虽然乙酰胆碱 (ACh) 的离子型谷氨酸受体和烟碱受体通常是分开研究的,但它们通常是共定位的,并且在功能上相互依赖。本综述的目的是调查两个受体家族之间相互作用的证据及其背后的机制。这些包括亚基表达的相互调节,这改变了 NMDA:AMPA 反应平衡,以及多功能受体复合物的存在,这使得难以区分个体受体位点,尤其是在体内。接下来是通过递质释放、细胞电生理学和行为方面的工作分析受体之间的功能关系,这些可以有助于理解受体相互作用。很明显,轴突末端的烟碱受体 (nAChRs) 直接调节谷氨酸和其他神经递质的释放,α7-nAChRs 通常促进释放。因此,α7-nAChR 反应不仅会被烟碱拮抗剂阻止,还会被阻断间接激活的谷氨酸受体的化合物阻止。这解释了一些谷氨酸拮抗剂的明显抗胆碱能活性,包括内源性拮抗剂犬尿氨酸。突触前 nAChR 的激活是由前末端突触、静脉曲张和神经胶质细胞释放的 ACh 的环境水平引起的,在突触和突触外部位充当“体积神经递质”。此外,乙酰胆碱和谷氨酸盐作为 CNS 共递质释放,包括“胆碱能”突触到脊髓 Renshaw 细胞上。得出的结论是,ACh 应主要被视为通过调节突触前谷氨酸释放以及谷氨酸受体的位置、亚基组成、亚型平衡和敏感性来调节谷氨酸能神经传递的调节剂,而不是主要被视为经典的快速神经递质。这些结论和警告应该有助于澄清谷氨酸和烟碱受体配体在寻找新的中枢作用药物时的作用位点。包括“胆碱能”突触到脊髓伦肖细胞上。得出的结论是,ACh 应主要被视为通过调节突触前谷氨酸释放以及谷氨酸受体的位置、亚基组成、亚型平衡和敏感性来调节谷氨酸能神经传递的调节剂,而不是主要被视为经典的快速神经递质。这些结论和警告应该有助于澄清谷氨酸和烟碱受体配体在寻找新的中枢作用药物时的作用位点。包括“胆碱能”突触到脊髓伦肖细胞上。得出的结论是,ACh 应主要被视为通过调节突触前谷氨酸释放以及谷氨酸受体的位置、亚基组成、亚型平衡和敏感性来调节谷氨酸能神经传递的调节剂,而不是主要被视为经典的快速神经递质。这些结论和警告应该有助于澄清谷氨酸和烟碱受体配体在寻找新的中枢作用药物时的作用位点。
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Relationships and interactions between ionotropic glutamate receptors and nicotinic receptors in the CNS
Although ionotropic glutamate receptors and nicotinic receptors for acetylcholine (ACh) have usually been studied separately, they are often co-localized and functionally inter-dependent. The objective of this review is to survey the evidence for interactions between the two receptor families and the mechanisms underlying them. These include the mutual regulation of subunit expression, which change the NMDA:AMPA response balance, and the existence of multi-functional receptor complexes which make it difficult to distinguish between individual receptor sites, especially in vivo. This is followed by analysis of the functional relationships between the receptors from work on transmitter release, cellular electrophysiology and aspects of behavior where these can contribute to understanding receptor interactions. It is clear that nicotinic receptors (nAChRs) on axonal terminals directly regulate the release of glutamate and other neurotransmitters, α7-nAChRs generally promoting release. Hence, α7-nAChR responses will be prevented not only by a nicotinic antagonist, but also by compounds blocking the indirectly activated glutamate receptors. This accounts for the apparent anticholinergic activity of some glutamate antagonists, including the endogenous antagonist kynurenic acid. The activation of presynaptic nAChRs is by the ambient levels of ACh released from pre-terminal synapses, varicosities and glial cells, acting as a ‘volume neurotransmitter’ on synaptic and extrasynaptic sites. In addition, ACh and glutamate are released as CNS co-transmitters, including ‘cholinergic’ synapses onto spinal Renshaw cells. It is concluded that ACh should be viewed primarily as a modulator of glutamatergic neurotransmission by regulating the release of glutamate presynaptically, and the location, subunit composition, subtype balance and sensitivity of glutamate receptors, and not primarily as a classical fast neurotransmitter. These conclusions and caveats should aid clarification of the sites of action of glutamate and nicotinic receptor ligands in the search for new centrally-acting drugs.