Regulation of putative muscarinic cholinergic receptor subtypes in rat brain |
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| Affiliation: | 1. Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany;2. Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany;3. Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA;1. Department of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany;2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany;3. Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany;4. Institute of Bio, and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich, Jülich, Germany;1. Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany;2. Walther-Straub-Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Goethestr. 33, 80336 Munich, Germany;3. Chemical, Biological and Radiological (CBR) Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK;1. Department of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany;2. Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany;1. Department of Chemistry, Maharaja Bir Bikram College, Agartala, 799 004, Tripura, India;2. Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500 007, India;3. Academy of Scientific & Innovative Research, 2 Rafi Marg, New Delhi, 110 001, India;4. Department of Pharmacy, BCDA College of Pharmacy and Technology, Hridaypur, Kolkata, 700 127, India;1. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany;2. Department of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität München, München, Germany;3. Bundeswehr Institute of Pharmacology and Toxicology, München, Germany;4. John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry) & Institute of Bio, and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich, Jülich, Germany |
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| Abstract: | Transection of the fimbria/fornix, producing a 75% reduction in the activity of the cholinergic marker choline-o-acetyltransferase (CAT EC. 2.3.1.6) in rat hippocampus, did not change the binding characteristics of the non-subtype selective, muscarinic cholinergic receptor antagonist ligand [3H](−)quinuclidinyl benzilate {[3H](−)QNB}. Pirenzepine competition for [3H](−)QNB binding in the hippocampus was best described by a computer derived model assuming two binding sites of high affinity (putative M1 receptors) and low affinity (putative M2 receptors). There was no change in the proportion of high and low affinity pirenzepine binding sites in the hippocampus following cholinergic deafferentation. Thus, these data provide no evidence for a discrete localization of either putative subtype of muscarinic receptor discriminated by pirenzepine restricted to the terminals of CAT containing neurons innervating the rat hippocampus.Chronic scopolamine treatment produced a 48% increase in the Bmax of [3H](−)QNB binding in the hippocampus, but again there was no change in the proportions of the sites discriminated by pirenzepine demonstrating that both putative subtypes were regulated identically. Similarly, carbachol competition for [3H](−)QNB was unaltered following cholinergic deafferentation or chronic scopolamine treatment. Furthermore, similar guanylyl-5′-imidodiphosphate [Gpp(NH)p] modulation of the proportions of high and low affinity carbachol binding sites was found in the hippocampus following transection of the fimbria/fornix or chronic scopolamine treatment. Thus there is no adaptation of receptor-effector coupling following these treatments that is reflected by changes in receptor recognition site characteristics.Carbachol competition for [3H]pirenzepine binding to putative M1 receptors in the hippocampus was biphasic and was also modulated by Gpp(NH)p. In the brainstem, there was a homogeneous population of putative M2 [3H](−)QNB binding sites having low affinity for pirenzepine. Carbachol competition for these binding sites was also biphasic and modulated by guanine nucleotides. Thus, both putative M1 and M2 muscarinic receptors, as defined by high or low affinity for pirenzepine respectively, may mediate their effects in rat brain via a guanine nucleotide regulatory subunit. |
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