Publication Date:
2019
Description:
〈p〉Highly selective, positive allosteric modulators (PAMs) of the M〈sub〉1〈/sub〉 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 M〈sub〉1〈/sub〉 receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M〈sub〉1〈/sub〉 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 M〈sub〉1〈/sub〉 receptor signaling in native systems, and it is not clear whether biased M〈sub〉1〈/sub〉 PAMs display differences in modulating M〈sub〉1〈/sub〉-mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M〈sub〉1〈/sub〉-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M〈sub〉1〈/sub〉 PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist–induced LTD but also blocked M〈sub〉1〈/sub〉-dependent LTD in the PFC. In contrast, biased and nonbiased M〈sub〉1〈/sub〉 PAMs acted similarly in potentiating M〈sub〉1〈/sub〉-dependent electrophysiological responses that were PLD independent. These findings demonstrate that PLD plays a critical role in the ability of M〈sub〉1〈/sub〉 PAMs to modulate certain central nervous system (CNS) functions and that biased M〈sub〉1〈/sub〉 PAMs function differently in brain regions implicated in cognition.〈/p〉
Print ISSN:
1945-0877
Electronic ISSN:
1937-9145
Topics:
Biology
,
Medicine
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