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Jurgen Wess - One of the best experts on this subject based on the ideXlab platform.
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Muscarinic Receptor subtype-3 gene ablation and scopolamine butylbromide treatment attenuate small intestinal neoplasia in Apcmin/+ mice.
Carcinogenesis, 2011Co-Authors: Jean-pierre Raufman, Kunrong Cheng, Xue-min Gao, Nirish Shah, Guofeng Xie, Jasleen Shant, Brian Shiu, Cinthia B. Drachenberg, Jonathon Heath, Jurgen WessAbstract:M3 subtype Muscarinic Receptors (CHRM3) are over-expressed in colon cancer. In this study, we used Apc min/+ mice to identify the role of Chnn3 expression in a genetic model of intestinal neoplasia, explored the role of Chrm3 in intestinal mucosal development and determined the translational potential of inhibiting Muscarinic Receptor activation. We generated Chrm3-deficient Apc min/+ mice and compared intestinal morphology and tumor number in 12-week-old Apc- min/+ Chrm3 -/- and Apc min/+ Chrm3 +/+ control mice. Compared with Apc min/+ Chrm3 +/+ mice, Apc min/+ Chrm3 -/- mice showed a 70 and 81 % reduction in tumor number and volume, respectively (P < 0.01). In adenomas, β-catenin nuclear staining was reduced in Apc min/+ Chrm3 -/- compared with Apc min/+ Chrm3 +/+ mice (P < 0.02). Whereas Apc gene mutation increased the number of crypt and Paneth cells and decreased villus goblet cells, these changes were absent in Apc min/+ Chrm3 -/- mice. To determine whether pharmacological inhibition of Muscarinic Receptor activation attenuates intestinal neoplasia, we treated 6-week-old Apc min/+ mice with scopolamine butylbromide, a non-subtype-selective Muscarinic Receptor antagonist. After 8 weeks of continuous treatment, scopolamine butylbromide-treated mice showed a 22% reduction in tumor number (P = 0.027) and a 36% reduction in tumor volume (P = 0.004) as compared with control mice. Compared with Chrm3 gene ablation, the Muscarinic antagonist was less efficacious, most probably due to shorter duration of treatment and incomplete blockade of Muscarinic Receptors. Overall, these findings indicate that interplay of Chrm3 and β-catenin signaling is important for intestinal mucosal differentiation and neoplasia and provide a proof-of-concept that pharmacological inhibition of Muscarinic Receptor activation can attenuate intestinal neoplasia in vivo.
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m3 Muscarinic Receptor promotes insulin release via Receptor phosphorylation arrestin dependent activation of protein kinase d1
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Kok Choi Kong, Jurgen Wess, Adrian J Butcher, Phillip Mcwilliams, Elizabeth M Rosethorne, David R Jones, Fadi F Hamdan, Tim D Werry, Steven J Charlton, Sarah E MunsonAbstract:The activity of G protein-coupled Receptors is regulated via hyper-phosphorylation following agonist stimulation. Despite the universal nature of this regulatory process, the physiological impact of Receptor phosphorylation remains poorly studied. To address this question, we have generated a knock-in mouse strain that expresses a phosphorylation-deficient mutant of the M3-Muscarinic Receptor, a prototypical Gq/11-coupled Receptor. This mutant mouse strain was used here to investigate the role of M3-Muscarinic Receptor phosphorylation in the regulation of insulin secretion from pancreatic islets. Importantly, the phosphorylation deficient Receptor coupled to Gq/11-signaling pathways but was uncoupled from phosphorylation-dependent processes, such as Receptor internalization and β-arrestin recruitment. The knock-in mice showed impaired glucose tolerance and insulin secretion, indicating that M3-Muscarinic Receptors expressed on pancreatic islets regulate glucose homeostasis via Receptor phosphorylation-/arrestin-dependent signaling. The mechanism centers on the activation of protein kinase D1, which operates downstream of the recruitment of β-arrestin to the phosphorylated M3-Muscarinic Receptor. In conclusion, our findings support the unique concept that M3-Muscarinic Receptor-mediated augmentation of sustained insulin release is largely independent of G protein-coupling but involves phosphorylation-/arrestin-dependent coupling of the Receptor to protein kinase D1.
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the m3 Muscarinic Receptor regulates learning and memory in a Receptor phosphorylation arrestin dependent manner
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Benoit Poulin, Jurgen Wess, Adrian J Butcher, Phillip Mcwilliams, Juliemyrtille Bourgognon, Robert Pawlak, Kok Choi Kong, Andrew R Bottrill, Sharad Mistry, Elizabeth M RosethorneAbstract:Degeneration of the cholinergic system is considered to be the underlying pathology that results in the cognitive deficit in Alzheimer's disease. This pathology is thought to be linked to a loss of signaling through the cholinergic M1-Muscarinic Receptor subtype. However, recent studies have cast doubt on whether this is the primary Receptor mediating cholinergic-hippocampal learning and memory. The current study offers an alternative mechanism involving the M3-Muscarinic Receptor that is expressed in numerous brain regions including the hippocampus. We demonstrate here that M3-Muscarinic Receptor knockout mice show a deficit in fear conditioning learning and memory. The mechanism used by the M3-Muscarinic Receptor in this process involves Receptor phosphorylation because a knockin mouse strain expressing a phosphorylation-deficient Receptor mutant also shows a deficit in fear conditioning. Consistent with a role for Receptor phosphorylation, we demonstrate that the M3-Muscarinic Receptor is phosphorylated in the hippocampus following agonist treatment and following fear conditioning training. Importantly, the phosphorylation-deficient M3-Muscarinic Receptor was coupled normally to Gq/11-signaling but was uncoupled from phosphorylation-dependent processes such as Receptor internalization and arrestin recruitment. It can, therefore, be concluded that M3-Muscarinic Receptor–dependent learning and memory depends, at least in part, on Receptor phosphorylation/arrestin signaling. This study opens the potential for biased M3-Muscarinic Receptor ligands that direct phosphorylation/arrestin-dependent (non-G protein) signaling as being beneficial in cognitive disorders.
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Muscarinic Receptor subtypes mediating central and peripheral antinociception studied with Muscarinic Receptor knockout mice: a review.
Life Sciences, 2003Co-Authors: Jurgen Wess, Masahisa Yamada, Christian C Felder, Alokesh Duttaroy, Jesus Gomeza, Weilie Zhang, Nadia Bernardini, Peter W ReehAbstract:To gain new insight into the physiological and pathophysiological roles of the Muscarinic cholinergic system, we generated mutant mouse strains deficient in each of the five Muscarinic acetylcholine Receptor subtypes (M(1)-M(5)). In this chapter, we review a set of recent studies dealing with the identification of the Muscarinic Receptor subtypes mediating Muscarinic agonist-dependent analgesic effects by central and peripheral mechanisms. Most of these studies were carried out with mutant mouse strains lacking M(2) or/and M(4) Muscarinic Receptors. It is well known that administration of centrally active Muscarinic agonists induces pronounced analgesic effects. To identify the Muscarinic Receptors mediating this activity, wild-type and Muscarinic Receptor mutant mice were injected with the non-subtype-selective Muscarinic agonist, oxotremorine (s.c., i.t., and i.c.v.), and analgesic effects were assessed in the tail-flick and hot-plate tests. These studies showed that M(2) Receptors play a key role in mediating the analgesic effects of oxotremorine, both at the spinal and supraspinal level. However, studies with M(2)/M(4) Receptor double KO mice indicated that M(4) Receptors also contribute to this activity. Recent evidence suggests that activation of Muscarinic Receptors located in the skin can reduce the sensitivity of peripheral nociceptors. Electrophysiological and neurochemical studies with skin preparations from Muscarinic Receptor mutant mice indicated that muscarine-induced peripheral antinociception is mediated by M(2) Receptors. Since acetylcholine is synthesized and released by different cell types of the skin, it is possible that non-neuronally released acetylcholine plays a role in modulating peripheral nociception. Our results highlight the usefulness of Muscarinic Receptor mutant mice to shed light on the functional roles of acetylcholine released from both neuronal and non-neuronal cells.
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m1 Muscarinic Receptor signaling in mouse hippocampus and cortex
Brain Research, 2002Co-Authors: Amy C Porter, Neil M Nathanson, Jurgen Wess, Frank P. Bymaster, Neil W Delapp, Masahisa Yamada, Susan E Hamilton, Christian C FelderAbstract:Abstract The five subtypes (M1–M5) of Muscarinic acetylcholine Receptors signal through Gαq or Gαi/Gαo. M1, M3 and M5 Receptors couple through Gαq and function predominantly as postsynaptic Receptors in the central nervous system. M1 and M3 Receptors are localized to brain regions involved in cognition, such as hippocampus and cortex, but their relative contribution to function has been difficult to ascertain due to the lack of subtype specific ligands. A functional and genetic approach was used to identify the predominant Muscarinic Receptor subtype(s) mediating responses in mouse hippocampus and cortex, as well as the relative degree of spare Muscarinic Receptors in hippocampus. The nonselective Muscarinic agonist oxotremorine-M stimulated Gαq/11-specific GTP-γ-35S binding in a concentration dependent manner with a Hill slope near unity in wild type mouse hippocampus and cortex. Muscarinic Receptor stimulated Gαq/11-specific GTP-γ-35S binding was virtually abolished in both the hippocampus and cortex of M1 Receptor knockout (KO) mice. In contrast, there was no loss of signaling in M3 Receptor KO mice in either brain region. Muscarinic Receptor reserve in wildtype mouse hippocampus was measured by Furchgott analysis after partial Receptor alkylation with propylbenzylcholine mustard. Occupation of just 15% of the M1 Receptors in mouse hippocampus was required for maximal efficacy of oxotremorine-M-stimulated GTP-γ-35S binding indicating a substantial level of spare Receptors. These findings support a role for the M1 Receptor subtype as the primary Gαq/11-coupled Muscarinic Receptor in mouse hippocampus and cortex.
Elizabeth M Rosethorne - One of the best experts on this subject based on the ideXlab platform.
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m3 Muscarinic Receptor promotes insulin release via Receptor phosphorylation arrestin dependent activation of protein kinase d1
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Kok Choi Kong, Jurgen Wess, Adrian J Butcher, Phillip Mcwilliams, Elizabeth M Rosethorne, David R Jones, Fadi F Hamdan, Tim D Werry, Steven J Charlton, Sarah E MunsonAbstract:The activity of G protein-coupled Receptors is regulated via hyper-phosphorylation following agonist stimulation. Despite the universal nature of this regulatory process, the physiological impact of Receptor phosphorylation remains poorly studied. To address this question, we have generated a knock-in mouse strain that expresses a phosphorylation-deficient mutant of the M3-Muscarinic Receptor, a prototypical Gq/11-coupled Receptor. This mutant mouse strain was used here to investigate the role of M3-Muscarinic Receptor phosphorylation in the regulation of insulin secretion from pancreatic islets. Importantly, the phosphorylation deficient Receptor coupled to Gq/11-signaling pathways but was uncoupled from phosphorylation-dependent processes, such as Receptor internalization and β-arrestin recruitment. The knock-in mice showed impaired glucose tolerance and insulin secretion, indicating that M3-Muscarinic Receptors expressed on pancreatic islets regulate glucose homeostasis via Receptor phosphorylation-/arrestin-dependent signaling. The mechanism centers on the activation of protein kinase D1, which operates downstream of the recruitment of β-arrestin to the phosphorylated M3-Muscarinic Receptor. In conclusion, our findings support the unique concept that M3-Muscarinic Receptor-mediated augmentation of sustained insulin release is largely independent of G protein-coupling but involves phosphorylation-/arrestin-dependent coupling of the Receptor to protein kinase D1.
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the m3 Muscarinic Receptor regulates learning and memory in a Receptor phosphorylation arrestin dependent manner
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Benoit Poulin, Jurgen Wess, Adrian J Butcher, Phillip Mcwilliams, Juliemyrtille Bourgognon, Robert Pawlak, Kok Choi Kong, Andrew R Bottrill, Sharad Mistry, Elizabeth M RosethorneAbstract:Degeneration of the cholinergic system is considered to be the underlying pathology that results in the cognitive deficit in Alzheimer's disease. This pathology is thought to be linked to a loss of signaling through the cholinergic M1-Muscarinic Receptor subtype. However, recent studies have cast doubt on whether this is the primary Receptor mediating cholinergic-hippocampal learning and memory. The current study offers an alternative mechanism involving the M3-Muscarinic Receptor that is expressed in numerous brain regions including the hippocampus. We demonstrate here that M3-Muscarinic Receptor knockout mice show a deficit in fear conditioning learning and memory. The mechanism used by the M3-Muscarinic Receptor in this process involves Receptor phosphorylation because a knockin mouse strain expressing a phosphorylation-deficient Receptor mutant also shows a deficit in fear conditioning. Consistent with a role for Receptor phosphorylation, we demonstrate that the M3-Muscarinic Receptor is phosphorylated in the hippocampus following agonist treatment and following fear conditioning training. Importantly, the phosphorylation-deficient M3-Muscarinic Receptor was coupled normally to Gq/11-signaling but was uncoupled from phosphorylation-dependent processes such as Receptor internalization and arrestin recruitment. It can, therefore, be concluded that M3-Muscarinic Receptor–dependent learning and memory depends, at least in part, on Receptor phosphorylation/arrestin signaling. This study opens the potential for biased M3-Muscarinic Receptor ligands that direct phosphorylation/arrestin-dependent (non-G protein) signaling as being beneficial in cognitive disorders.
Kok Choi Kong - One of the best experts on this subject based on the ideXlab platform.
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m3 Muscarinic Receptor promotes insulin release via Receptor phosphorylation arrestin dependent activation of protein kinase d1
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Kok Choi Kong, Jurgen Wess, Adrian J Butcher, Phillip Mcwilliams, Elizabeth M Rosethorne, David R Jones, Fadi F Hamdan, Tim D Werry, Steven J Charlton, Sarah E MunsonAbstract:The activity of G protein-coupled Receptors is regulated via hyper-phosphorylation following agonist stimulation. Despite the universal nature of this regulatory process, the physiological impact of Receptor phosphorylation remains poorly studied. To address this question, we have generated a knock-in mouse strain that expresses a phosphorylation-deficient mutant of the M3-Muscarinic Receptor, a prototypical Gq/11-coupled Receptor. This mutant mouse strain was used here to investigate the role of M3-Muscarinic Receptor phosphorylation in the regulation of insulin secretion from pancreatic islets. Importantly, the phosphorylation deficient Receptor coupled to Gq/11-signaling pathways but was uncoupled from phosphorylation-dependent processes, such as Receptor internalization and β-arrestin recruitment. The knock-in mice showed impaired glucose tolerance and insulin secretion, indicating that M3-Muscarinic Receptors expressed on pancreatic islets regulate glucose homeostasis via Receptor phosphorylation-/arrestin-dependent signaling. The mechanism centers on the activation of protein kinase D1, which operates downstream of the recruitment of β-arrestin to the phosphorylated M3-Muscarinic Receptor. In conclusion, our findings support the unique concept that M3-Muscarinic Receptor-mediated augmentation of sustained insulin release is largely independent of G protein-coupling but involves phosphorylation-/arrestin-dependent coupling of the Receptor to protein kinase D1.
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the m3 Muscarinic Receptor regulates learning and memory in a Receptor phosphorylation arrestin dependent manner
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Benoit Poulin, Jurgen Wess, Adrian J Butcher, Phillip Mcwilliams, Juliemyrtille Bourgognon, Robert Pawlak, Kok Choi Kong, Andrew R Bottrill, Sharad Mistry, Elizabeth M RosethorneAbstract:Degeneration of the cholinergic system is considered to be the underlying pathology that results in the cognitive deficit in Alzheimer's disease. This pathology is thought to be linked to a loss of signaling through the cholinergic M1-Muscarinic Receptor subtype. However, recent studies have cast doubt on whether this is the primary Receptor mediating cholinergic-hippocampal learning and memory. The current study offers an alternative mechanism involving the M3-Muscarinic Receptor that is expressed in numerous brain regions including the hippocampus. We demonstrate here that M3-Muscarinic Receptor knockout mice show a deficit in fear conditioning learning and memory. The mechanism used by the M3-Muscarinic Receptor in this process involves Receptor phosphorylation because a knockin mouse strain expressing a phosphorylation-deficient Receptor mutant also shows a deficit in fear conditioning. Consistent with a role for Receptor phosphorylation, we demonstrate that the M3-Muscarinic Receptor is phosphorylated in the hippocampus following agonist treatment and following fear conditioning training. Importantly, the phosphorylation-deficient M3-Muscarinic Receptor was coupled normally to Gq/11-signaling but was uncoupled from phosphorylation-dependent processes such as Receptor internalization and arrestin recruitment. It can, therefore, be concluded that M3-Muscarinic Receptor–dependent learning and memory depends, at least in part, on Receptor phosphorylation/arrestin signaling. This study opens the potential for biased M3-Muscarinic Receptor ligands that direct phosphorylation/arrestin-dependent (non-G protein) signaling as being beneficial in cognitive disorders.
Adrian J Butcher - One of the best experts on this subject based on the ideXlab platform.
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m3 Muscarinic Receptor promotes insulin release via Receptor phosphorylation arrestin dependent activation of protein kinase d1
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Kok Choi Kong, Jurgen Wess, Adrian J Butcher, Phillip Mcwilliams, Elizabeth M Rosethorne, David R Jones, Fadi F Hamdan, Tim D Werry, Steven J Charlton, Sarah E MunsonAbstract:The activity of G protein-coupled Receptors is regulated via hyper-phosphorylation following agonist stimulation. Despite the universal nature of this regulatory process, the physiological impact of Receptor phosphorylation remains poorly studied. To address this question, we have generated a knock-in mouse strain that expresses a phosphorylation-deficient mutant of the M3-Muscarinic Receptor, a prototypical Gq/11-coupled Receptor. This mutant mouse strain was used here to investigate the role of M3-Muscarinic Receptor phosphorylation in the regulation of insulin secretion from pancreatic islets. Importantly, the phosphorylation deficient Receptor coupled to Gq/11-signaling pathways but was uncoupled from phosphorylation-dependent processes, such as Receptor internalization and β-arrestin recruitment. The knock-in mice showed impaired glucose tolerance and insulin secretion, indicating that M3-Muscarinic Receptors expressed on pancreatic islets regulate glucose homeostasis via Receptor phosphorylation-/arrestin-dependent signaling. The mechanism centers on the activation of protein kinase D1, which operates downstream of the recruitment of β-arrestin to the phosphorylated M3-Muscarinic Receptor. In conclusion, our findings support the unique concept that M3-Muscarinic Receptor-mediated augmentation of sustained insulin release is largely independent of G protein-coupling but involves phosphorylation-/arrestin-dependent coupling of the Receptor to protein kinase D1.
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the m3 Muscarinic Receptor regulates learning and memory in a Receptor phosphorylation arrestin dependent manner
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Benoit Poulin, Jurgen Wess, Adrian J Butcher, Phillip Mcwilliams, Juliemyrtille Bourgognon, Robert Pawlak, Kok Choi Kong, Andrew R Bottrill, Sharad Mistry, Elizabeth M RosethorneAbstract:Degeneration of the cholinergic system is considered to be the underlying pathology that results in the cognitive deficit in Alzheimer's disease. This pathology is thought to be linked to a loss of signaling through the cholinergic M1-Muscarinic Receptor subtype. However, recent studies have cast doubt on whether this is the primary Receptor mediating cholinergic-hippocampal learning and memory. The current study offers an alternative mechanism involving the M3-Muscarinic Receptor that is expressed in numerous brain regions including the hippocampus. We demonstrate here that M3-Muscarinic Receptor knockout mice show a deficit in fear conditioning learning and memory. The mechanism used by the M3-Muscarinic Receptor in this process involves Receptor phosphorylation because a knockin mouse strain expressing a phosphorylation-deficient Receptor mutant also shows a deficit in fear conditioning. Consistent with a role for Receptor phosphorylation, we demonstrate that the M3-Muscarinic Receptor is phosphorylated in the hippocampus following agonist treatment and following fear conditioning training. Importantly, the phosphorylation-deficient M3-Muscarinic Receptor was coupled normally to Gq/11-signaling but was uncoupled from phosphorylation-dependent processes such as Receptor internalization and arrestin recruitment. It can, therefore, be concluded that M3-Muscarinic Receptor–dependent learning and memory depends, at least in part, on Receptor phosphorylation/arrestin signaling. This study opens the potential for biased M3-Muscarinic Receptor ligands that direct phosphorylation/arrestin-dependent (non-G protein) signaling as being beneficial in cognitive disorders.
Phillip Mcwilliams - One of the best experts on this subject based on the ideXlab platform.
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m3 Muscarinic Receptor promotes insulin release via Receptor phosphorylation arrestin dependent activation of protein kinase d1
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Kok Choi Kong, Jurgen Wess, Adrian J Butcher, Phillip Mcwilliams, Elizabeth M Rosethorne, David R Jones, Fadi F Hamdan, Tim D Werry, Steven J Charlton, Sarah E MunsonAbstract:The activity of G protein-coupled Receptors is regulated via hyper-phosphorylation following agonist stimulation. Despite the universal nature of this regulatory process, the physiological impact of Receptor phosphorylation remains poorly studied. To address this question, we have generated a knock-in mouse strain that expresses a phosphorylation-deficient mutant of the M3-Muscarinic Receptor, a prototypical Gq/11-coupled Receptor. This mutant mouse strain was used here to investigate the role of M3-Muscarinic Receptor phosphorylation in the regulation of insulin secretion from pancreatic islets. Importantly, the phosphorylation deficient Receptor coupled to Gq/11-signaling pathways but was uncoupled from phosphorylation-dependent processes, such as Receptor internalization and β-arrestin recruitment. The knock-in mice showed impaired glucose tolerance and insulin secretion, indicating that M3-Muscarinic Receptors expressed on pancreatic islets regulate glucose homeostasis via Receptor phosphorylation-/arrestin-dependent signaling. The mechanism centers on the activation of protein kinase D1, which operates downstream of the recruitment of β-arrestin to the phosphorylated M3-Muscarinic Receptor. In conclusion, our findings support the unique concept that M3-Muscarinic Receptor-mediated augmentation of sustained insulin release is largely independent of G protein-coupling but involves phosphorylation-/arrestin-dependent coupling of the Receptor to protein kinase D1.
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the m3 Muscarinic Receptor regulates learning and memory in a Receptor phosphorylation arrestin dependent manner
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Benoit Poulin, Jurgen Wess, Adrian J Butcher, Phillip Mcwilliams, Juliemyrtille Bourgognon, Robert Pawlak, Kok Choi Kong, Andrew R Bottrill, Sharad Mistry, Elizabeth M RosethorneAbstract:Degeneration of the cholinergic system is considered to be the underlying pathology that results in the cognitive deficit in Alzheimer's disease. This pathology is thought to be linked to a loss of signaling through the cholinergic M1-Muscarinic Receptor subtype. However, recent studies have cast doubt on whether this is the primary Receptor mediating cholinergic-hippocampal learning and memory. The current study offers an alternative mechanism involving the M3-Muscarinic Receptor that is expressed in numerous brain regions including the hippocampus. We demonstrate here that M3-Muscarinic Receptor knockout mice show a deficit in fear conditioning learning and memory. The mechanism used by the M3-Muscarinic Receptor in this process involves Receptor phosphorylation because a knockin mouse strain expressing a phosphorylation-deficient Receptor mutant also shows a deficit in fear conditioning. Consistent with a role for Receptor phosphorylation, we demonstrate that the M3-Muscarinic Receptor is phosphorylated in the hippocampus following agonist treatment and following fear conditioning training. Importantly, the phosphorylation-deficient M3-Muscarinic Receptor was coupled normally to Gq/11-signaling but was uncoupled from phosphorylation-dependent processes such as Receptor internalization and arrestin recruitment. It can, therefore, be concluded that M3-Muscarinic Receptor–dependent learning and memory depends, at least in part, on Receptor phosphorylation/arrestin signaling. This study opens the potential for biased M3-Muscarinic Receptor ligands that direct phosphorylation/arrestin-dependent (non-G protein) signaling as being beneficial in cognitive disorders.
