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An allosteric potentiator suggests a role for M4 muscarinic acetylcholine receptor (mAChR) in modulating excitatory hippocampal synaptic transmission
Author(s) -
Shirey Jana K,
Xiang Zixiu,
Orton Darren,
Brady Ashley E,
Johnson Kari A,
Williams Richard,
Ayala Jennifer E,
Rodriguez Alice L,
Wess Jurgen,
Weaver David,
Niswender Colleen M,
Conn P Jeffrey
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.714.3
Subject(s) - excitatory postsynaptic potential , neuroscience , muscarinic acetylcholine receptor , long term potentiation , allosteric regulation , neurotransmission , acetylcholine , muscarinic acetylcholine receptor m4 , chemistry , muscarinic acetylcholine receptor m5 , muscarinic acetylcholine receptor m1 , muscarinic acetylcholine receptor m2 , inhibitory postsynaptic potential , hippocampus , muscarinic acetylcholine receptor m3 , pharmacology , receptor , biology , biochemistry
Numerous animal and human studies suggest that muscarinic acetylcholine receptors (mAChRs), specifically M 1 and M 4 , may be viable targets for the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). We have used cheminformatic and medicinal chemistry to develop novel, highly selective M 4 allosteric potentiators. VU10010, the lead compound, potentiates the M 4 response to acetylcholine (ACh) 47‐fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor and increases affinity for ACh and coupling to G proteins. Whole cell patch clamp recordings revealed that selective potentiation of M 4 with VU10010 increased carbachol‐induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus. The effect was not mimicked by an inactive analog of VU10010 and was absent in M 4 knockout (KO) mice. This provides compelling evidence for selective regulation of excitatory transmission in this important forebrain structure by M 4 . We are now examining the effects of selective M 1 and M 4 activation on field excitatory postsynaptic potentials in the CA1 region to understand the involvement of these receptors in muscarinic long‐term potentiation and depression. This work supported by NIMH grants MH073676‐01A1 and 1 F31 MH80559‐01.