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Muscarinic Acetylcholine Receptor Expression
Published by Anonymous on 2007/9/30 (2831 reads)
1: Life Sci. 1999;64(6-7):479-86.


Control elements of muscarinic receptor gene expression.

Saffen D, Mieda M, Okamura M, Haga T.

Department of Neurochemistry, Graduate School of Medicine, Tokyo University, Japan.

Studies describing the structures of the M1, M2 and M4 muscarinic acetylcholine receptors (mAChR) genes and the genetic elements that control their expression are reviewed. In particular, we focus on the role of the neuron-restrictive silencer element/restriction element-1 (NRSE/RE-1) in the regulation of the M4 mAChR gene. The NRSE/RE-1 was first identified as a genetic control element that prevents the expression of the SCG-10 and type II sodium channel (NaII) genes in non-neuronal cells in culture. The NRSE/RE-1 inhibits gene expression by binding the repressor/silencer protein NRSF/REST, which is present in many non-neuronal cell lines and tissues. Our studies show that although the expression of the M4 mAChR gene is inhibited by NRSF/REST, this inhibition is not always complete. Rather, the efficiency of silencing by NRSF/REST is different in different cells. A plausible explanation for this differential silencing is that the NRSF/RE-1 interacts with distinct sets of promoter binding proteins in different types of cells. We hypothesize that modulation of NRSF/REST silencing activity by these proteins contributes to the cell-specific pattern of expression of the M4 mAChR in neuronal and non-neuronal cells. Recent studies that suggest a more complex role for the NRSE/RE-1 in regulating gene expression are also discussed.

Publication Types:
Review

PMID: 10069513 [PubMed - indexed for MEDLINE]

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2: Life Sci. 1999;64(6-7):375-9.


Molecular analysis of the regulation of muscarinic receptor expression and function.

Nadler LS, Rosoff ML, Hamilton SE, Kalaydjian AE, McKinnon LA, Nathanson NM.

Department of Pharmacology, University of Washington, Seattle 98195-7750, USA.

We have investigated the molecular mechanisms involved in the regulation of muscarinic acetylcholine receptor gene expression and localization and generated knockout mice to study the role of the M1 muscarinic receptor in vivo. We have used the MDCK cell system to demonstrate that different subtypes of mAChR can be targeted to different regions of polarized cells. We have also examined the developmental regulation of mAChR expression in the chick retina. Early in development, the M4 receptor is the predominant mAChR while the levels of the M2 and M3 receptors increase later in development. The level of M2 receptor is also initially very low in retinal cultures and undergoes a dramatic increase over several days in vitro. The level of M2 receptor can be increased by a potentially novel, developmentally regulated, secreted factor produced by retinal cells. The promoter for the chick M2 receptor gene has been isolated and shown to contain a site for GATA-family transcription factors which is required for high level cardiac expression. The M2 promoter also contains sites which mediate induction of transcription in neural cells by neurally active cytokines. We have generated knockout mice lacking the M1 receptor and shown that these mice do not exhibit pilocarpine-induced seizures and muscarinic agonist-induced suppression of the M-current potassium channel in sympathetic neurons.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 10069499 [PubMed - indexed for MEDLINE]

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3: Trends Pharmacol Sci. 1998 Aug;19(8):322-7.


Regulation of the expression and function of the M2 muscarinic receptor.

Haddad el-B , Rousell J.

Department of Pharmacology, Rhône-Poulenc Rorer, Dagenharn, UK.

Since the cloning and expression of many of the G protein-coupled receptors during the 1980s, there has been a massive increase in our understanding of many aspects of their function. The use of molecular biology to engineer and express mutant receptors has made it possible to determine key amino acids involved in receptor function. Although advances in molecular biology have contributed greatly to our understanding of the pharmacology and structure of the five subtypes of muscarinic receptor, much remains to be learned about the factors that regulate their expression and function. This review by El-Bdaoui Haddad and Jonathan Rousell describes the current state of awareness and highlights recent advances made in the elucidation of the mechanisms involved in muscarinic receptor regulation. Because most is known about the regulation of expression of the M2 receptor subtype, particular attention will be paid to it. Furthermore, this receptor subtype plays an important role in regulating acetylcholine output from airway cholinergic nerves, and there is substantial evidence from studies both in vivo and in vitro in human and animal models that these receptors are dysfunctional in asthma.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 9745360 [PubMed - indexed for MEDLINE]

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4: Life Sci. 1998;62(17-18):1701-5.


Acetylcholine synthesis and muscarinic receptor subtype mRNA expression in T-lymphocytes.

Kawashima K, Fujii T, Watanabe Y, Misawa H.

Department of Pharmacology, Kyoritsu College of Pharmacy, Tokyo, Japan.

We used a sensitive and specific radioimmunoassay for acetylcholine (ACh), and detected significant amounts of ACh in the blood of various mammals, including humans. About 60% of human blood ACh was localized in mononuclear leukocytes. Human leukemic T-cell lines, used as T-lymphocyte models, contained both ACh and choline acetyltransferase (ChAT) activity. Furthermore, ChAT mRNA and protein were detected in the T-cell line MOLT-3. Phytohemagglutinin, a T-cell activator, increased both synthesis and release of ACh by MOLT-3 cells. Muscarinic receptor subtype mRNA expression was confirmed in various T-cell lines. These findings indicate that ACh synthesized by ChAT in T-lymphocytes acts on the muscarinic receptors on lymphocytes in autocrine and/or paracrine pathways and suggest that ACh in blood functions as a modulator of T-cell-dependent immune responses.

Publication Types:
Review

PMID: 9585160 [PubMed - indexed for MEDLINE]

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5: Life Sci. 1997;60(13-14):1101-4.


Regulation of muscarinic receptor expression and function in cultured cells and in knock-out mice.

McKinnon LA, Rosoff M, Hamilton SE, Schlador ML, Thomas SL, Nathanson NM.

Department of Pharmacology, University of Washington, Seattle 98195-7750, USA.

We have investigated the molecular and cellular basis for the regulation of expression and function of the muscarinic acetylcholine receptors. Treatment of cultured chick cardiac cells with the agonist carbachol results in decreased levels of mRNA encoding the m2 and m4 receptors. Treatment of chick embryos in ovo with carbachol results in decreased levels of mRNA encoding the potassium channel subunits GIRK1 and GIRK4 as well as the m2 receptor. There are thus multiple pathways for the regulation of mAChR responsiveness by long-term agonist exposure. Immunoblot, immunoprecipitation, and solution hybridization analyses have been used to quantitate the regulation of mAChR expression in chick retina during embryonic development. The m4 receptor is the predominant subtype expressed early in development, while the expression of the m3 and m2 receptors increases later in development. A cAMP-regulated luciferase reporter gene has been used to demonstrate that the m2 and m4 receptors have distinct specificities for coupling to G-protein subtypes to mediate inhibition of adenylyl cyclase. This system has also been used to demonstrate that beta-arrestin1 and beta-adrenergic receptor kinase-1 act synergistically to promote receptor desensitization. We have isolated the promoter region for the chick m2 receptor gene, identified regions of the promoter required to drive high level expression in cardiac and neural cells, and have identified a region which confers sensitivity of gene expression to neurally active cytokines. Finally, in order to determine the role of individual receptor subtypes in muscarinic-mediated responses in vivo, we have used the method of targeted gene disruption by homologous recombination to generate mice deficient in the m1 receptor.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 9121353 [PubMed - indexed for MEDLINE]

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6: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13541-6.


Muscarinic acetylcholine receptor expression in memory circuits: implications for treatment of Alzheimer disease.

Levey AI.

Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.

Cholinergic transmission at muscarinic acetylcholine receptors (mAChR) has been implicated in higher brain functions such as learning and memory, and loss of synapses may contribute to the symptoms of Alzheimer disease. A heterogeneous family of five genetically distinct mAChR subtypes differentially modulate a variety of intracellular signaling systems as well as the processing of key molecules involved in the pathology of the disease. Although many muscarinic effects have been identified in memory circuits, including a diversity of pre- and post-synaptic actions in hippocampus, the identities of the molecular subtypes responsible for any given function remain elusive. All five mAChR genes are expressed in hippocampus, and subtype-specific antibodies have enabled identification, quantification, and localization of the encoded proteins. The m1, m2, and m4 mAChR proteins are most abundant in forebrain regions and they have distinct cellular and subcellular localizations suggestive of various pre- and postsynaptic functions in cholinergic circuits. The subtypes are also differentially altered in postmortem brain samples from Alzheimer disease cases. Further understanding of the molecular pharmacology of failing synapses in Alzheimer disease, together with the development of new subtype-selective drugs, may provide more specific and effective treatments for the disease.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 8942969 [PubMed - indexed for MEDLINE]

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7: Prog Brain Res. 1996;109:165-8.


Regulation of muscarinic acetylcholine receptor expression and function.

Nathanson NM.

Department of Pharmacology, University of Washington, Seattle 98195-7750, USA.

Publication Types:
Review

PMID: 9009703 [PubMed - indexed for MEDLINE]

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8: Life Sci. 1995;56(11-12):939-43.


Molecular analysis of the regulation of muscarinic receptor expression and function.

Hamilton SE, McKinnon LA, Jackson DA, Goldman PS, Migeon JC, Habecker BA, Thomas SL, Nathanson NM.

Department of Pharmacology, University of Washington, Seattle 98195, USA.

Several systems are being used to determine the molecular and cellular basis for the regulation of expression and function of the muscarinic receptors. Treatment of chick heart cells in culture results in decreased levels of mRNA encoding the cm2 and cm4 receptors. This probably results from decreased gene transcription which requires concomitant mAChR-mediated inhibition of adenylyl cyclase and mAChR-mediated stimulation of phospholipase C. Site-directed mutagenesis was used to demonstrate that the single tyrosine residue in the carboxyl-terminal cytoplasmic tail of the m2 receptor is involved in agonist-induced down-regulation but not sequestration. Activation of heterologous receptors in chick heart cells can also regulate mAChR mRNA levels. A cAMP-regulated luciferase reporter gene, has been used to demonstrate that the m4 receptor preferentially couples to Gi alpha-2 or Go alpha over Gi alpha-1 or Gi alpha-3 to mediate inhibition of adenylyl cyclase activity. Finally, in order to determine the role of individual receptor subtypes in muscarinic-mediated responses in vivo, we are beginning to use the method of targeted gene disruption by homologous recombination to generate mice deficient in specific receptor subtypes.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 10188796 [PubMed - indexed for MEDLINE]

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9: Ann N Y Acad Sci. 1990;588:185-9.


Regulation of muscarinic receptor and G-protein expression during cardiac development.

Nathanson NM.

Department of Pharmacology, University of Washington, Seattle 98195.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 2113369 [PubMed - indexed for MEDLINE]
 

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