Aprison M H, Galvez-Ruano E, Robertson D H, Lipkowitz K B
Department of Psychiatry and Biochemistry, Indiana University School of Medicine, Indianapolis, USA.
J Neurosci Res. 1996 Feb 1;43(3):372-81. doi: 10.1002/(SICI)1097-4547(19960201)43:3<372::AID-JNR12>3.0.CO;2-7.
We have been able to show that the three clearly identified atoms common to the inhibitory neurotransmitters glycine and GABA, that we previously hypothesized to serve as attachment points at the glycinergic and gabanergic receptor, can indeed interact through both electrostatic and hydrogen bonding to several amino acids, which have been identified in molecular biological investigations as both present and critical in the physiological functioning of key polypeptides common to these inhibitory receptors. In addition, amino acids also involved in stabilizing the interaction between the antagonists strychnine and R5135 at the glycinergic and gabanergic receptors, respectively, have been shown to fit our complex model. We identify in detail molecular mechanisms to explain how glycine and GABA initiate chloride ion movement from extraneuronal fluid in the synaptic cleft to intraneuronal volume. In addition, we also identify the molecular mechanisms involved in the blocking of chloride ion movement by strychnine at the glycinergic receptor and by R5135 at the gabanergic receptor. We also present two computer-generated color prints, one for the glycine receptor and one for the GABA receptor, which show the quantum mechanically geometry optimized complex formed between receptor side chains, i.e., the part of the amino acids in the polypeptide that interacts with the zwitterionic inhibitory neurotransmitters. These computer-generated color figures also show a) the important electrostatic and hydrogen bonding in these interactions, b) a van der Waals model of this complex to illustrate that no steric repulsions exist, and c) the molecular electrostatic potential energy map showing the electrostatic potentials of neurotransmitter bound to the receptor model. Finally, we show with computer calculations that the pseudo-rings, formed between the positive quanidinium group in arginine and one of the oxygen atoms in the carboxyl group in both glycine or GABA, result in a positive planar region which appears to be involved in a charge-transfer complex with aromatic benzene groups in amino acids such as phenylalanine and tryosine.
我们已经能够证明，抑制性神经递质甘氨酸和γ-氨基丁酸（GABA）共有的三个明确识别出的原子，我们之前假设它们作为甘氨酸能和GABA能受体的附着点，确实可以通过静电作用和氢键与几种氨基酸相互作用，这些氨基酸在分子生物学研究中已被确定在这些抑制性受体共有的关键多肽的生理功能中既存在且至关重要。此外，分别参与稳定拮抗剂士的宁与甘氨酸能受体以及R5135与GABA能受体之间相互作用的氨基酸，已被证明符合我们的复杂模型。我们详细确定了分子机制，以解释甘氨酸和GABA如何启动氯离子从突触间隙中的细胞外液向细胞内体积的移动。此外，我们还确定了士的宁在甘氨酸能受体处以及R5135在GABA能受体处阻断氯离子移动所涉及的分子机制。我们还展示了两张计算机生成的彩色打印图，一张是甘氨酸受体的，一张是GABA受体的，它们展示了受体侧链之间形成的量子力学几何优化复合物，即多肽中与两性离子抑制性神经递质相互作用的氨基酸部分。这些计算机生成的彩色图还展示了：a）这些相互作用中重要的静电作用和氢键；b）该复合物的范德华模型，以说明不存在空间排斥；c）分子静电势能图，显示与受体模型结合的神经递质的静电势。最后，我们通过计算机计算表明，精氨酸中的正胍基与甘氨酸或GABA中羧基的一个氧原子之间形成的假环，产生了一个正平面区域，该区域似乎参与了与苯丙氨酸和酪氨酸等氨基酸中的芳香苯环的电荷转移复合物。
