Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics.
Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics.
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DOI：
10.1038/s41467-023-37259-5
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发表时间：
2023-03-25
影响因子：
16.6
通讯作者：
Greger, Ingo H.
中科院分区：
文献类型：
--
作者：
Zhang, Danyang;Lape, Remigijus;Shaikh, Saher A.;Kohegyi, Bianka K.;Watson, Jake F.;Cais, Ondrej;Nakagawa, Terunaga;Greger, Ingo H.
AMPA谷氨酸受体（AMPAR）介导整个大脑的兴奋性神经传递。它们的信号传导通过脑区域特异性辅助亚基而独特地多样化，为选择性疗法的开发提供了机会。与TARP γ8相关的AMPAR在海马中富集，并且是新兴抗癫痫药物的靶点。为了了解它们的治疗活性，我们确定了GluA 1/2-γ8受体与三种有效的、化学上不同的配体相关的冷冻电镜结构。我们发现，尽管共享一个脂质暴露和水接触的结合口袋，药物作用的差异受结合位点突变体。连同膜片钳记录和MD模拟，我们也证明了配体触发重组的AMPAR-TARP接口有助于调制。出乎意料的是，一种配体（JNJ-61432059）发挥双功能作用，对GluA 1产生负面影响，但以TARP化学计量依赖性方式对含GluA 2的AMPAR产生正面调节作用。这些结果进一步阐明了TARP的作用，证明了正和负调节作用之间的敏感平衡，并为开发正和负选择性AMPAR调节剂提供了机制平台。与TARP亚基相关的AMPA受体使得选择性AMPA受体药物的开发成为可能。在这里，作者提供了与三种TARP-γ8选择性药物结合的受体的冷冻电镜结构，并揭示了一种配体的双功能性。
AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse ligands. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we also demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators. AMPA receptors associated with TARP subunits enable the development of selective AMPA receptor drugs. Here, the authors provide cryo-EM structures of receptors bound to three TARP-γ8 selective drugs, and reveal bifunctionality of one ligand.
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