[Receptor diseases. 1: Disorders of adrenergic receptors, cholinergic receptors and neurotransmitters].
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Humans↗
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The rabbit cornea lacks cholinergic receptors.
Cholinergic receptors were studied in membranes prepared from rabbit cornea, iris-ciliary body, and retina, using 3H-quinuclidinyl benzilate (3H-QNB) to identify muscarinic receptors and 125I-alpha-bungarotoxin (125I-BGT) to identify nicotinic receptors. Muscarinic cholinergic receptors were not found in the cornea. As a positive control, muscarinic cholinergic receptors were characterized in preparations of the iris-ciliary body. Specific binding of 3H-QNB to iris-ciliary body membrane preparations was saturable, with a Kd of 1.3 nM QNB. Specificity of the assay for muscarinic receptors was confirmed by the relative abilities of the following compounds to displace 3H-QNB: atropine greater than pilocarpine greater than hexamethonium. Nicotinic cholinergic receptors were not found in the cornea. As a positive control, nicotinic cholinergic receptors were characterized in preparations of the retina. Specific binding of 1252-BGT to retinal membrane preparations was saturable with both high and low affinity receptors (Kd values of 1.0 nM and 93 nM BGT, respectively). Specificity of the assay for nicotinic receptors was confirmed by the relative abilities of the following compounds to prevent 125I-BGT binding: curare greater than or equal to nicotine greater than hexamethonium greater than atropine. The lack of cholinergic receptors in the cornea, which has high levels of acetylcholine and related enzymes, suggests either an extraordinary use or a lack of function for acetylcholine in this tissue.
Animals↗
Hippocampal sympathetic ingrowth and cholinergic denervation alter hippocampal muscarinic cholinergic receptors.
Cholinergic denervation of the hippocampus by medial septal (MS) lesions results in the ingrowth of peripheral sympathetic fibers, originating from the superior cervical ganglia, into the hippocampus. To determine the effect of hippocampal sympathetic ingrowth (HSI) [3H]-QNB (L-quinuclidinyl [benzilic-4,4(n)] binding was assessed in the dorsal and ventral hippocampus four weeks after MS lesions. In dorsal hippocampus, HSI was found to significantly increase the number (Bmax) of [3H]-QNB binding sites and to normalize the decrease in affinity found in animals with MS lesions plus ganglionectomy (i.e., no ingrowth). In ventral hippocampus, HSI was found to normalize the increased number of binding sites and decreased affinity found in animals with MS lesions without ingrowth. No effect on either Kd or Bmax was found in animals that had undergone ganglionectomy with sham MS lesions. These results suggest that HSI can induce changes in hippocampal muscarinic cholinergic receptors.
Animals↗
[Changes in muscarinic cholinergic receptors and cholinergic neurons in experimental hydrocephalic rat brain].
Recently, the relationship between neurological disorders and neurotransmitters has received much attention. Many studies have been reported about the changes of neurotransmitters and their metabolites in cerebrospinal fluid (CSF) in hydrocephalus, and it is presumed that neurotransmitters may play a role in the regulation of CSF dynamics. We injected kaolinum suspension into the cisterna magna of rats and created experimental hydrocephalus. Here we define the acute hydrocephalic stage to be the seventh day after injection and the chronic to be the twenty-first day after injection. We made studies about the changes of muscarinic cholinergic receptors in experimental hydrocephalic rat brains using binding assay, macroautoradiography, and microautoradiography with 3H-quinuclidinyl benzilate (QNB), which has a high and specific affinity for muscarinic receptors. We also studied the changes of cholinergic neurons in experimental hydrocephalic rat brains by immunohistochemical methods with anti-choline acetyltransferase (CAT), the antibody for the synthetic enzyme of acetylcholine which is thought to exist only in cholinergic neurons. Muscarinic cholinergic receptors were increased in acute hydrocephalus, and tended to normalize in chronic hydrocephalus but no change was observed in its distribution. There seemed to be no difference in the number of CAT positive cells between normal and hydrocephalic rat brains, but in hydrocephalic rat brain, CAT positive cells were compressed by the dilated ventricles, and they might have fallen into hypofunction. It is thought that muscarinic receptors were increased by some mechanism like denervation hypersensitivity because of the reduction of ACh production or release. Recent advancement of PET or SPECT has made it possible to investigate the changes of neurotransmitter receptors in human brain. Such biochemical examination may offer some information to assess the functional state of hydrocephalus and to find a new approach to its treatment.
Animals↗
Interaction between alpha and beta adrenergic receptors and cholinergic receptors in isolated perfused rat heart: effects on cAMP-protein kinase and phosphorylase.
The ability of acetylcholine to antagonize catecholamine-induced activation of myocardial cyclic AMP dependent protein kinase and glycogen phosphorylase activity was assessed using isolated perfused rat hearts. Perfused hearts were treated with either saline, epinephrine, epinephrine plus phentolamine or isoproterenol. After 1 minute of infusion of the indicated drug a second infusion containing acetylcholine was started. After an additional minute hearts were frozen and analyzed for cyclic nucleotide content and enzyme activity. In the presence of the alpha receptor blocking agent, phentolamine, epinephrine is a more effective activator of protein kinase than in its absence. Under these conditions the antagonistic action of acetylcholine on protein kinase activation is more pronounced. In the presence of epinephrine plus phentolamine or in the presence of isoproterenol the antagonistic action of acetylcholine on phosphorylase activity can be accounted for by a reduction in cyclic AMP-protein kinase. This same action of acetylcholine on epinephrine-stimulated phosphorylase in the aabsence of phentolamine, however, cannot be totally accounted for by a reduction in cyclic AMP content or in protein kinase activity.
Acetylcholine↗
The levamisole receptor, a cholinergic receptor of the nematode Caenorhabditis elegans.
We describe a glass fiber filter binding assay for the levamisole receptor, a putative acetylcholine receptor of the nematode Caenorhabditis elegans, and we show that receptor detected in vitro binds both levamisole derivatives and cholinergic agonists with the pharmacological specificity expected of the physiologically functional nematode receptor. The receptor is detected by the binding of tritiated meta-aminolevamisole ([3H]MAL, 27 Ci/mmol). In extracts of the wild-type nematode, there is a saturable, high affinity binding activity for [3H]MAL (Kd approximately 5-10 nM). Well fed wild-type worms contain as much as 3 fmol of high affinity binding activity per mg of extract protein (0.14 pmol/g of wet weight of worms) and dauer larvae, a special juvenile stage, contain as much as 15 fmol of activity per mg of protein. Specific binding activity per mg of protein is highest in larval stages and decreases severalfold in the adult worm. The rates of formation and dissociation of the [3H]MAL-receptor complex are relatively slow (dissociation half-life, 17 min), in agreement with physiological studies of levamisole on Ascaris muscle strips. Levamisole derivatives and cholinergic agonists have the same relative potencies in inhibiting [3H]MAL binding as they do in causing nematode muscle contraction. Vertebrate cholinergic antagonists do not inhibit [3H]MAL binding, but several antagonists (mecamylamine, alpha-bungarotoxin, and cobra venom) potentiate the binding of [3H]MAL and can be used to demonstrate more clearly the presence of a second, lower affinity binding activity whose ligand-binding affinity is also potentiated by these agents. Both high and low affinity wild-type binding components are missing in the extremely levamisole-resistant mutant unc-74(x19).
Age Factors↗
Beta-adrenergic receptors and m-cholinergic receptors in human lung. Findings following in vivo and in vitro exposure to the beta-adrenergic receptor agonist, terbutaline.
In order to investigate whether treatment with terbutaline (1 mg subcutaneously) in patients with bronchial obstruction is accompanied by changes in the densities of receptors of the autonomic nervous system, beta-adrenergic receptors or m-cholinergic receptors were measured in membrance preparations of human peripheral lung tissue from patients undergoing lung resection for bronchial carcinoma. The density of beta-adrenergic receptors and mononuclear leukocytes (MNLs) of treated and untreated patients and beta-adrenergic receptors and m-cholinergic receptors in lung strips from the same patients exposed to terbutaline in vitro were studied for comparison. In patients, treatment with terbutaline did not have any effect on human lung beta-adrenergic receptors and m-cholinergic receptors, whereas a 57 percent decline was measured in the number of beta-receptors on MNLs of the very same patients. In contrast, in vitro exposure of human peripheral lung strips to terbutaline (100 mumol/L for 36 hours) evoked a time-dependent and concentration-dependent decline of 46 percent in beta-adrenergic receptors. Again, there was no change in the number of m-cholinergic receptors. The antagonist affinities, as judged from the KD values, did not differ under either condition. We concluded that lung beta-adrenergic receptors are subject to down-regulation when exposed to agonists in vitro. This down-regulation in the human lung is not accompanied by alterations in m-cholinergic receptors. Down-regulation of beta-adrenergic receptors or up-regulation of m-cholinergic receptors appears not to play a role in the proposed tolerance to beta-adrenergic receptor agonist treatment in clinical situations. The reduction of beta-adrenergic receptors in MNLs provides evidence that treatment with terbutaline was sufficient to affect beta-adrenergic receptors in vivo in certain cell types but also shows that alterations in blood cells do not necessarily reflect the situation in the lung.
Aged↗
Chagasic IgG binding with cardiac muscarinic cholinergic receptors modifies cholinergic-mediated cellular transmembrane signals.
The interaction of the IgG from Trypanosoma cruzi-infected mice (chagasic IgG) with cardiac cholinergic receptors by means of specific radioligand binding and by production of cholinergic-mediated cellular transmembrane signals was characterized. Chagasic IgG inhibited, in a noncompetitive manner, the binding of [3H]quinuclidinyl benzilate to the cardiac membrane. Moreover, chagasic IgG could modify all of the muscarinic cholinergic effects mediated by a G regulatory protein, i.e., decrement of atria contractility, inhibition of cAMP, or activation of the turnover of phosphoinositides via phospholipase C. The cGMP production was also increased by the antibody. The data demonstrated that chagasic IgG interacting with cardiac muscarinic cholinergic receptor triggers the biological effects associated with cholinergic-mediated cellular transmembrane signals. The implications of the results in the pathogenesis of Chagas' myocarditis are discussed.
Animals↗
Effects of bifemelane hydrochloride on loss of N-methyl-D-aspartate receptor and muscarinic cholinergic receptor binding in the gerbil hippocampus after transient ischemia.
The effects of bifemelane hydrochloride on changes of N-methyl-D-aspartate receptors and muscarinic cholinergic receptors were examined in the gerbil hippocampus after transient ischemia with radioactive-specific ligands. There were marked reductions in both these receptors in the gerbil hippocampus 14 days after transient ischemia, without changes in the respective affinities. Post-ischemia bifemelane treatment almost completely prevented the ischemia-induced decreases in the numbers of these receptors, and had no effect in sham-operated controls. The results of the present study suggest that this drug prevents postsynaptic dysfunction induced by transient ischemia, and may be useful in the therapy of both the chronic and the acute stage of cerebrovascular disease.
Animals↗
Characterization of postsynaptic beta-adrenergic receptors and presynaptic muscarinic cholinergic receptors in the rat spleen.
The beta-adrenergic and muscarinic cholinergic receptors in the splenic homogenates of control and 6-hydroxydopamine (6-OHDA) treated rats were characterized. The specific binding of [3H]dihydroalprenolol (DHA) and [3H]quinuclidinyl benzilate (QNB) in the rat spleen were saturable and of high affinity and showed pharmacological specificity of splenic beta-adrenergic and muscarinic cholinergic receptors. Following 6-OHDA treatment, the Bmax value for specific [3H](-)DHA binding to the rat spleen was significantly increased by 26 percent and 22 percent compared to control at 2 and 3 weeks without a change in the Kd. In contrast, there was a 38 percent decrease in the Bmax for [3H](-)QNB in the 6-Ohda treated rat spleen at 2 and 3 weeks respectively without a change in the Kd. The Bmax value at 5 weeks was significantly greater than that at 2 or 3 weeks. The splenic norepinephrine (NE) concentration was markedly reduced by the 6-OHDA treatment at 1 to 3 weeks, while there was a significant recovery in the splenic NE concentration at 5 weeks. Thus, our results strongly suggest that we are biochemically localizing muscarinic cholinergic receptors on the sympathetic nerves of the rat spleen and that the beta-adrenergic receptors of the spleen are localized postsynaptically.
Alprenolol↗
Monoclonal antibodies detect the conservation of muscarinic cholinergic receptor structure from Drosophila to human brain and detect possible structural homology with alpha 1-adrenergic receptors.
Muscarinic cholinergic receptors isolated from Drosophila heads, rat and human brain, dog heart, and monkey ciliary muscle were examined for structural similarities/differences by utilizing isoelectric focusing, sodium dodecyl sulfate/polyacrylamide gel electrophoresis, and monoclonal antibody crossreactivity. Muscarinic receptors were affinity labeled with [3H]propylbenzilylcholine mustard and subjected to isoelectric focusing. Muscarinic receptors from each species focused with an isoelectric point of 5.9. The same proteins all migrated with an apparent molecular mass of 80,000 daltons on sodium dodecyl sulfate gels. Six hybridomas secreting monoclonal antibodies specific for muscarinic receptors were developed by using purified rat brain muscarinic receptors as the antigen. The six different monoclonal antibodies immunoprecipitated muscarinic receptors from all tissues and species tested, including human and Drosophila brains, with equal efficacy. These data indicate that muscarinic receptors are highly conserved over a considerable evolutionary period. One of the six muscarinic receptor monoclonal antibodies also immunoprecipitated rat liver alpha 1-adrenergic receptors. Furthermore, two out of five monoclonal antibodies raised against alpha 1-receptors immunoprecipitated muscarinic receptors. These data suggest that some degree of structural homology exists between muscarinic cholinergic receptors and alpha 1-adrenergic receptors.
Animals↗
Chronic thyrotropin releasing hormone (TRH) administration on TRH receptors and muscarinic cholinergic receptors in CNS.
Intraperitoneal injections of thyrotropin releasing hormone (TRH, 6 mg/kg/day) to rats for 14 days resulted in a significant loss (20 25%) of TRH binding sites in the hippocampus, hypothalamus and cerebral cerebral cortex. The TRH-mediated loss was reversible and reflected a decrease in binding sites but no change in affinity. On the other hand, this TRH treatment did not affect the specific brain binding of [3H]QNB. The results suggest that TRH participates in regulating CNS-TRH receptors.
Animals↗
[Effect of activation of alpha- and beta-adrenergic receptors, M-cholinergic receptors and H1-histamine receptors on mechanical tension in the frog subclavian vein].
The effects of adrenaline, noradrenaline, isoproterenol, dopamine, histamine, acetylcholine, and serotonin on the wall tension in the isolated frog subclavian vein and modification of these effects by appropriate antagonists were examined. The existence of alpha- and beta-adreno-, M-choline- and H1-histamine receptors was demonstrated. Stimulation of alpha-adreno- and H1-histamine receptors augments and that of beta-adreno- and M-cholinoreceptors diminishes active wall tension in the vein.
Adrenergic Agonists↗
Cholinergic receptor labelling specific irreversible binding of bromoacetylcholine to cholinergic receptors at neuromuscular junctions.
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Acetylcholine↗
Studies on the cholinergic receptor protein of Electrophorus electricus. I. An assay in vitro for the cholinergic receptor site and solubilization of the receptor protein from electric tissue.
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Animals↗
Molecular requirements of the active sites of the cholinergic receptors. XVI - Synthesis and cholinergic activity of 2- or 5-alkyl or 5-phenyl-4-methyl-3-oxo-1-dimethylaminomethylcyclopentane methiodide.
In order to study the cholinergic receptor through affinity chromatography, some derivatives of deoxamuscarone (I a) incorporating alkyl and phenyl substituents at the positions 2 and 5 were synthesized as model compounds. However, the sharp drop in activity and the lack of discrimination between nicotinic and muscarinic receptors exhibited by the compounds discourage their further development as affinity reagents.
Animals↗
The effect of hippocampal sympathetic ingrowth and cholinergic denervation on hippocampal M2 cholinergic receptors.
After cholinergic denervation of the hippocampus, via medial septal (MS) lesions, peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus. In this study, we sought to determine the effect of hippocampal sympathetic ingrowth (HSI) on the M2 subtype of muscarinic cholinergic receptors, by examining the membrane binding of [3H]AF-DX 384 in hippocampal tissue from control rats, rats with HSI and rats with MS lesions + concurrent ganglionectomy (CD group). In dorsal hippocampus, Kd was found to be increased while Bmax was decreased in the CD group as compared with both the HSI and control group which did not differ from one another. In ventral hippocampus, Kd was found to be increased while Bmax was decreased in the CD group when compared only with the control group. These results suggest that sympathetic ingrowth, which has its greatest concentration in dorsal hippocampus, can 'normalize' the M2 receptor in hippocampus.
Animals↗
Design, synthesis and functional characterization of a pentameric channel protein that mimics the presumed pore structure of the nicotinic cholinergic receptor.
Nicotinic cholinergic receptors are membrane proteins composed of five subunits organized around a central aqueous pore. A pentameric channel protein, T5M2 delta, that emulates the presumed pore-forming structure of this receptor was generated by assembling five helix-forming peptide modules at the lysine epsilon-amino groups of the 11-residue template [K*AK*KK*PGK*EK*G], where * indicates attachment sites. Helical modules represent the sequence of the M2 segment of the Torpedo californica acetylcholine receptor (AChR) delta subunit; M2 segments are considered involved in pore-lining. Purified T5M2 delta migrates in SDS-PAGE with an apparent M(r) approximately 14,000, concordant with a protein of 126 residues. T5M2 delta forms cation-selective channels when reconstituted in planar lipid bilayers. The single channel conductance in symmetric 0.5 M KCl is 40 pS. This value approximates the 45 pS single channel conductance characteristic of authentic purified Torpedo AChR, recorded under otherwise identical conditions. These results, together with conformational energy calculations, support the notion that a bundle of five amphipathic alpha-helices is a plausible structural motif underlying the inner bundle that forms the pore of the pentameric AChR channel.
Amino Acid Sequence↗