Ng G Y, Bertrand S, Sullivan R, Ethier N, Wang J, Yergey J, Belley M, Trimble L, Bateman K, Alder L, Smith A, McKernan R, Metters K, O'Neill G P, Lacaille J C, Hébert T E
Merck Frosst Center for Therapeutic Research, Kirkland, Canada.
Mol Pharmacol. 2001 Jan;59(1):144-52.
Gamma-aminobutyric acid (GABA) activates two qualitatively different inhibitory mechanisms through ionotropic GABA(A) multisubunit chloride channel receptors and metabotropic GABA(B) G protein-coupled receptors. Evidence suggests that pharmacologically distinct GABA(B) receptor subtypes mediate presynaptic inhibition of neurotransmitter release by reducing Ca2+ conductance, and postsynaptic inhibition of neuronal excitability by activating inwardly rectifying K+ (Kir) conductance. However, the cloning of GABA(B) gb1 and gb2 receptor genes and identification of the functional GABA(B) gb1-gb2 receptor heterodimer have so far failed to substantiate the existence of pharmacologically distinct receptor subtypes. The anticonvulsant, antihyperalgesic, and anxiolytic agent gabapentin (Neurontin) is a 3-alkylated GABA analog with an unknown mechanism of action. Here we report that gabapentin is an agonist at the GABA(B) gb1a-gb2 heterodimer coupled to Kir 3.1/3.2 inwardly rectifying K+ channels in Xenopus laevis oocytes. Gabapentin was practically inactive at the human gb1b-gb2 heterodimer, a novel human gb1c-gb2 heterodimer and did not block GABA agonism at these heterodimer subtypes. Gabapentin was not an agonist at recombinant GABA(A) receptors as well. In CA1 pyramidal neurons of rat hippocampal slices, gabapentin activated postsynaptic K+ currents, probably via the gb1a-gb2 heterodimer coupled to inward rectifiers, but did not presynaptically depress monosynaptic GABA(A) inhibitory postsynaptic currents. Gabapentin is the first GABA(B) receptor subtype-selective agonist identified providing proof of pharmacologically and physiologically distinct receptor subtypes. This selective agonism of postsynaptic GABA(B) receptor subtypes by gabapentin in hippocampal neurons may be its key therapeutic advantage as an anticonvulsant.
γ-氨基丁酸（GABA）通过离子型GABA(A)多亚基氯离子通道受体和代谢型GABA(B) G蛋白偶联受体激活两种性质不同的抑制机制。有证据表明，药理学上不同的GABA(B)受体亚型通过降低Ca2+电导介导神经递质释放的突触前抑制，并通过激活内向整流钾离子（Kir）电导介导神经元兴奋性的突触后抑制。然而，到目前为止，GABA(B) gb1和gb2受体基因的克隆以及功能性GABA(B) gb1-gb2受体异二聚体的鉴定未能证实药理学上不同的受体亚型的存在。抗惊厥、抗痛觉过敏和抗焦虑药物加巴喷丁（Neurontin）是一种3-烷基化的GABA类似物，其作用机制尚不清楚。在此我们报告，加巴喷丁是非洲爪蟾卵母细胞中与Kir 3.1/3.2内向整流钾离子通道偶联的GABA(B) gb1a-gb2异二聚体的激动剂。加巴喷丁对人gb1b-gb2异二聚体、一种新型人gb1c-gb2异二聚体实际上无活性，并且不阻断这些异二聚体亚型上的GABA激动作用。加巴喷丁对重组GABA(A)受体也不是激动剂。在大鼠海马切片的CA1锥体神经元中，加巴喷丁可能通过与内向整流器偶联的gb1a-gb2异二聚体激活突触后钾离子电流，但不突触前抑制单突触GABA(A)抑制性突触后电流。加巴喷丁是首个被鉴定的GABA(B)受体亚型选择性激动剂，证明了药理学和生理学上不同的受体亚型的存在。加巴喷丁在海马神经元中对突触后GABA(B)受体亚型的这种选择性激动作用可能是其作为抗惊厥药的关键治疗优势。
