Presynaptic Receptors and Neuronal Transporters

Official Satellite Symposium to the IUPHAR 1990 Congress Held in Rouen, France, on 26–29 June 1990

S.Z. Langer, A.M. Galzin, J. Costentin

• Publisher: Pergamon
• Year: 2013
• Print ISBN: 9780080411651
• eBook ISBN: 9781483278223
• Topic: Biological Sciences
• Subtopic: Zoology
• Index: Biological Sciences

Advances in the Biosciences, Volume 82: Presynaptic Receptors and Neuronal Transporters documents the proceedings of the Official Satellite Symposium to the IUPHAR 1990 Congress held in Rouen, France on June 26-29, 1990. The first part of this book deals with the extensive and still increasing list of presynaptic release-modulating auto and heteroreceptors, emphasizing the various subtypes of presynaptic receptors that are characterized by functional studies, both in vitro and in vivo, using a number of experimental approaches. The next chapters are devoted to the molecular pharmacology of presynaptic receptors, of which can interfere with G proteins and modify the activity of adenylate cyclase, guanylate cyclase, or protein kinase C. The purification and molecular biology of transporter systems, including cloning and sequencing of the neuronal sodium-ion coupled GABA transporter are also discussed. This compilation concludes with insights on the function of presynaptic receptors and neuronal transporters both in the periphery and in the CNS, as well as their ubiquitous locations and physiological roles. This publication is a good reference for students and individuals researching on the presynaptic autoreceptors and neurotransmitters.

Physiological and Pharmacological Relevance of Presynaptic Receptors in Neurotransmission

S.Z. Langer, I. Angel and H. Schoemaker, Synthélabo Recherche (L.E.R.S.), 58 rue de la Glacière, 75013 Paris, France

ABSTRACT

During the last twenty years, the concept that noradrenaline can regulate its own release through an action on presynaptic autoreceptors, has been confirmed and extended to several neurotransmitters in the periphery and in the central nervous system. In addition, many nerve terminals possess presynaptic heteroreceptors which can be acted upon by transmitters released from adjacent terminals, by cotransmitter neuropeptides or by locally produced or blood-borne endocoids to either inhibit or facilitate transmitter release. In the noradrenergic system, the concept of presynaptic modulation of transmitter release developped in parallel with pharmacological evidence for the existence of α₂-and α₂-adrenoceptor subtypes. In the meanwhile three different α₂-adrenoceptor clones were identified by molecular biologists that may correspond to pharmacologically different subtypes of α₂-adrenoceptors. The heterogeneity of presynaptic release-modulating α₂-adrenoceptors may offer the opportunity of developping selective drugs with novel and useful therapeutic properties.

KEYWORDS

Presynaptic autoreceptors

Transmitter release

Alpha adrenoceptor subtypes

Presynaptic heteroreceptors

Noradrenaline

Neuropeptide cotransmitters

Introduction

Neurotransmitters can regulate their own release through an action on inhibitory autoreceptors located on the synaptic nerve terminal (for recent reviews see Langer and Lehmann, 1988; Starke et al, 1989). The physiological role of presynaptic inhibitory autoreceptors was first established for noradrenaline in the peripheral nervous system through the demonstration of a negative feed-back mechanism through which this transmitter can modulate its own release (Langer, 1974). The pharmacological possibilities for intervention through selective agonists, partial agonists or antagonists acting on presynaptic, release modulating receptors, resulted from the characterization of the autoreceptor subtype for each of the neurotransmitters. In addition to presynaptic autoreceptors, many nerve terminals possess presynaptic heteroreceptors that are sensitive to endogenous mediators other than the neuron’s own transmitter. Activation of these terminal presynaptic heteroreceptors can either inhibit or facilitate the release of a neurotransmitter. In contrast to presynaptic terminal autoreceptors, the physiological role of presynaptic heteroreceptors remains to be established. Nevertheless, selective agonists or partial agonists should be expected to produce pharmacological effects through the activation of presynaptic heteroreceptors even if these receptors are not involved in a physiologically relevant mechanism modulating transmitter release.

While it is well established that the presynaptic autoreceptor that regulates noradrenaline release corresponds to the α₂-subtype (Langer, 1974, 1981), recent molecular biology and receptor binding studies indicate that the α₂-adrenoceptor is expressed as three distinct receptor subtypes (Bylund 1988, Harrison et al. 1991). The functional relevance of the three cloned α₂-adrenoceptor subtypes is still an open question.

One example of a peripheral neuroeffector junction where α₂-adrenoceptors are present both pre-and-postsynaptically is offered by the insulin secreting β-cells of the pancreas. The present article reports the pharmacological profile of SL 84.0418, a pyrrolo-indole derivative with high selectivity for α₂-adrenoceptors in the periphery (Langer et al. 1990; Langer and Angel, 1991). This α₂-adrenoceptor antagonist is at present being tested in man as a novel therapeutic approach for the treatment of type Π or non-insulin dependent diabetes mellitus (NIDDM).

Materials and Methods

The twitch response of the isolated rat vas deferens was employed to study drug effects at presynaptic α₂-adrenoceptors as described by Hicks et al (1985) and the rabbit pulmonary artery was used to determine postsynaptic α₂-adrenoceptor antagonism in-vitro according to Schoemaker et al (1989). Drug effects on α₂-adrenoceptor agonist-induced hyperglycemia were studied according to Angel et al (1990).

Results

The pyrrolo-indole derivative SL 84.0418 is a potent, competitive antagonist of the inhibition by clonidine of the twitch response of the rat vas deferens and the pA₂ is similar to that obtained with idazoxan (Table 1). SL 84.0418 has a chiral center and is a racemic mixture of two enantiomers, SL 86.0715 ((+) enantiomer) and SL 86.0714 ((-) enantiomer). The (+) enantiomer, SL 86.0715 is at least 100-fold more potent than the (-) enantiomer, SL 86.0714 (Table 1).

Table 1

Comparison of the alpha-2 and alpha-1 antagonist properties of SL 84.0418 and its enantiomers with idazoxan

^(a)rat vas deferens;

^(b)rabbit pulmonary artery

As shown in table 1, SL 84.0418 and its (+) enantiomer, SL 86.0715 are considerably less potent at α,-adrenoceptors, and they possess a selectivity ratio of more than 1000 when their α₂-and α₁-adrenoceptor antagonist properties are compared under in-vitro conditions.

As shown in Table 2, SL 84.0418 antagonized in a dose-dependent manner the hyperglycemia induced by UK 14304 in mice. This α₂-adrenoceptor blocking property resides in the active enantiomer SL 86.0715 (table 2) while SL 86.0714 was much less active in this test (table 2). Consequently both in-vitro and in-vivo SL 84.0418 and 86.0715 elicit α₂-adrenoceptor antagonist effects.

Table 2

STEROSPECIFICITY OF SL 84.0418 AGAINST HYPERGLYCEMIA MEDIATED BY ACTIVATION OF ADRENOCEPTORS IN MICE

Discussion

The novel α₂-adrenoceptor antagonist SL 84.0418 and its active enantiomer SL 86.0715 represent the most selective compound so far reported in this pharmacological class. From our experimental models it appears that SL 84.0418 possesses similar potency as an antagonist of presynaptic as well as postsynaptic α₂-adrenoceptors. For exemple, in the in situ blood perfused dog pancreas SL 84.0418 enhances the release of endogenous noradrenaline during sympathetic nerve stimulation in the same range of doses in which it antagonizes the inhibition of insulin release induced by activation of postsynaptic α₂-adrenoceptors (Duval et al., 1991). In contrast to idazoxan, which blocks both central and peripheral α₂-adrenoceptors, upon oral administration, SL 84.0418 antagonizes preferentiall...

Table of contents

• Cover image
• Title page
• Table of Contents
• ADVANCES IN THE BIOSCIENCES
• Copyright
• Preface
• Chapter 1: Physiological and Pharmacological Relevance of Presynaptic Receptors in Neurotransmission
• Chapter 2: Pre- and Postjunctional Muscarinic Receptors in the Guinea-pig Trachea
• Chapter 3: Presynaptic α-autoadrenoceptors on Peripheral Noradrenergic Neurones of Newborn Rabbits and Dogs
• Chapter 4: Cholinergic–Adrenergic Presynaptic Interactions in the Heart and Characterization of the Receptors Involved
• Chapter 5: Structural Requirements for DA2 (peripheral) Dopamine Receptor Agonist Activity
• Chapter 6: α2-adrenoceptor Modulation of Noradrenaline Release in Human and Rabbit Renal Arteries: Clonidine Acts as a Partial Agonist
• Chapter 7: Effect of α2-adrenoceptor Antagonists on Norepinephrine Release and Inhibition of Insulin Secretion During Pancreatic Nerve Stimulation. Interactions at Pre- and Postsynaptic Sites
• Chapter 8: Antagonist Activity of SL 84.0418 and Idazoxan at Pre and Postsynaptic α2-adrenoceptors
• Chapter 9: Does the Distance Between Nerve Varicosities and Adrenoceptors Play Any Role in the Relative Contribution of ATP/Noradrenaline for Postjunctional Response?
• Chapter 10: In vivo Presynaptic Interaction Between 5-HT and Adrenergic Antagonists on Noradrenergic Neurotransmission
• Chapter 11: Activity of N-ethyl-nor-arecaidine Propargyl Ester and (R)-nipecotic Acid Ethyl Ester at Pre- and Postsynaptic Muscarinic Receptor Subtypes
• Chapter 12: Effects of Neuromuscular Blocking Agents on Neuronal Nicotine Receptors of Motor Nerves: Blockade of Nicotinic Autofacilitation and Backfiring
• Chapter 13: A Rapid in vitro Assay of the Histamine H3-receptor: Inhibition of Electrically Evoked Contractions of Guinea-pig Ileum Preparations
• Chapter 14: Factors Influencing the Function of Presynaptic α2-adrenoceptors in Rat Brain
• Chapter 15: Presynaptic Dopaminergic Autoreceptors as Targets for Drugs
• Chapter 16: DOPA Itself Facilitates Noradrenaline Release via Presynaptic β-adrenoceptors in Rat Hypothalamic Slices — DOPA is Probably a Neuroactive Substance
• Chapter 17: The Third Dopamine Receptor (D3) as an Autoreceptor
• Chapter 18: Terminal Dopaminergic Autoreceptors are of Minor Importance for the Sedation Produced by DA Receptor Agonists in Rats
• Chapter 19: Modulation of 5-HT Release by Presynaptic Inhibitory and Facilitatory 5-HT Receptors in Brain Slices
• Chapter 20: Modulation of 5-hydroxytryptamine and Noradrenaline Release in the Brain and Retina via Presynaptic Heteroreceptors: Some New Aspects
• Chapter 21: Autoreceptors and Heteroreceptors Evidenced by Histamine H3 Receptor Ligands
• Chapter 22: Somato-dendritic 5-HT1A Autoreceptors in the Dorsal Raphe Nucleus; Pharmacological and Functional Properties
• Chapter 23: Autoreceptor-mediated Control of Serotonin Release in the Rat Brain in vivo
• Chapter 24: Effects of α2-adrenoceptor Agonist and Antagonist on Spatial Memory in Rats
• Chapter 25: Modulation of the Ca2+-evoked Release of Dopamine from Synaptosomes
• Chapter 26: Evidence Against a Direct Link Between Serotonin Uptake Sites and Presynaptic Serotonin Autoreceptors
• Chapter 27: A Comparison of Presynaptic Serotonin Autoreceptors in Rabbit, Rat and Guinea-pig Brain Cortex
• Chapter 28: Serotonergic Modulation of the Release of [3H]GABA from Guinea-pig Hippocampal Synaptosomes
• Chapter 29: Pre- and Postsynaptic Location of 5-HT3 Receptors in the Rat Spinal Cord
• Chapter 30: Distribution of [3H]SCH 23390 Binding Sites in the Human Substantia Nigra
• Chapter 31: Presynaptic Regulation of Dopamine Release from Synaptosomes of the Rat Striatum is Controlled by Different Types of Glutamate Receptors
• Chapter 32: Microdialysis Studies of the Effects of Local Apomorphine Infusions on Dopamine Release in Rat Striatum
• Chapter 33: Dopaminergic Hetero-regulation of Striatal μ-Opiate Receptors: Further Evidence for Their Postsynaptic Location
• Chapter 34: Presynaptic Modulation of Striatal Dopamine Release by Enkephalins
• Chapter 35: Modulation of Dopamine and Acetylcholine Release in the Rabbit Caudate Nucleus by Opioids: Receptor Type and Interaction with Autoreceptors
• Chapter 36: Presynaptic Autoreceptors May Control the Release of Metenkephalin from the Rat Spinal Cord
• Chapter 37: Involvement of NMDA Receptors in the Presynaptic Regulation of Dopamine Release in Striosome-and Matrix-enriched Areas of the Rat Striatum
• Chapter 38: Inhibition of Synaptosomal Tyrosine Hydroxylase by Dopamine Autoreceptors: Role of Ca2+ and K+
• Chapter 39: Dopaminergic Modulation of Striatal Sensory Responses
• Chapter 40: Selective Presynaptic Dopamine Agonist Treatment of Schizophrenia with BHT-920
• Chapter 41: Effects of the Antiparkinsonian Drugs Amantadine and Memantine on Striatal Neurotransmitter Release in vitro
• Chapter 42: Transmitter Interactions in Striatum May Occur via Effects on High Affinity Transporters
• Chapter 43: A Comparison of the Effect of Baclofen on Radiolabelled GABA and Noradrenaline Release in Rat Cortical Slices
• Chapter 44: Effects of Chronic Treatment with Flunitrazepam on GABAA, Adenosine and Glutamate Receptor Plasticity in Rats
• Chapter 45: Modulation of N-Methyl-D-Aspartate (NMDA)-stimulated Noradrenaline Release in Rat Brain Cortex by Presynaptic α2-adrenoceptors and Histamine H3 Receptors
• Chapter 46: Noradrenaline Release in the Pig Retina and Its Histamine H3 Receptor-mediated Inhibition
• Chapter 47: Structure and Function of the GABA Reuptake System
• Chapter 48: Energizing the Vacuolar System of Eukaryotic Cells
• Chapter 49: The Molecular Size of the Neuronal Noradrenaline Carrier
• Chapter 50: Identification and Regulation of High-affinity-choline Transporter
• Chapter 51: Ketanserin as a Ligand of the Vesicular Monoamine Transporter
• Chapter 52: Dopamine Transporter — Cocaine Receptor: Characterization and Purification
• Chapter 53: Characterization and Purification of the Serotonin Transporter Located at the Cytoplasmic Membrane of Human Platelets: A Three-step Strategy
• Chapter 54: Molecular Characterization of the Neuronal Sodium-ion Coupled 5-hydroxytryptamine Transporter
• Chapter 55: Kinetic Analyses of the Na+ and Cl−-Dependences of the Synaptosomal Specific Uptake of 3H Dopamine
• Chapter 56: Localization of Dopamine Uptake Complex by BTCP on Rat Brain Sections and Dopaminergic Neurons in vitro
• Chapter 57: In vivo Binding of [3H]GBR 12783 in Mouse Brain — Characteristics of the Labelling of Striatal Dopamine Uptake Sites
• Chapter 58: [3H]GBR12935 Binds to Membrane from the Human Platelet
• Chapter 59: Dopamine Transporter in Aging
• Chapter 60: Sodium Dependent, High Affinity Choline Transport Expressed in Oocytes
• Chapter 61: Comparison of the Effects of Vesamicol and of Cetiedil Analogues on Acetylcholine Release and Vesicular Acetylcholine Transport
• Chapter 62: Dopamine Modulates [3H]BTCP (a Phencyclidine Derivative) Binding to the Dopamine Uptake Complex
• Chapter 63: The Heterogeneous Labelling with 3H-noradrenaline of the Incubated Vas Deferens of the Rat
• Chapter 64: Alterations in Platelet [3H]-Imipramine Binding, 5HT Uptake and Plasma α1-acid Glycoprotein Concentrations in Patients with Major Depression
• Chapter 65: Ionic and Temperature Dependences of the 3H Dopamine Specific Uptake and 3H GBR 12783 or 3H Mazindol Specific Binding on the Dopamine Neuronal Carrier
• Chapter 66: Dynamic Properties of Monoamine Storage Vesicles: Pharmacological and Physiological Implications
• Chapter 67: GABA Uptake Inhibitors: Kinetics and Molecular Pharmacology
• Chapter 68: Coexistence of More Than One Neurotransmitter Uptake System on the Same Nerve Terminal in the Brain
• Chapter 69: Peptidergic Regulation of Striatal Dopamine Transporter Complex
• Chapter 70: Different Interactions of Citalopram with the Prejunctional Effects of Serotonin in Peripheral Tissues
• Chapter 71: Evolution of the Vesicular Monoamine Transporter During Ageing in the Rat Brain: a Quantitative Autoradiographic Study with 3H Dihydrotetrabenazine
• Chapter 72: Influence of the Oxygen Disponibility on the Efficiency of the Neuronal Dopamine Uptake Complex
• Chapter 73: Differences in Behavioural Responses Elicited by Dexamphetamine and the Pure Dopamine Uptake Inhibitor GBR 12783
• Chapter 74: Protection of the Synaptosomal 5-HT Uptake System by a Ginkgo Biloba Extract (GBE 761)
• Chapter 75: The Binding of Noradrenaline to the Substrate Recognition Site of the Neuronal Noradrenaline Carrier (Uptake1) Depends on Sodium and Chloride
• Chapter 76: In vivo Distribution of Radiolabelled Citalopram in Brain as a Marker of 5-HT Uptake Sites for PET
• Chapter 77: Relationship of [3H]Paroxetine Binding and 5-HT Recognition Sites on the Neuronal Serotonin Transporter
• Chapter 78: Effects of Repeated Administration of Antidepressants on Serotonin Uptake Sites Measured Using [3H]Cyanoimipramine Autoradiography
• Chapter 79: Rapid Changes in 3H-Imipramine Binding in Platelets of Depressed Patients After Amineptine Treatment
• Chapter 80: Brain 5-HT Uptake Sites, Labelled with [3H]Paroxetine, in Depressed Suicides
• Chapter 81: Pinoline, the Natural Ligand of Serotonin Transporter in Retina and Pineal Gland
• Chapter 82: Differential Interaction of Phencyclidine (PCP) with the Dopamine Uptake Complex and the PCP Receptor in vivo
• Chapter 83: The Uptake of the Amino Acid L-alanine on Its Inhibitory Presynaptic Effects in Rat Isolated Atria
• Chapter 84: Role of Omega (BZD) Sites of the GABAA Receptor Macromolecular Complex in the Modulation of Serotonin Release
• Chapter 85: Mechanisms of Inhibition of Transmitter Release by Adenosine Analogs
• Chapter 86: Dependence of the A1-adenosine Receptor-mediated Inhibition of [3H]Noradrenaline Release in Hippocampus on the Stimulation Conditions
• Chapter 87: Modulation of [3H]-serotonin Release in Rat Spinal Cord Synaptosomes via Dihydropyridine-sensitive Calcium Channels and Protein Kinase C
• Chapter 88: G-proteins and Prejunctional α-adrenoceptors
• Chapter 89: Opioid Inhibition of Oxytocin Release, but not Autoinhibition of Dopamine Release May Involve Activation of Potassium (K+) Channels
• Chapter 90: 3,4-diaminopyridine-evoked Noradrenaline Release in Hippocampal Slices: Further Properties and Involvement of Adenylate Cyclase
• Chapter 91: Interneuronal Cyclic GMP and ‘EDRF-like Substance’ Modulate Norepinephrine Release from Peripheral Sympathetic Nerves
• Chapter 92: Modulatory Role of Neuropeptide Y and Peptide YY at the NMDA Receptor Complex
• Chapter 93: Prejunctional Neuropeptide Y Receptors Are Linked to a G-protein: a Study with N-Ethylmaleimide and Pertussis Toxin
• Chapter 94: Protein Kinase C and Modulation of Neurotransmission: Studies With Protein Kinase Inhibitors
• Chapter 95: Intrasynaptosomal Protein Phosphorylation and Its Inhibition by Plasma Membrane Oxidoreductases
• Chapter 96: Functional and Regulatory Properties of Presynaptic Autoreceptors of the 5-HT1A Subtype on Dorsal Raphe Neurons in Brain Stem Slices
• Chapter 97: Do Schwann Cells Play a Role in ‘Upstream’ Regulation of the Release Probability in Sympathetic Nerve Varicosities?
• Chapter 98: Changes in α2 Presynaptic Receptor Sensitivity During Production of Dependence to Morphine in Conscious Rats
• Chapter 99: Role of Presynaptic α2 Heteroreceptors in Nonsynaptic Modulation of Transmitter Release
• Chapter 100: Autoregulation of Catecholamine Release at Central and Sympathetic Nerve Terminals: Common Features
• Chapter 101: Autoreceptor Mediated Changes in Dopaminergic Terminal Excitability in vivo
• Chapter 102: Prejunctional Autoreceptors in Mouse vas deferens
• Chapter 103: SK&F 104078 Identifies Subtypes of Prejunctional α2-adrenoceptors in the Rat vas deferens
• Chapter 104: Clonidine Inhibition of Norepinephrine Release from Normal and Morphine-Tolerant Guinea Pig Cortical Slices
• Chapter 105: Human Caki-1 Cells Are the First Clonal Cell Line Known to Possess the Extraneuronal Transport Mechanism for Noradrenaline (Uptake2)
• Chapter 106: Inhibition of NA Uptake by (+)-oxaprotiline Inhibits Sympathetic Nerve Activity
• Chapter 107: Autoregulation of Evoked Noradrenaline Release at the Surface of the Isolated Rat Tail Artery Studied by Electrochemistry
• Chapter 108: Autoregulation of Evoked Noradrenaline Release in the Rat Hypothalamic Paraventricular Nucleus Studied in vivo by Electrochemistry
• Chapter 109: Clonidine Early in Life: Effect on Brain Morphofunctional Disturbances Induced by Neonatal Malnutrition in the Rat
• Chapter 110: μ and κ Agonists Inhibit Carbachol-evoked Release of Catecholamines and [Met]enkephalin from ex situ Perfused Dog Adrenals
• Chapter 111: Electrophysiological Evidences for the Preferential Location of D2 Autoreceptors on Dendrites of DA Neurons in the Rat Substantia Nigra
• Chapter 112: Increase of Postsynaptic Dopaminergic Transmission by Presynaptic Actions of Cocaine
• Chapter 113: Autoregulation of Evoked Dopamine Release in the Rat at Central Terminal Sites Studied in vivo by Electrochemistry
• Chapter 114: Combined Effect of (–)-Vesamicol and (+)-Tubocurarine on Endplate Current Amplitude in Rat Skeletal Muscle at High Frequencies of Nerve Stimulation
• Chapter 115: Effect of (–)-Vesamicol on Miniature Endplate Current and Endplate Current Amplitudes in Rat Skeletal Muscle
• Subject Index