Therapeutic opportunities from muscarinic receptor research

Eglen, Richard M.; Choppin, Agnès; Watson, N.

doi:10.1016/s0165-6147(00)01737-5

Cited by 153 publications

(109 citation statements)

References 44 publications

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“…The significance of M 3 -R at the SMC membrane of the GI tract in the pathophysiology and therapy of the GI disorders is well known (17,20,25,36,45). This has been confirmed by using animals with targeted deletion of the M 3 -R gene (16,46).…”

Section: Discussionmentioning

confidence: 86%

Immunoglobulins from scleroderma patients inhibit the muscarinic receptor activation in internal anal sphincter smooth muscle cells

Singh¹,

Mehendiratta²,

Galdo

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Section: Discussionmentioning

confidence: 86%

Immunoglobulins from scleroderma patients inhibit the muscarinic receptor activation in internal anal sphincter smooth muscle cells

Singh¹,

Mehendiratta²,

Galdo

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…2 Five muscarinic receptors have been identified in the human CNS 2 but investigations on the involvement of changes in muscarinic receptors in schizophrenia have been hampered by the lack of receptor-specific radioligands and drugs. 6 This laboratory has reported a decrease in tex, 7,8 hippocampus 9 and caudate-putamen 10 from subjects with schizophrenia. [ 3 H]pirenzepine binds selectively to muscarinic 1 (M1R) and muscarinic 4 (M4R) receptors 11 and we therefore suggested that deficits in M1R and/or M4R are present in various CNS regions from subjects with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia

et al. 2002

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To test the hypothesis that muscarinic receptors are involved in the pathology of schizophrenia, we measured muscarinic 1 (M1R) and muscarinic 4 (M4R) protein and mRNA as well as [ 3 H]pirenzepine binding in Brodmann's areas (BA) 9 and 40 obtained postmortem from 20 schizophrenic and 20 age/sex-matched control subjects. There was a significant decrease in [ 3 H]pirenzepine binding to BA 9 (mean ± SEM: 151 ± 15 vs 195 ± 10 fmol mg −1 ETE; P Ͻ 0.02), but not BA 40 (143 ± 13 vs 166 ± 11 fmol mg −1 ETE), from subjects with schizophrenia. The level of M1R protein (0.11 ± 0.007 vs 0.15 ± 0.008 OD; P Ͻ 0.01), but not M4R protein, was decreased in BA9 from schizophrenic subjects with neither receptor protein being altered in BA 40. The level of M1R mRNA was decreased in BA 9 (30 ± 7.0 vs 79 ± 14 dpm × 10 3 mg −1 ETE, P Ͻ 0.01) and BA 40 (28 ± 5.9 vs 99 ± 14, P Ͻ 0.01) with schizophrenia but M4R mRNA was only decreased in BA 40 (48 ± 6.6 vs 89 ± 9.9, P Ͻ 0.005). These data suggest that the M1R, at least in the dorsolateral prefrontal cortex, may have a role in the pathology of schizophrenia.

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“…However, research in this field has been impeded because of the complex pharmacology of muscarinic receptors. 8,11 Five distinct muscarinic acetylcholine receptors (M1-M5) have been cloned and characterized, all of which belong to the superfamily of G-protein-coupled receptors. Expression models have established the signal transduction pathways mediating the actions of each subtype.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice

et al. 2003

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Among the five different muscarinic receptors that have been cloned and characterized, M2 and M4 receptors are localized both post-and presynaptically and are believed to have a pronounced autoreceptor role. The functional importance of these receptors in the regulation of acetylcholine release in the hippocampus and in cognitive processes was investigated by using M2 and M4 receptor single knockout (KO) as well as M2/M4 receptor double KO mice. We found profound alterations in acetylcholine homeostasis in the hippocampus of both M2-and M4-KO mice as well as of the combined M2/M4-KOs, as assessed by in vivo microdialysis. Basal acetylcholine efflux in the hippocampus was significantly increased in M4-KO and was elevated further in M2/M4-KOs. The increase in hippocampal acetylcholine induced by local administration of scopolamine was markedly reduced in M2-KO and completely abolished in M2/M4-KOs. In M2-KO and much more in M2/M4-KOs, the increase in hippocampal acetylcholine triggered by exposure to a novel environment was more pronounced both in amplitude and duration, with a similar trend observed for M4-KOs. Dysregulation of cholinergic function in the hippocampus, as it could result from perturbed autoreceptor function, may be associated with cognitive deficits. Importantly, M2-and M2/M4-KO, but not M4-KO, animals showed an impaired performance in the passive avoidance test. Together these results suggest a crucial role for muscarinic M2 and M4 receptors in the tonic and phasic regulation of acetylcholine efflux in the hippocampus as well as in cognitive processes.

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Therapeutic opportunities from muscarinic receptor research

Cited by 153 publications

References 44 publications

Immunoglobulins from scleroderma patients inhibit the muscarinic receptor activation in internal anal sphincter smooth muscle cells

Immunoglobulins from scleroderma patients inhibit the muscarinic receptor activation in internal anal sphincter smooth muscle cells

Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice

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