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1.
Mol Cell Neurosci ; 20(2): 244-56, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12093157

ABSTRACT

Acetylcholinesterase inhibitors (AChE-I) of various pharmacological classes have been used to provoke acute and chronic hypercholinergy in brain. Each condition induces a dramatic decrease of the abundance of muscarinic receptors at the membrane of neurons with simultaneous increase of these receptors in the cytoplasm in association with different subcellular organelles with characteristics depending on the duration of the treatment (short-term versus long term treatment). Each condition also induces a dramatic increase of cytoplasmic receptors associated with endosomes and multivesicular bodies. Chronic treatment with MTF induces a general decrease of m4R in the striatum without modification of the mRNA level but with an exaggerated abundance of muscarinic receptors in the cytoplasm at the sites of synthesis and maturation, i.e., endoplasmic reticulum, nuclear membrane and Golgi apparatus. These results suggest that the membrane abundance and intraneuronal distribution of neurotransmitter receptors are modified following drug treatment with specificity depending on the nature and the duration of treatment.


Subject(s)
Acetylcholinesterase/metabolism , Cell Membrane/metabolism , Cholinesterase Inhibitors/pharmacology , Cytoplasm/metabolism , Neostriatum/enzymology , Neurons/enzymology , Receptors, Muscarinic/metabolism , Acetylcholinesterase/drug effects , Acetylcholinesterase/genetics , Animals , Atropine/pharmacology , Cell Membrane/drug effects , Cell Membrane/ultrastructure , Cytoplasm/drug effects , Cytoplasm/ultrastructure , Dendrites/drug effects , Dendrites/metabolism , Dendrites/ultrastructure , Drug Administration Schedule , Immunohistochemistry , Male , Microscopy, Electron , Muscarinic Antagonists/pharmacology , Neostriatum/drug effects , Neostriatum/ultrastructure , Neurons/drug effects , Neurons/ultrastructure , Organelles/drug effects , Organelles/metabolism , Organelles/ultrastructure , Physostigmine/pharmacology , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Muscarinic M2 , Receptor, Muscarinic M4 , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/ultrastructure , Tacrine/pharmacology , Trichlorfon/pharmacology , Up-Regulation/drug effects , Up-Regulation/physiology
2.
Am J Physiol Gastrointest Liver Physiol ; 280(4): G729-37, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11254500

ABSTRACT

The duodenal glands have been thought to play an important role in defense against proximal duodenal ulcer; however, the secretory mechanisms of these glands remain to be determined. In isolated duodenal acinar cells of the pig, we investigated the effects of ACh on intracellular Ca(2+) concentration ([Ca(2+)](i)) and on membrane currents with fura 2 fluorometry and the patch clamp technique. ACh caused a transient increase in [Ca(2+)](i), and the increase was markedly inhibited by atropine or 4-diphenylacetoxy-N-methylpiperidine methiodide but not by hexamethonium, pirenzepine, or methoctramine. The expression of mRNA for the M(3) subtype far exceeded that for either M(1) or M(2) as revealed by real-time quantitative PCR and in situ hybridization. The rise in [Ca(2+)](i) evoked by ACh was largely inhibited by thapsigargin but slightly affected by extracellular Ca(2+) deprivation. Caffeine had no effect on [Ca(2+)](i). ACh elicited Ca(2+)-dependent K(+) currents, a finding similar to the response to inositol 1,4,5,-trisphosphate applied intracellularly. These results suggest the presence of M(3) receptors linked to Ca(2+) release in porcine duodenal glands.


Subject(s)
Calcium Signaling/physiology , Duodenum/physiology , Exocrine Glands/physiology , Receptors, Muscarinic/physiology , Adenosine Triphosphatases/antagonists & inhibitors , Animals , Calcium/physiology , Calcium Signaling/drug effects , Duodenum/drug effects , Duodenum/ultrastructure , Electrophysiology , Enzyme Inhibitors/pharmacology , Exocrine Glands/drug effects , Exocrine Glands/ultrastructure , In Situ Hybridization , In Vitro Techniques , Microscopy, Electron , Muscarinic Agonists/pharmacology , Muscarinic Antagonists/pharmacology , Patch-Clamp Techniques , RNA , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/ultrastructure , Reverse Transcriptase Polymerase Chain Reaction , Swine , Thapsigargin/pharmacology
3.
Brain Res ; 894(1): 109-20, 2001 Mar 09.
Article in English | MEDLINE | ID: mdl-11245821

ABSTRACT

In this study, to identify the precise localization of m2 and m3 muscarinic receptors in the anteroventral and anterodorsal thalamic nuclei of the rat, we used receptor-subtype-specific antibodies and characterized their immunolocalization patterns by light and electron microscopy. Many m2-positive neurons were distributed throughout these nuclei. Ultrastructural analysis showed that more than 30% of m2-positive dendritic profiles in these nuclei are proximal dendritic shafts. Moreover, a few m2-positive fiber terminals were found only in the anterodorsal thalamic nucleus. These m2-positive terminals were large (1.10+/-0.30 microm in diameter) and formed asymmetrical synapses with dendritic profiles. The m3-positive neurons were also distributed in both nuclei, and the m3-positive neuropil exhibited a significant staining gradient, with the most intense staining in the ventrolateral part of the anteroventral thalamic nucleus. This region receives the densest cholinergic input originating from the dorsal tegmental region. At the ultrastructural level, the majority of m3-positive dendritic profiles were more distal regions of the dendrites compared to the m2 receptors in the anteroventral thalamic nucleus. However, no significant difference in the intradendritic distribution pattern between m2 and m3 receptors was found in the anterodorsal thalamic nucleus, which receives no cholinergic input. These findings show the differential localization of m2 and m3 receptors in the anteroventral and anterodorsal thalamic nuclei, and suggest that the m3 receptors are spatially more closely associated with ascending cholinergic afferent fibers in the anteroventral thalamic nucleus.


Subject(s)
Anterior Thalamic Nuclei/chemistry , Cholinergic Fibers/chemistry , Dendrites/chemistry , Receptors, Muscarinic/analysis , Animals , Anterior Thalamic Nuclei/ultrastructure , Cholinergic Fibers/ultrastructure , Dendrites/ultrastructure , Immunohistochemistry , Rats , Rats, Sprague-Dawley , Receptor, Muscarinic M2 , Receptor, Muscarinic M3 , Receptors, Muscarinic/ultrastructure
4.
Life Sci ; 66(18): 1675-82, 2000 Mar 24.
Article in English | MEDLINE | ID: mdl-10809164

ABSTRACT

Hexane-bisammonium-type compounds containing lateral phthalimide moieties are known to have a rather high affinity for the allosteric site of muscarinic M2 receptors. In order to get more insight into the contribution of the lateral substituents for alloster binding affinity, a series of compounds with unilaterally varying imide substituents were synthesized and tested for their ability to retard allosterically the dissociation of [3H]N-methylscopolamine from the receptor protein (control t1/2 = 2 min; 3 mM MgHCO4, 50 mM Tris, pH 7.3, 37 degrees C). Among the test compounds, the naphthalimide containing agent (half maximum effect at ECs5,diss = 60 nM) revealed the highest potency. Apparently, its affinity for the allosteric site in NMS-occupied receptors is 20fold higher compared with the phthalimide containing parent compound W 84. Analysis of quantitative structure-activity relationships yielded a parabolic correlation between the volume of the lateral substituents and the allosteric potency. The maximal volume was determined to be approximately 600 A3 suggesting that the allosteric binding site contains a binding pocket of a defined size for the imide moiety.


Subject(s)
Muscarinic Antagonists/chemical synthesis , Receptors, Muscarinic/chemistry , Animals , Heart/drug effects , In Vitro Techniques , Membranes/drug effects , Membranes/metabolism , Muscarinic Antagonists/chemistry , Myocardium/metabolism , Quaternary Ammonium Compounds/chemical synthesis , Quaternary Ammonium Compounds/pharmacology , Receptor, Muscarinic M2 , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/ultrastructure , Structure-Activity Relationship , Swine
5.
Prog Neurobiol ; 58(5): 409-71, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10380240

ABSTRACT

Immunocytochemical mapping studies employing the extensively used monoclonal anti-muscarinic acetylcholine receptor (mAChR) antibody M35 are reviewed. We focus on three neuronal muscarinic cholinoceptive substrates, which are target regions of the cholinergic basal forebrain system intimately involved in cognitive functions: the hippocampus; neocortex; and amygdala. The distribution and neurochemistry of mAChR-immunoreactive cells as well as behaviorally induced alterations in mAChR-immunoreactivity (ir) are described in detail. M35+ neurons are viewed as cells actively engaged in neuronal functions in which the cholinergic system is typically involved. Phosphorylation and subsequent internalization of muscarinic receptors determine the immunocytochemical outcome, and hence M35 as a tool to visualize muscarinic receptors is less suitable for detection of the entire pool of mAChRs in the central nervous system (CNS). Instead, M35 is sensitive to and capable of detecting alterations in the physiological condition of muscarinic receptors. Therefore, M35 is an excellent tool to localize alterations in cellular cholinoceptivity in the CNS. M35-ir is not only determined by acetylcholine (ACh), but by any substance that changes the phosphorylation/internalization state of the mAChR. An important consequence of this proposition is that other neurotransmitters than ACh (especially glutamate) can regulate M35-ir and the cholinoceptive state of a neuron, and hence the functional properties of a neuron. One of the primary objectives of this review is to provide a synthesis of our data and literature data on mAChR-ir. We propose a hypothesis for the role of muscarinic receptors in learning and memory in terms of modulation between learning and recall states of brain areas at the postsynaptic level as studied by way of immunocytochemistry employing the monoclonal antibody M35.


Subject(s)
Amygdala/chemistry , Hippocampus/chemistry , Neocortex/chemistry , Neuronal Plasticity/physiology , Receptors, Muscarinic/analysis , Age Factors , Amygdala/blood supply , Animals , Cerebral Arteries/metabolism , Cerebral Veins/metabolism , Glutamate Decarboxylase/analysis , Hippocampus/blood supply , History, 19th Century , History, 20th Century , Humans , Immunohistochemistry , Interneurons/chemistry , Learning/physiology , Memory/physiology , Neocortex/blood supply , Protein Kinase C/analysis , Receptors, Muscarinic/history , Receptors, Muscarinic/ultrastructure
6.
Arch Oral Biol ; 43(3): 197-204, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9631172

ABSTRACT

The purpose of this study was to determine whether presynaptic cholinergic receptors are present in sympathetic nerves in human dental pulp. Pulp was incubated with [3H]noradrenaline (0.6 mumol/l) for 30 min and then superfused with Krebs' solution at 1.0 ml/min. Electrical stimulation (100 sec, 5 Hz) increased the overflow of [3H]noradrenaline into the superfusate. Carbachol (10 and 100 mumol/l), an agonist of muscarinic receptors, decreased the stimulation-induced (SI) overflow of 3H, an effect blocked by atropine but not hexamethonium. Carbachol, atropine and hexamethonium had no effect on the resting overflow. Nicotine (10 mumol/l) increased the resting overflow and inhibited the SI overflow, although the inhibition was variable. Cytisine, another agonist of nicotinic receptors, also increased the resting overflow, but did not affect the SI overflow. To ascertain whether the actions of nicotine and electrical stimulation were influenced by the release of nitric oxide (NO), the effects of an NO donor and two NO-synthase inhibitors were examined. With the exception of one of the NO-synthase inhibitors (L-NAME), the agents were without effect on the overflow of 3H in the absence or presence of nicotine. It was concluded that sympathetic nerves in human dental pulp possess (a) presynaptic muscarinic receptors that inhibit the SI release of noradrenaline, and (b) nicotinic receptors that evoke the release of noradrenaline and that inhibit the SI release of the transmitter. The results do not point to a significant role for NO in the effects of stimulation or nicotine on the overflow of 3H.


Subject(s)
Dental Pulp/innervation , Receptors, Muscarinic/ultrastructure , Receptors, Presynaptic/ultrastructure , Sympathetic Nervous System/ultrastructure , Adolescent , Adult , Alkaloids/pharmacology , Atropine/pharmacology , Azocines , Carbachol/pharmacology , Electric Stimulation , Enzyme Inhibitors/pharmacology , Female , Hexamethonium/pharmacology , Humans , Isotonic Solutions , Male , Muscarinic Agonists/pharmacology , Muscarinic Antagonists/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/pharmacology , Nitric Oxide/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Norepinephrine/pharmacology , Quinolizines , Radiopharmaceuticals , Receptors, Muscarinic/drug effects , Receptors, Nicotinic/drug effects , Receptors, Nicotinic/ultrastructure , Receptors, Presynaptic/antagonists & inhibitors , Receptors, Presynaptic/drug effects , Sympathetic Nervous System/drug effects , Sympathomimetics/pharmacology , Tritium
7.
Brain Res ; 720(1-2): 225-9, 1996 May 13.
Article in English | MEDLINE | ID: mdl-8782916

ABSTRACT

Cholinergic innervation of the cerebrovasculature is known to regulate vascular tone, perfusion rate and permeability of the microvascular wall. Notably the cholinergic innervation of cerebral capillaries is of interest since these capillaries form the blood-brain barrier. Although there is a general consensus as to the presence of nicotinic and muscarinic receptors in the domain of the capillary wall, their precise anatomical position is unknown. The subcellular localization of muscarinic receptors in rat cortical capillaries was approached by way of immunocytochemistry at the ultrastructural level using monoclonal antibody M35 against muscarinic receptor protein. Binding of this antibody in the microvascular domain was found in 5% of the capillaries studied and was exclusively present in perivascular astroglia, and never in endothelium or pericytes. Combined with reported data on presynaptic cholinergic innervation the results indicate a cholinergic innervation pattern of non-directed presynaptic terminal structures in apposition to cholinoceptive perivascular astroglia with muscarinic receptor positive endfeet embracing the capillary basement membrane. The possible functional significance of such a cholinergic vascular innervation pattern is discussed with respect to capillary dynamics and barrier function.


Subject(s)
Cerebral Cortex/ultrastructure , Receptors, Muscarinic/ultrastructure , Acetylcholine/metabolism , Animals , Antibodies, Monoclonal , Astrocytes/metabolism , Astrocytes/ultrastructure , Capillaries/enzymology , Capillaries/metabolism , Capillaries/ultrastructure , Cerebral Cortex/blood supply , Cerebral Cortex/metabolism , Cerebrovascular Circulation/physiology , Choline O-Acetyltransferase/biosynthesis , Forelimb/innervation , Forelimb/physiology , Immunohistochemistry , Male , Microscopy, Electron , Rats , Rats, Wistar , Receptors, Muscarinic/metabolism
8.
Eur J Biochem ; 227(1-2): 466-75, 1995 Jan 15.
Article in English | MEDLINE | ID: mdl-7851424

ABSTRACT

The m3 muscarinic acetylcholine receptor from rat heterologously produced in insect cells after infection with a recombinant baculovirus has an apparent molecular mass of approximately 75 kDa. Polyclonal antibodies raised against a carboxy-terminal nonapeptide that is unique to the m3 subtype can detect the receptors produced in the insect cells by Western blot and can also immunoprecipitate solubilized receptor. Immunofluorescence microscopy as well as electron microscopy revealed that the receptor was located intracellularly, visualized as a ring around the nucleus of the infected insect cells. Solubilization of the receptor was accomplished with digitonin which was added in increments (over 10 min) to a final concentration of 0.8% (mass/vol). The solubilized receptor is unstable when the ligand-binding site is not protected by a ligand. Here the low-affinity ligand propylbenzilylcholine (approximately 10 nM) has demonstrable protective ability during solubilization, but the usefulness of this ligand is limited by a very slow off rate. From the behaviour of the solubilized receptor during DEAE-Sephacel chromatography and lectin-affinity chromatography it can be deduced that the receptor produced in insect cells is heterogeneously glycosylated in the producing insect cells.


Subject(s)
Receptors, Muscarinic/metabolism , Affinity Labels , Amino Acid Sequence , Animals , Baculoviridae/genetics , Blotting, Western , Cells, Cultured , Chromatography, Affinity , Chromatography, Ion Exchange , Cloning, Molecular , Microscopy, Electron , Molecular Sequence Data , Precipitin Tests , Rats , Receptors, Muscarinic/genetics , Receptors, Muscarinic/ultrastructure , Spodoptera
9.
Life Sci ; 56(11-12): 931-8, 1995.
Article in English | MEDLINE | ID: mdl-10188795

ABSTRACT

We have utilized subtype specific antibodies to determine the cellular and subcellular distributions of the muscarinic acetylcholine receptor subtypes that are highly expressed in the rat striatum (m1-m4). Each receptor is expressed in distinct populations of striatal neurons in the relative proportions predicted by their mRNAs. They concentrate at post-synaptic sites and each of the four subtypes are also transported to pre-synaptic sites. m2 appears to be the only presynaptic autoreceptor in the striatum, but it is also localized in non-cholinergic terminals. These distinct pre- and post-synaptic localizations suggest that muscarinic receptor subtype diversity evolved to enable increasingly complex responses to acetylcholine release.


Subject(s)
Neostriatum/metabolism , Neurons, Afferent/metabolism , Receptors, Muscarinic/metabolism , Receptors, Presynaptic/metabolism , Synapses/metabolism , Animals , Axons/metabolism , Axons/ultrastructure , Cell Count , Immunoenzyme Techniques , Microscopy, Electron , Neostriatum/cytology , RNA, Messenger/biosynthesis , Rabbits , Rats , Receptors, Muscarinic/genetics , Receptors, Muscarinic/ultrastructure , Synapses/ultrastructure
10.
Prog Brain Res ; 98: 121-7, 1993.
Article in English | MEDLINE | ID: mdl-8248499

ABSTRACT

Based on the sequence of the five cloned muscarinic receptor subtypes (m1-m5), subtype selective antibody and cDNA probes have been prepared. Use of these probes has demonstrated that each of the five subtypes has a markedly distinct distribution within the brain and among peripheral tissues. The distributions of these subtypes and their potential physiological roles are discussed. By use of molecular genetic manipulation of cloned muscarinic receptor cDNAs, the regions of muscarinic receptors that specify G-protein coupling and ligand binding have been defined in several recent studies. Overall, these studies have shown that amino acids within the third cytoplasmic loop of the receptors define their selectivities for different G-proteins and that multiple discontinuous epitopes contribute to their selectivities for different ligands. The residues that contribute to ligand binding and G-protein coupling are described, as well as the implied structures of these functional domains.


Subject(s)
Receptors, Muscarinic/classification , Animals , Binding Sites , Brain Chemistry , GTP-Binding Proteins/metabolism , Humans , Ligands , Muscle Proteins/classification , Muscle Proteins/physiology , Muscle, Smooth/chemistry , Myocardium/chemistry , Nerve Tissue Proteins/classification , Nerve Tissue Proteins/physiology , Organ Specificity , Receptors, Muscarinic/physiology , Receptors, Muscarinic/ultrastructure
12.
FASEB J ; 6(3): 845-52, 1992 Feb 01.
Article in English | MEDLINE | ID: mdl-1740234

ABSTRACT

Acetylcholine signals through two types of unrelated membrane receptors referred to as nicotinic (nAChR) and muscarinic (mAChR) acetylcholine receptors. Nicotinic acetylcholine receptors were the first neurotransmitter receptors to be purified, cloned, and sequenced, and much is known about these proteins. In contrast, until 5 years ago relatively little was known about the muscarinic receptors. Since then there has been an explosion of information concerning the structure, signaling, and regulation of what is now known to be a family of muscarinic receptors. This review discusses the five identified members of the mAChR family and their coupling to the multiple G proteins that allow mAChRs to modulate many different types of signal transduction pathways. The five members of this family that have been identified so far have striking homology in their hydrophobic membrane domains but possess distinct cytoplasmic domains between the fifth and sixth membrane-spanning regions. These cytoplasmic domains appear to contain important determinants for receptor/G protein interaction and are likely to contain phosphorylation sites that regulate these interactions. mAChR agonists have been shown to induce phosphorylation of mAChR in intact cells, and the evidence that suggests that receptor phosphorylation may play a role in the regulation of receptor function is discussed.


Subject(s)
Cyclic AMP-Dependent Protein Kinases , Receptors, Muscarinic/physiology , Signal Transduction/physiology , Animals , Chickens , GTP-Binding Proteins/physiology , Humans , Mice , Phosphorylation , Protein Kinase C/physiology , Protein Kinases/physiology , Receptors, Muscarinic/ultrastructure , Receptors, Nicotinic/physiology , beta-Adrenergic Receptor Kinases
13.
Curr Eye Res ; 10(5): 437-55, 1991 May.
Article in English | MEDLINE | ID: mdl-1889229

ABSTRACT

Cynomolgus monkeys underwent unilateral panretinal scatter photocoagulation (PRP) and/or nasal and temporal horizontal retinal meridional photocoagulation (HRMP) with xenon arc or argon or krypton laser light. Shortly thereafter, in the PRP-treated eyes, accommodative responsiveness to topical eserine and electrical stimulation of the Edinger-Westphal nucleus (EWN) was diminished, accommodative responsiveness to intramuscular (i.m.) pilocarpine was enhanced, and the number of muscarinic receptors in the ciliary muscle was reduced compared to the contralateral controls. In most instances, these parameters returned to normal over 6-12 wks and the abnormalities could be induced again by another round of PRP. However, in some PRP-treated eyes, accommodative responsiveness to EWN stimulation and topical eserine remained subnormal permanently (greater than 1 yr). Shortly after HRMP alone, accommodative responses to i.m. pilocarpine, topical eserine, and central stimulation did not differ markedly in the treated and control eyes. Morphologic studies 1 to 78 wk following PRP revealed that myelinated and unmyelinated nerves within the entire circumference of the choroid and ciliary muscle were severely damaged early on. The number of unmyelinated nerves between the individual ciliary muscle fibers was drastically reduced, those which remained were swollen or deteriorated, and agranular synaptic vesicles were rarely seen. Thereafter, the nerves in the choroid and ciliary muscle gradually regenerated. Following HRMP, only the choroidal nerves which passed through the photocoagulated areas and the ciliary muscle nerves in the corresponding meridians showed signs of deterioration, and there was minimal effect on the physiologic responses examined. These findings collectively indicate that intraocular parasympathetic denervation of the ciliary muscle is produced by PRP, although all nerve types are likely damaged.


Subject(s)
Ciliary Body/ultrastructure , Light Coagulation/adverse effects , Muscle Denervation , Parasympathetic Nervous System/ultrastructure , Retina/surgery , Accommodation, Ocular , Animals , Ciliary Body/innervation , Female , Fundus Oculi , Macaca fascicularis , Male , Myelin Sheath/ultrastructure , Nerve Regeneration , Receptors, Muscarinic/ultrastructure , Reflex, Pupillary
15.
Acta Psychiatr Scand Suppl ; 366: 14-26, 1991.
Article in English | MEDLINE | ID: mdl-1680268

ABSTRACT

The first part of this article deals with several aspects of efferents and afferents of the rat basal forebrain cholinergic system (BFChS) studied with anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L). PHA-L tracing of the BFChS efferents revealed topographically differentiated axonal trajectories and patterns of presynaptic endings to the neocortex, mesocortex, olfactory nuclei and hippocampus. Combining this method with second immunolabeling, we identified the muscarinic cholinoceptive neurons in the neocortex and the somatostatinergic neurons in the hippocampus as being directly innervated by the magnocellular basal nucleus and the medial septum, respectively. The prefrontal cortex was identified as a source of afferent input to the basal forebrain cholinergic neurons. This projection also exhibits a topographic organization, which shows a reciprocal relationship with the BFChS efferents to the cortex. The second part of this article describes the anatomical changes of cortical cholinergic and some other neurotransmitter systems after long-term cholinergic denervation in the aged rat cortex. The spared cholinergic projection in the largely denervated areas shows abundant malformations, which are similar in appearance to the anatomical alterations of the surviving cholinergic fibers in dementia of the Alzheimer type (AD). Hypertrophic changes also occur in the serotonergic system. The neuropeptide-Y- and somatostatin-containing cortical systems respond with an increment of their axonal densities, in contrast to the decline of these peptides in AD. Although transsynaptic effects are mediated by long-term cholinergic lesions, they do not support the hypothesis that the cholinergic deficiency is a primary event in the pathophysiology of AD.


Subject(s)
Brain/anatomy & histology , Cerebral Cortex/anatomy & histology , Cholinergic Fibers/ultrastructure , Receptors, Cholinergic/ultrastructure , Synaptic Transmission/physiology , Afferent Pathways/anatomy & histology , Aging/physiology , Amygdala/anatomy & histology , Animals , Brain Mapping , Brain Stem/anatomy & histology , Efferent Pathways/anatomy & histology , Frontal Lobe/physiology , Hippocampus/anatomy & histology , Male , Microscopy, Electron , Nerve Degeneration/physiology , Neurons/physiology , Neuropeptide Y/physiology , Rats , Rats, Inbred Strains , Receptors, Muscarinic/ultrastructure , Septum Pellucidum/anatomy & histology , Serotonin/physiology , Somatostatin/physiology , Synapses/ultrastructure
16.
J Comput Aided Mol Des ; 4(2): 131-45, 1990 Jun.
Article in English | MEDLINE | ID: mdl-2213061

ABSTRACT

Today, more than 40 protein amino acid (AA) sequences of membrane receptors coupled to guanine nucleotide binding proteins (G-proteins) are available. For those working in the field of medicinal chemistry, these sequences present a new type of information that should be taken into consideration. To make maximal use of sequence data it is essential to be able to compare different protein sequences in a similar way to that used for small molecules. A prerequisite, however, is the availability of a processing environment that enables one to handle sequences in an easy way, both by hand and by computer. In order to meet these ends, the package CGEMA (Colour Graphics Editor for Multiple Alignment) was developed in our laboratory. The programme uses a user-definable colour coding for the different AAs. Sequences can be aligned by hand or by computer, using VGAP, and both approaches can be combined. VGAP is a novel in-house written alignment programme with a variable gap penalty that also handles consecutive alignments using one sequence as a probe. In addition, secondary structure prediction tools are available. From the 20 protein sequences, available for the muscarinic acetylcholine receptor, 13 different sequences were selected, covering the subtypes m1 to m5. By comparing the sequences, two major groups are revealed that correspond to those found by considering the transducing system coupled to the various receptor subtypes. Different parts of the protein sequences are identified as characterizing the subtype and binding the ligands, respectively.


Subject(s)
Computer Graphics , Receptors, Muscarinic/genetics , Sequence Homology, Nucleic Acid , Software , Amino Acid Sequence , Animals , Binding Sites , Data Display , Drug Design , Humans , Man-Machine Systems , Molecular Sequence Data , Protein Conformation , Receptors, Muscarinic/ultrastructure , Species Specificity
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