期刊
BIOCHEMICAL PHARMACOLOGY
卷 177, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2020.114011
关键词
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资金
- National Health & Medical Research Council of Australia (NHMRC)
- CJ Martin Overseas Biomedical postdoctoral training fellowship [APP1013709]
- Australian Research Council Future Fellowships [FT160100075, FT170100392]
- [APP1084775]
- [APP1127322]
Allosteric modulators of metabotropic glutamate receptor subtype 5 (mGlu(5)) represent an attractive therapeutic strategy for multiple CNS disorders. Chemically distinct mGlu(5) positive allosteric modulators (PAMs) that interact with a common binding site can demonstrate biased allosteric agonism relative to the orthosteric agonist, DHPG, when comparing activity in signaling assays such as IP1 accumulation, ERK1/2 phosphorylation (pERK1/2) and iCa(2+) mobilization. However, the structural basis for such biased agonism is not well understood. Therefore, we evaluated biased allosteric agonism mediated by four mGlu(5) PAM-agonists from diverse chemical scaffolds (i.e., DPFE, VU0409551, VU29, and VU0424465) for three measures of mGlu(5) activation (i.e., iCa(2)(+) mobilization, IP1 accumulation and ERK1/2 phosphorylation) at eight single-point mutations within the common allosteric binding pocket of mGlu(5). In particular, mGlu(5) allosteric site mutations had differential effects on the intrinsic efficacy of mGlu(5) PAMs for multiple signaling pathways. Specifically, a loss of agonism for iCa(2)(+) mobilization was evident for DPFE and VU0409551 for most mutants, whereas IP1 accumulation and ERK phosphorylation were retained, albeit with reduced maximal responses. Additionally, bias profiles between iCa (2)(+) mobilization and IP1/ERK pathways remained similar to wild type for most mutants. However, W784A and A809G mutants lost bias between IP1 accumulation and ERK phosphorylation for VU0424465, whereas a loss of bias between iCa(2)(+) mobilization and ERK1/2 phosphorylation was evident for F787A, S808A and A809G mutants. These data provide further insight into the structural requirements for allosteric agonism across multiple mGlu(5)-mediated signaling pathways. An understanding of mGlu(5) biased agonism at a structural level may provide the foundation for rational structure-based design of biased allosteric ligands for the treatment of neurological disorders.
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