Highly selective, positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer's disease and schizophrenia. Discovery programs have produced a structurally diverse range of M1 receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M1 receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD). However, little is known about the role of PLD in M1 receptor signaling in native systems, and it is not clear whether biased M1 PAMs display differences in modulating M1-mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M1-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M1 PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist-induced LTD but also blocked M1-dependent LTD in the PFC. In contrast, biased and nonbiased M1 PAMs acted similarly in potentiating M1-dependent electrophysiological responses that were PLD independent. These findings demonstrate that PLD plays a critical role in the ability of M1 PAMs to modulate certain central nervous system (CNS) functions and that biased M1 PAMs function differently in brain regions implicated in cognition.

中文翻译：

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偏向M1受体阳性的变构调节剂揭示了磷脂酶D在M1依赖性啮齿动物皮层可塑性中的作用。

毒蕈碱乙酰胆碱受体M1亚型的高度选择性，正构构调节剂（PAM）已成为一种令人兴奋的新方法，可以潜在地改善阿尔茨海默氏病和精神分裂症患者的认知功能。发现程序已经产生了具有不同药理特性的M1受体PAM，其结构多样，包括激动剂活性的不同程度和信号偏差的差异。这包括偏向性的M1受体PAM，可以增强受体与磷脂酶C（PLC）而非磷脂酶D（PLD）活化的偶联。但是，关于PLD在天然系统中M1受体信号传导中的作用了解甚少，并且尚不清楚偏倚的M1 PAM是否在调节天然组织中的M1介导的反应中显示差异。使用PLD抑制剂和PLD基因敲除小鼠，我们表明PLD是诱导额叶皮层（PFC）中M1依赖性长期抑郁症（LTD）所必需的。此外，未偶联至PLD的偏向M1 PAM不仅无法增强正构激动剂诱导的LTD，而且还阻止了PFC中依赖于M1的LTD。相反，有偏的和无偏的M1 PAM在增强MLD依赖性的M1依赖性电生理反应方面的作用相似。这些发现表明，PLD在M1 PAM调节某些中枢神经系统（CNS）功能的能力中起着至关重要的作用，并且偏向M1 PAM在涉及认知的大脑区域中的功能有所不同。没有偶联到PLD的偏向M1 PAM不仅不能增强正构激动剂诱导的LTD，而且还阻止了PFC中依赖M1的LTD。相反，有偏的和无偏的M1 PAM在增强MLD依赖性的M1依赖性电生理反应方面的作用相似。这些发现表明，PLD在M1 PAM调节某些中枢神经系统（CNS）功能的能力中起关键作用，并且偏向M1 PAM在涉及认知的大脑区域中的功能有所不同。没有偶联到PLD的偏向M1 PAM不仅不能增强正构激动剂诱导的LTD，而且还阻止了PFC中依赖M1的LTD。相反，有偏的和无偏的M1 PAM在增强MLD依赖性的M1依赖性电生理反应方面的作用相似。这些发现表明，PLD在M1 PAM调节某些中枢神经系统（CNS）功能的能力中起关键作用，并且偏向M1 PAM在涉及认知的大脑区域中的功能有所不同。