Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA.
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee, USA.
J Biol Chem. 2022 Oct;298(10):102458. doi: 10.1016/j.jbc.2022.102458. Epub 2022 Sep 5.
Glutamate acts at eight metabotropic glutamate (mGlu) receptor subtypes expressed in a partially overlapping fashion in distinct brain circuits. Recent evidence indicates that specific mGlu receptor protomers can heterodimerize and that these heterodimers can exhibit different pharmacology when compared to their homodimeric counterparts. Group III mGlu agonist-induced suppression of evoked excitatory potentials and induction of long-term potentiation at Schaffer collateral-CA1 (SC-CA1) synapses in the rodent hippocampus can be blocked by the selective mGlu negative allosteric modulator (NAM), ADX71743. Curiously, a different mGlu NAM, 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one, failed to block these responses in brain slices despite its robust activity at mGlu homodimers in vitro. We hypothesized that this might result from heterodimerization of mGlu with another mGlu receptor protomer and focused on mGlu as a candidate given the reported effects of mGlu-targeted compounds in the hippocampus. Here, we used complemented donor acceptor-resonance energy transfer to study mGlu heterodimer activation in vitro and observed that ADX71743 blocked responses of both mGlu homodimers and mGlu heterodimers, whereas 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one only antagonized responses of mGlu homodimers. Taken together with our electrophysiology observations, these results suggest that a receptor with pharmacology consistent with an mGlu heterodimer modulates the activity of SC-CA1 synapses. Building on this hypothesis, we identified two additional structurally related mGlu NAMs that also differ in their activity at mGlu heterodimers, in a manner consistent with their ability to inhibit synaptic transmission and plasticity at SC-CA1. Thus, we propose that mGlu heterodimers are a key molecular target for modulating the activity of hippocampal SC-CA1 synapses.
谷氨酸作用于在不同的脑回路中以部分重叠方式表达的 8 种代谢型谷氨酸 (mGlu) 受体亚型。最近的证据表明，特定的 mGlu 受体原聚体可以异二聚化，并且这些异二聚体的药理学与它们的同二聚体相比可以不同。在啮齿动物海马体中的 Schaffer 侧枝-CA1 (SC-CA1) 突触中，III 组 mGlu 激动剂诱导的诱发兴奋性潜能抑制和长时程增强可以被选择性 mGlu 负变构调节剂 (NAM) ADX71743 阻断。奇怪的是，另一种不同的 mGlu NAM，6-(4-甲氧基苯基)-5-甲基-3-吡啶-4-基异恶唑并[4,5-c]吡啶-4(5H)-酮，尽管在体外对 mGlu 同二聚体具有很强的活性，但未能在脑片中阻断这些反应。我们假设这可能是由于 mGlu 与另一种 mGlu 受体原聚体的异二聚化所致，并且鉴于 mGlu 靶向化合物在海马体中的报道效果，我们将重点放在 mGlu 上。在这里，我们使用互补供体-受体共振能量转移来研究 mGlu 异二聚体在体外的激活情况，并观察到 ADX71743 阻断了 mGlu 同二聚体和 mGlu 异二聚体的反应，而 6-(4-甲氧基苯基)-5-甲基-3-吡啶-4-基异恶唑并[4,5-c]吡啶-4(5H)-酮仅拮抗 mGlu 同二聚体的反应。这些结果与我们的电生理学观察结果一起表明，一种药理学与 mGlu 异二聚体一致的受体调节 SC-CA1 突触的活性。基于这一假设，我们鉴定了另外两种结构相关的 mGlu NAMs，它们在 mGlu 异二聚体中的活性也不同，这与它们抑制 SC-CA1 突触传递和可塑性的能力一致。因此，我们提出 mGlu 异二聚体是调节海马体 SC-CA1 突触活性的关键分子靶点。
