中影响GABAB受体功能这一事实，结果表明存在多种药理学上不同的GABAB受体识别位点。这一发现为开发具有不同治疗潜力的更具选择性的GABAB受体激动剂和拮抗剂铺平了道路。
