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首页> 外文期刊>Neuron >Biased mGlu(5)-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu(5) Modulation of NMDAR Currents
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Biased mGlu(5)-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu(5) Modulation of NMDAR Currents

机译：偏置的mGlu（5）正变构调节剂可提供体内功效，而不会增强NMDAR电流的mGlu（5）调节。

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摘要

Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu5 PAM that exhibits distinct stimulus bias and selectively potentiates mGlu5 coupling to Gaq-mediated signaling but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu5 PAMs and suggest that modulation of NMDAR currents is not critical for in vivo efficacy.
机译：精神分裂症与N-甲基-D-天冬氨酸谷氨酸受体亚型（NMDAR）介导的兴奋性突触信号转导相关。代谢型谷氨酸受体亚型5（mGlu5）是与NMDAR密切相关的信号伴侣，并调节与精神分裂症病理相关的前脑区域的NMDAR功能。 mGlu5阳性变构调节剂（PAM）在精神病和认知动物模型中的功效先前归因于NMDAR功能的增强。为了直接检验该假设，我们将VU0409551确定为一种新型的mGlu5 PAM，它表现出独特的刺激偏差，并选择性增强mGlu5与Gaq介导的信号传导的耦合，但对大鼠海马体中NMDAR电流或NMDAR依赖性突触可塑性的mGlu5调制却不起作用。有趣的是，VU0409551在动物模型中产生了强大的抗精神病药样和增强认知能力。这些数据为mGlu5 PAM的作用提供了令人惊讶的新机制，并表明NMDAR电流的调节对于体内功效不是关键。

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