Muscarinic Cholinergic Receptor Regulation of Inositol Phospholipid Metabolism and Calcium Mobilization

Brown, Joan Heller; McDonough, Patrick M.

doi:10.1007/978-1-4612-4498-1_7

Cited by 11 publications

(7 citation statements)

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“…101 and 102). Indeed, both nicotinic and muscarinic classes of acetylcholine receptors have been shown to affect functioning of structural and adhesion proteins through cascade reactions mediated by protein kinases (103)(104)(105)(106)(107)(108). The presence of anti-KC autoantibodies may therefore explain why PV IgG but not normal IgG induced phosphorylation of adhesion molecules.…”

Section: Discussionmentioning

confidence: 99%

Pemphigus Vulgaris IgG and Methylprednisolone Exhibit Reciprocal Effects on Keratinocytes

Nguyen

Arredondo

Chernyavsky

et al. 2004

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Pemphigus Vulgaris IgG and Methylprednisolone Exhibit Reciprocal Effects on Keratinocytes

Nguyen

Arredondo

Chernyavsky

et al. 2004

Journal of Biological Chemistry

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“…Muscarinic acetylcholine receptors belong to the large group of receptors coupled with G proteins (1). Signal transduction from the M2 and M4 muscarinic receptor subtypes occurs preferentially via the guanine nucleotide-binding regulatory proteins Gi and Go, whereas the M1, M3, and M5 receptor subtypes couple preferentially with proteins of the Gq family (2,3).…”

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confidence: 99%

Activation of muscarinic acetylcholine receptors via their allosteric binding sites.

Jakubík

Bačáková

Vaccari

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

107

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Ligands that bind to the allosteric-binding sites on muscarinic acetylcholine receptors alter the conformation of the classical-binding sites of these receptors and either diminish or increase their affinity for muscarinic agonists and classical antagonists. It is not known whether the resulting conformational change also affects the interaction between the receptors and the G proteins. We classical-binding site (12-18). The attachment of the allosteric modulator to the allosteric-binding site brings about a change in the conformation of the classical (orthosteric)-binding site and thereby an increase or (more usually) a decrease in the affinity of the receptor for muscarinic agonists and competitive antagonists.The effects of the activation of the allosteric-binding site on the function of the classical-binding site (as reflected by changes in the association, dissociation, and equilibrium binding of muscarinic agonists and competitive antagonists) have been amply investigated (6-8). However, little attention has been paid to the possibility that the allosteric modulators might also affect the conformation and function of the G protein binding site and, consequently, the interaction between muscarinic receptors, G proteins, and the G protein-regulated effector molecules. We present evidence that the allosteric modulators alcuronium, gallamine, and strychnine acting in the absence of agonists have profound agonist-like effects on the synthesis of cAMP and inositol phosphates (IPs) in cells stably transfected with the genes for muscarinic receptors and that, apparently, muscarinic receptors can be activated not only by ligands acting via their classical-binding site, but also by ligands acting via the allosteric-binding site. We suggest that the same novel mechanism of receptor activation may operate on the other G protein-coupled receptors.Muscarinic acetylcholine receptors belong to the large group of receptors coupled with G proteins (1). Signal transduction from the M2 and M4 muscarinic receptor subtypes occurs preferentially via the guanine nucleotide-binding regulatory proteins Gi and Go, whereas the M1, M3, and M5 receptor subtypes couple preferentially with proteins of the Gq family (2, 3). Muscarinic agonists bind to the classical-binding site, which is located in the depth of the cell membrane in a barrel formed by the seven transmembrane segments of the receptor molecule (4, 5). Agonist binding brings about a change in the conformation of the intracellular receptor domain responsible for the contact with the G protein, and this change brings about the activation of the G protein. Although details of these interactions are the subject of scrutiny and debate, it is generally believed that the attachment of the signal molecule to the classical-binding site is the necessary first step in muscarinic receptor-mediated signal transduction across the cell membrane.However, it is well known that the binding properties of the classical-binding sites of muscarinic receptors are subject to allosteric reg...

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“…(Fig. 2), suggesting that the presynaptic muscarinic receptors on the two sets of nerve terminals might differ; these compounds are somewhat selective for Ml receptors in other tissues (15). [B] is the antagonist concentration and DR is the ratio of equi-effective agonist concentrations in the absence and presence of pirenzepine.…”

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confidence: 99%

Distinct muscarinic receptors inhibit release of gamma-aminobutyric acid and excitatory amino acids in mammalian brain.

Sugita

Uchimura

Jiang

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

147

117

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Intracellular recordings were made from neurons of rat lateral amygdala, nucleus accumbens, and striatum in vitro. Synaptic potentials mediated by Y-aminobutyric acid and by excitatory amino acids were isolated pharmacologically by using receptor antagonists, and their amplitudes were used as a measure oftransmitter release. Mucanrne and acetylcholine inhibited the release of both y-aminobutyric acid and excitatory amino acids, but measurements of the dissociation equilibrium constants for the antagonists piren- ,4]benzodiazepine-6-one, methoctramine, and hexahydrosiladifenidol indicated clearly that different muscarinic receptors were involved (MI and probably M3, respectively). The differential localization of distinct muscarinc receptor subtypes on terminals releasing the major inhibitory and excitatory transmitters of the brain could be exploited therapeutically in some movement disorders and Alzheimer disease.Acetylcholine (AcCho) has diverse functional roles in the mammalian brain, including actions at muscarinic receptors that are important for memory (1). Cholinergic neurons are lost in Alzheimer disease, and one therapeutic approach has been to develop drugs that mimic the neurotransmitter action of missing AcCho (1). However, such drugs, like AcCho itself, will have different effects at different muscarinic receptors in the brain, and not all of these effects may be desired. Three muscarinic receptors (M1-M3) can be distinguished pharmacologically, but five (ml-mS) have been identified by molecular cloning (ml-m3 correspond to M1-M3) (2-8).Fibers containing 'y-aminobutyric acid (GABA) and excitatory amino acids such as glutamate provide synaptic inputs to virtually all central neurons; therefore, in addition to their direct effects on neurons (9, 10), muscarinic agonists will also excite or inhibit cells by acting presynaptically to change release of these neurotransmitters. In the present experiments, the release of GABA and excitatory amino acids (glutamate) was assayed by recording the amplitude of depolarizing synaptic potentials from neurons in three brain regions where AcCho is known to play an important functional role-the amygdala, nucleus accumbens, and striatum. METHODSAdult rats were anesthetized with halothane and killed by a heavy blow to the chest. The brain was rapidly removed, and a block of tissue containing nucleus accumbens, dorsal striatum, or amygdaloid complex was sectioned with a Vibratome. Intracellular recordings were made from slices (300 ,am thick) by using electrodes containing 2 M KCI (11-13).The superfusing solution was a bicarbonate buffer gassed with 95% 02/5% CO2 and contained 2.5 mM KCI, 2.4 mM CaC12, 1.3 mM MgCl2, 1.2 mM NaH2PO4, 26 mM NaHCO3, 126 mM NaCi, and 10 mM glucose. The slice was completely submerged in this flowing solution, which was prewarmed to 370C. Drugs were applied by changing this solution to one that contained the drug. A bipolar tungsten-in-glass stimulating electrode was used for focal stimulation. The components of the synaptic potential...

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Muscarinic Cholinergic Receptor Regulation of Inositol Phospholipid Metabolism and Calcium Mobilization

Cited by 11 publications

References 202 publications

Pemphigus Vulgaris IgG and Methylprednisolone Exhibit Reciprocal Effects on Keratinocytes

Pemphigus Vulgaris IgG and Methylprednisolone Exhibit Reciprocal Effects on Keratinocytes

Activation of muscarinic acetylcholine receptors via their allosteric binding sites.

Distinct muscarinic receptors inhibit release of gamma-aminobutyric acid and excitatory amino acids in mammalian brain.

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