Drug Discovery Opinion

The cognitive improvement in Alzheimer’s disease patients brought about by treatment with acetyl cholinesterase inhibitors has been largely attributed to enhanced M1-muscarinic receptor signalling. Recently, however, studies with M1-receptor knockout mice and with more selective M1-receptor modulators have suggested that this receptor may not directly mediate learning and memory.

A team led by researchers at the University of Leicester has now suggested an alternative mechanism involving the M3-muscarinic receptor which is widely expressed in many brain regions, including the hippocampus. M3-receptor knockout mice were found to show a deficit in fear conditioning learning and memory. A knock-in mouse strain expressing a phosphorylation-deficient receptor also showed a deficit in fear conditioning learning, indicating that the learning process involves receptor phosphorylation. Agonist treatment and fear conditioning training led to phosphorylation of the M3-receptor in the hippocampus, confirming the importance of receptor phoshorylation on learning and memory. The phosphorylation-deficient receptor was expressed normally at the cell surface and was able to signal via the Gq/11 calcium pathway, but was uncoupled from phosphorylation-dependent processes such as receptor internalization and arrestin recruitment. The study, which is published in PNAS, suggests that an M3-receptor modulator that enhances phosphorylation/arrestin-dependent (non-G protein) signalling may be beneficial in treating cognitive disorders. ‘Biased’ ligands – those able to direct signalling of GPCRs selectively through the phosphorylation/arrestin-dependent pathway – have recently been described for a number of other GPCRs.

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