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PubMed2005

Phosphorylation of the A-kinase-anchoring protein Yotiao contributes to protein kinase A regulation of a heart potassium channel.

Regulation of the heart by the sympathetic nervous system, fundamental to the physiological response to stress and exercise, requires coordinated phosphorylation of multiple downstream molecular targets, including the I(Ks) (slowly activating potassium current) channel. Sympathetic nervous system stimulation increases intracellular cAMP for which targeted regulation is directed in large part by distinct scaffold or anchoring proteins. Yotiao is an A-kinase-anchoring protein (AKAP) that recruits the cyclic AMP-dependent protein kinase (protein kinase A (PKA)) and protein phosphatase 1 to the carboxyl terminus of the I(Ks) channel to form a molecular complex and control its phosphorylation state, crucial to the cardiac cellular response to sympathetic nervous system stimulation. Here we report that Yotiao itself is a substrate for PKA phosphorylation, and we identify a Yotiao amino-terminal (N-T) residue (Ser-43) that is PKA-phosphorylated in response to beta-adrenergic receptor stimulation. The replacement of Ser-43 by Ala ablates the PKA phosphorylation of N-T Yotiao and markedly diminishes the functional response of the wild type and pseudo-phosphorylated I(Ks) channel to cAMP but neither prevents the PKA phosphorylation of KCNQ1 nor its binding to Yotiao. These results suggest, for the first time, a critical role for the PKA phosphorylation of an AKAP in the functional regulation of an ion channel protein and postphosphorylation allosteric modulation of the I(Ks) channel by Yotiao.

A Kinase Anchor Proteins↗
PubMed1989

Pharmacologic discrimination between receptor heterogeneity and allosteric interaction: resultant analysis of gallamine and pirenzepine antagonism of muscarinic responses in rat trachea.

The antagonism of muscarinic receptor-mediated contraction of rat trachea by a range of muscarinic antagonists was quantified by Schild and resultant analysis. Dose-response curves to carbachol, muscarine and oxotremorine were shifted to the right by gallamine and pirenzepine in a parallel manner with no change in maximal response ostensibly indicating simple competitive inhibition. However, Schild analysis indicated differences in the blockade and estimated pKb values with each agonist for both gallamine and pirenzepine. This suggested either that the responses to these three agonists were mediated by a heterogeneous receptor population in this tissue or that the blockade produced by gallamine and by pirenzepine was not competitive. Further Schild analysis with the muscarinic antagonists scopolamine, atropine, 4-diphenylacetoxy-N-methyl piperidine methiodide and (11 [(2-[(diethylamino)methyl]-1-piperidinyl]acetyl)-5,11- dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine 6-one) with carbachol, muscarine and oxotremorine indicated simple competitive antagonism of a homogeneous population of muscarinic receptors. Therefore, the competitivity of binding of atropine, gallamine and pirenzepine with the scopolamine binding site was measured with the recently reported technique of resultant analysis. With this method the effect of various concentrations of the test antagonist on the antagonism produced by specified concentrations of the reference antagonist scopolamine was measured and the equilibrium dissociation constant of the test antagonist-receptor complex estimated. These data indicated that atropine and scopolamine bind to a common binding site on the muscarinic receptor, but that scopolamine and both gallamine and pirenzepine bind to mutually exclusive sites. This result is mine and pirenzepine are allosteric modulators of muscarinic receptors which bind at sites other than that utilized by agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric Regulation↗
PubMed1992

GABAA receptors: ligand-gated Cl- ion channels modulated by multiple drug-binding sites.

GABAA receptors are ligand-gated Cl- ion channels and the site of action of a variety of pharmacologically and clinically important drugs. In this review evidence is summarized indicating that these drugs, by interacting with several distinct binding sites at these receptors, allosterically modulate GABA-induced Cl- ion flux. Other results indicate that the affinity, as well as the modulatory efficacy of drugs, changes with receptor composition. A though investigation of the pharmacological properties of the individual binding sites on different GABAA receptor subtypes could open new avenues for selective modulation of GABAA receptors in different brain regions.

Animals↗
PubMed2006

Structure-activity relationships of new 1H-imidazo[4,5-c]quinolin-4-amine derivatives as allosteric enhancers of the A3 adenosine receptor.

1H-Imidazo[4,5-c]quinolin-4-amine derivatives have been synthesized as allosteric modulators of the human A3 adenosine receptor (AR). Structural modifications were made at the 4-amino and 2 positions. The compounds were tested in both binding and functional assays, and many were found to be allosteric enhancers of the action of A3AR agonists by several different criteria. First, a potentiation of the maximum efficacy of the agonist Cl-IB-MECA was observed for numerous derivatives. Also, a number of these compounds decreased the rate of dissociation of the agonist [125I]I-AB-MECA from the A3AR. Most prominently, compound 43 (LUF6000) was found to enhance agonist efficacy in a functional assay by 45% and decrease dissociation rate similarly without influencing agonist potency. The structural requirements for allosteric enhancement at the A3AR were distinct from the requirements to inhibit equilibrium binding. Thus, we have prepared allosteric enhancers of the human A3AR that have an improved allosteric effect in comparison to the inhibition of equilibrium binding at the orthosteric site.

Adenosine A3 Receptor Agonists↗
PubMed1988

ICI 169,369 is both a competitive antagonist and an allosteric activator of the arterial 5-hydroxytryptamine2 receptor system.

The mode of action of ICI 169,369, a novel 5-hydroxytryptamine2 (5-HT2) receptor antagonist, was investigated in arterial muscle. Isolated preparations from calf coronary artery and from rat tail artery with the endothelium rubbed off were set up to contract isometrically with 5-HT. ICI 169,369 (1-3000 nM) antagonized surmountably and competitively the contractile effects of 5-HT in coronary artery (pKB, 9.1) and tail artery (pKB, 8.8). Methysergide antagonized unsurmountably 5-HT-induced contractions by reducing maximum effects to 25% (coronary artery: pIC50, 9.8) and 60% (tail artery: pIC80, 9.0). ICI 169,369 (100-300 nM) restored the maximum effects of 5-HT that had been depressed by methysergide (20 nM coronary artery, 100 nM tail artery). Preincubation with ICI 169,369 also prevented the methysergide-induced depression of the maximum effects of 5-HT. The protective effect of ICI 169,369 was overcome by high methysergide concentrations (up to 3 microM), suggesting competition between the two drugs for a common site. The data are consistent with an allosterically modulated interconversion of the 5-HT2 receptor between two states (R in equilibrium R'). ICI 169,369 competes with 5-HT for the 5-HT2 receptor. ICI 169,369 and methysergide also compete for an allosteric site of the 5-HT2 receptor system, thereby facilitating the highly active R-state and low active R'-state, respectively.

Allosteric Site↗
PubMed1986

Kinetic regulation of convulsant (TBPS) binding by GABAergic agents.

The kinetics of specific [35S]-t-butylbicyclophosphorothionate (TBPS) binding was studied in rat brain synaptosomal membrane preparations. The effects of a representative depressant barbiturate, R-(-)-N-(1)-Me-5-Phe-5-Pr-barbituric acid [R(-)MPPB, and gamma-aminobutyric acid (GABA) were biphasic on TBPS binding, but the enhancements of binding by low concentrations of R(-)MPPB or GABA disappeared when binding equilibrium was reached. The slope factors of TBPS displacement and the IC50 values of R(-)MPPB and GABA decreased when TBPS binding approached equilibrium. Up to 70 min, binding in the presence of 300 microM R(-)MPPB exceeded, then remained below, the level of the control. R(-)MPPB decreased the apparent association half-life of TBPS binding from 41.5 min to 11.9 min. The GABA agonist, muscimol, in the concentration range of 20 and 200 nM, progressively accelerated the rate of TBPS dissociation. This effect was completely reversed by 20 microM bicuculline methochloride. GABA antagonists, bicuculline methochloride (20 microM) and R 5135 (20 nM), alone decelerated the rate of TBPS dissociation. Dissociation of TBPS was also initiated by dilution in the presence of various salts. Replacement of Cl- by Br- ions (0.5 molar) accelerated the rate of dissociation, whereas replacement of K+ by Na+ ions had no effect. This indicates the role of Eccles anions, not of cations, in TBPS binding and the possible involvement of the chloride inophore. A kinetic model is discussed for the allosteric modulation of TBPS binding by various GABAergic agents. Interconvertible populations of TBPS sites are proposed with rapid and slow kinetics. Model calculations involving modulation in the same direction of the on and off rates of binding can reproduce observed phenomena. The model predicts that GABA agonists, barbiturate and pyrazolopyridine depressants, as well as 1,4-benzodiazepine agonists, would allosterically increase the proportion of a rapid kinetic population of TBPS sites. In contrast, the model predicts that a decrease in the contribution of the rapid phase might be brought about by GABA antagonists and beta-carboline inverse agonists. The slow and rapid kinetic populations of TBPS sites might represent the closed and open states of the chloride ionophores, respectively.

Animals↗
PubMed2003

Nitric oxide and cardiac function: ten years after, and continuing.

Nitric oxide (NO) is produced from virtually all cell types composing the myocardium and regulates cardiac function through both vascular-dependent and -independent effects. The former include regulation of coronary vessel tone, thrombogenicity, and proliferative and inflammatory properties as well as cellular cross-talk supporting angiogenesis. The latter comprise the direct effects of NO on several aspects of cardiomyocyte contractility, from the fine regulation of excitation-contraction coupling to modulation of (presynaptic and postsynaptic) autonomic signaling and mitochondrial respiration. This multifaceted involvement of NO in cardiac physiology is supported by a tight molecular regulation of the three NO synthases, from cellular spatial confinement to posttranslational allosteric modulation by specific interacting proteins, acting in concert to restrict the influence of NO to a particular intracellular target in a stimulus-specific manner. Loss of this specificity, such as produced on excessive NO delivery from inflammatory cells (or cytokine-stimulated cardiomyocytes themselves), may result in profound cellular disturbances leading to heart failure. Future therapeutic manipulations of cardiac NO synthesis will necessarily draw on additional characterization of the cellular and molecular determinants for the net effect of this versatile radical on the cardiomyocyte biology.

Animals↗
PubMed1990

An aspartate conserved among G-protein receptors confers allosteric regulation of alpha 2-adrenergic receptors by sodium.

The residue involved in sodium regulation of G-protein-coupled receptors has been identified by site-directed mutagenesis of the alpha 2-adrenergic receptor gene. Mutation of Asp-79 to Asn-79 entirely eliminates allosteric regulation of ligand binding by monovalent cations without perturbing the selectivity of adrenergic binding or allosteric modulation of that binding by amiloride analogs. The high degree of conservation of this aspartate residue in all G-protein-coupled receptors, without even a conservative change to glutamate, underscores the probable importance of this allosteric regulation.

Affinity Labels↗
PubMed2000

Acute hypoxic hypoxia transiently reduces GABA(A) binding site number in developing chick optic lobe.

The Central Nervous System is known to be critically affected in the prenatal-perinatal period by hypoxic-ischemic insults, which produce several disorders such as loss of neural projections, increased susceptibility to seizures, apoptosis and an imbalance in normal activity of glutamatergic and GABAergic neurones, resulting in acute cell excitotoxicity. The aim of the present work was to establish a chick embryo model of normobaric acute hypoxic hypoxia as well as to evaluate modifications in GABA(A) receptor complex from chick optic lobe, that may result from this injury. Fertile chicken (Gallus gallus domesticus) eggs from White Leghorn were incubated and at embryonic days (ED) 12 to 18, subjected to a stream of 8%O(2)/92%N(2) during1 h, and then were either returned to their shelves in the incubator for recovery, or immediately processed for biochemical studies. Hypoxic treatment produced a significant age dependent reduction in GABA binding sites showing the greatest decrease at the earliest stages studied (ED12-ED16). Saturation curves of GABA binding performed at ED12 showed a decrease in B(max), (control, 5.48+/-0.20, hypoxic, 3.90+/-0.39 pmol/mg protein), but no significant change in K(d). Following 48 h in normoxic atmosphere post-hypoxia reduction in [3H]GABA binding was reversed. Pharmacological properties of GABA(A) receptor at ED12 showed that positive allosteric modulation effects of the steroid 3alpha-hydroxy-5alpha-pregnan-20-one and the barbiturate pentobarbital sodium were enhanced by the treatment. This model of acute prenatal hypoxic hypoxia produced marked alterations in inhibitory CNS neurotransmission that proved reversible and age dependent.

Acute Disease↗
PubMed2003

Investigations into the potential neurotoxicity induced by diselenides in mice and rats.

It is well known that selenium is highly toxic to several species of mammals. Here we report the potential neurotoxicity of diselenides, as measured by the manifestation of seizures. The modulation of various neurotransmitter systems potentially involved in seizure episodes and death was also evaluated. The results of the present investigation suggest that toxicity of diselenides depends on the route of administration as well the species (rats or mice). These data show that modulation of more than one neuronal system can account for diselenide-induced seizures in mice. Additionally, changes in structure of diselenides, such as to introduce a functional group, influence the appearance of seizure episode. Conversely, all allosteric modulators tested did not protect dipropyl diselenide-induced seizures, indicating that aliphatic is more toxic than aromatic diselenides. Acute treatment with dipropyl diselenide inhibited [3H]-glutamate uptake to the crude synaptosomes. In contrast animals injected with diphenyl diselenide did not inhibit [3H]-glutamate uptake.

Animals↗
PubMed1998

Specific interaction of 5-HT-moduline with human 5-HT1b as well as 5-HT1d receptors expressed in transfected cultured cells.

5-HT1B receptors are the predominant auto- and heteroreceptors located on serotonergic and non-serotonergic terminals where they regulate the neuronal release of neurotransmitters. 5-HT-moduline (Leu-Ser-Ala-Leu) has been shown to specifically interact with a very high apparent affinity and in a non-competitive manner with 5-HT1B receptors (Massot et al. 1996; Rousselle et al. 1996). Using transfected cells expressing either 5-HT1B or 5-HT1D receptors, it was shown that 5-HT-moduline prevents the binding of [3H]5-HT to 5-HT1B as well as to 5-HT1D receptors with similar biochemical characteristics: the IC50 of the peptide was 1.2x10(-12) M for 5-HT1B and 9x10(-13) M for 5-HT1D receptors. The observed effect corresponds to a marked decrease of the maximal binding for [3H]5-HT on 5-HT1B (-51.2 +/- 1%) as well as 5-HT1D binding (-47.2 +/- 7.7% of the control binding) whereas the affinity of 5-HT is increased by a factor close to 3. No effect is observed using the "scrambled" peptide (Ala-Leu-Leu-Ser). Parallel assays using transfected cells expressing 5-HT1A or 5-ht6 receptors did not show any significant change induced by the peptide under similar assay conditions. The interaction of the peptide was also studied on the functional activity related to the stimulation of the receptors as measured by the increase in [35S]GTPgammaS binding reflecting the coupling of the receptor to the G-protein. 5-HT-moduline yields an antagonistic effect on the 5-HT induced coupling with a corresponding IC50 = 1.2 +/- 0.7x10(-12) M for 5-HT1B and 9.8 +/- 4.0x10(-12) M for 5-HT1D receptors, respectively. The present results demonstrate that 5-HT-moduline interacts with 5-HT1D as well as 5-HT1B receptors and possesses a non-competitive antagonistic activity, likely corresponding to its role of endogenous allosteric modulator, specific for both 5-HT1B and 5-HT1D receptors.

Allosteric Regulation↗
PubMed2003

Positive regulation of GABA(B) receptors dually coupled to cyclic AMP by the allosteric agent CGP7930.

The ability of 2,6 Di-tert-butyl-4-(-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930), a positive allosteric modulator of GABA(B) receptors, to regulate GABA(B) receptor-induced stimulation and inhibition of adenylyl cyclase activity in rat brain was investigated. In olfactory bulb granule cell layer and in frontal cortex, CGP7930 potentiated the stimulatory effects of (-)-baclofen and gamma-aminobutyric acid (GABA) on basal and corticotropin-releasing hormone-stimulated adenylyl cyclase activities, respectively. In these stimulatory responses, CGP7930 enhanced both agonist potencies and maximal effects. When GABA(B) receptor-mediated inhibition of forskolin-stimulated adenylyl cyclase activity of frontal cortex was examined, CGP7930 increased the agonist potencies but failed to affect the maximal effect of (-)-baclofen and modestly increased that of GABA. Similar results were obtained for the inhibition of Ca(2+)/calmodulin-stimulated adenylyl cyclase in striatum and cerebellum. Western blot analysis of each membrane preparation showed the presence of GABA(B2) receptor subunit, a putative site of action of CGP7930. These data indicate that CGP7930 positively modulates brain GABA(B) receptors coupled to either stimulation or inhibition of cyclic AMP signalling.

Adenylyl Cyclases↗
PubMed1999

EDPC: a novel high affinity ligand for the benzodiazepine site on rat GABA(A) receptors.

Rat recombinant alpha1beta2gamma2 gamma-aminobutyric acid type A (GABAA) receptors were functionally expressed in Xenopus laevis oocytes and analyzed for the action of EDPC (Ethyl 3-(1,3-dithian-2-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate) using electrophysiological techniques. EDPC inhibited GABA currents at low concentrations (IC50 approximately/= 2 nM). The inhibition by 100 nM EDPC could be reversed by 1 microM of the benzodiazepine antagonistflumazenil (Ro 15-1788), indicating a negative allosteric modulation via the benzodiazepine binding site. In line with this conclusion are radioactive ligand binding studies. EDPC inhibited the binding of 2 nM [3H]flunitrazepam to membranes from the cerebellum or the cortex with IC50 values of about 8 and 25 nM, respectively.

Allosteric Regulation↗
PubMed1995

Allosteric regulation by calcium of rabbit polyclonal anti-cyclic GMP antibody.

Calcium increased the binding of rabbit polyclonal antibodies and cGMP by increasing antibody affinity without altering the number of binding sites (Bmax). Competitive binding studies revealed that calcium increased the affinity of antibody for cGMP derivatives similarly, suggesting that the effects of this cation were antigen-independent. Kinetic binding studies demonstrated that calcium increased affinity by decreasing the dissociation rate without altering the association rate of antigen and antibody. Studies of the dissociation of antigen-antibody complexes preformed in the absence of calcium suggested that this cation regulated antibody function allosterically. These data contrast with those obtained previously suggesting that calcium regulated the interaction of cAMP and antibodies by increasing Bmax without altering affinity by reaction coupling. Re-analysis of those data demonstrated that calcium increased the affinity without altering the number of binding sites of antibodies to cAMP, in close agreement with the present results. These data suggest that allosteric modulation of antibody function by calcium may be a general mechanism regulating the interaction of polyclonal antibodies with cyclic nucleotides.

Allosteric Regulation↗
PubMed1995

Effects of AMPA receptor modulators on the production of arachidonic acid from striatal neurons.

The abilities of different compounds acting at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors to modulate the overflow of [3H]arachidonic acid from rat striatal neurons were examined. The combination of AMPA (0.1 mM) and carbachol (1mM) stimulated [3H]arachidonic acid production, this effect could be dose-dependently enhanced by the newly discovered allosteric modulator of AMPA receptors: cyclothiazide. Competitive (6-cyano-7-nitroquinoxaline-2,3-dione [CNQX] and 6-(1-imidazolyl)-7-nitroquinazoline-2,3-dione [YM 900]) and non-competitive antagonists, like 1-(amino)-phenyl)-4-methyl -7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), antagonized the responses induced by either AMPA + carbachol or AMPA + carbachol + cyclothiazide. In order to appreciate the respective part of AMPA-versus kainate-preferring receptors experiments were performed with kainic acid (0.1 mM) and the more specific kainate agonist domoic acid (0.1 mM). Kainic acid behaves like AMPA, but the response induced by the combination domoic acid + carbachol could not be potentiated by cyclothiazide. On the contrary, concanavalin A potentiated the responses evoked by kainic acid or domoic acid (in combination with carbachol) but did not enhance the AMPA-evoked response. It could be concluded that both AMPA- and kainate-preferring receptors are present in cultured rat striatal neurons and that these two types of receptors were involved together with muscarinic receptors in the overflow of [3H]arachidonic acid.

Animals↗
PubMed1997

The role of alpha1 and alpha6 subtype amino-terminal domains in allosteric regulation of gamma-aminobutyric acida receptors.

The gamma-aminobutyric acidA (GABA) receptor in the mammalian central nervous system is composed of pentameric combinations of alpha1-6, beta1-4, gamma1-3, delta1, and/or epsilon1 subunit subtypes. Although each of the different subunits influences the functional properties of gamma-aminobutyric acidA receptors (GABARs), the alpha subunit subtypes have been shown to be important for activation of the receptor by GABA and pentobarbital and the regulation of GABARs by numerous allosteric regulators, including benzodiazepines, furosemide, zinc, and lanthanum. However, with the exception of the benzodiazepines, the alpha subtype domain that is responsible for the action of these allosteric compounds is unknown. The alpha1 and alpha6 subtypes are among the most diverse of the alpha subunit family and confer a different responsiveness of GABARs to GABA and many of the allosteric modulators. These regulatory compounds act after extracellular application and therefore likely act on extracellular GABAR sites, the largest of which is the amino-terminal extracellular domain. To determine the role of this domain in the action of these allosteric regulatory agents, we constructed chimeras of the rat alpha1 and alpha6 subtypes with a splice site within the first putative transmembrane domain (TM). This separated the large extracellular amino-terminal domain from the transmembrane, intracellular, and TM2-3 and carboxyl-terminal extracellular domains of the subunit. The chimeric subtypes were expressed in L929 fibroblasts along with beta3 and gamma2L subtypes, and their pharmacological properties were determined with whole-cell electrophysiological recording. The alpha subtype amino-terminal extracellular domain was the primary determinant of GABA sensitivity and was responsible for the functional properties of activation by pentobarbital, sensitivity to diazepam, potentiation by lanthanum, and high affinity inhibition by furosemide. The remaining carboxyl-terminal domains influenced the GABA sensitivity and determined zinc sensitivity and low affinity inhibition by furosemide. Both domains were apparently required for inhibition by lanthanum.

Allosteric Regulation↗
PubMed1998

5-HT-moduline, a 5-HT(1B/1D) receptor endogenous modulator, interacts with dopamine release measured in vivo by microdialysis.

5-Hydroxytryptamine-moduline (5-HT-moduline) is an endogenous tetrapeptide (Leu-Ser-Ala-Leu) recently isolated and characterized from mammalian brain. This compound interacts with 5-HT1B receptors as a non-competitive, high-affinity antagonist and has the properties of an allosteric modulator. 5-HT-moduline could play an important role in the regulation of serotonergic transmission and also, through heteroreceptors, dopaminergic transmission. The aim of this work was to examine the potential ability of 5-HT-moduline to modify the basal extracellular concentration of dopamine and its metabolites (3-methoxytyramine, dihydroxyphenylacetic acid and homovanillic acid), in the rat striatum and to determine its potential interaction with the stimulating activity of a specific 5-HT1B receptor agonist, 3-(1,2,5,6-tetrahydropyrid-4-yl) pyrrolo [3,2-b] pyrid-5-one (CP-93,129), on the release of dopamine. The technique is based on in vivo microdialysis using probes implanted in the striatum of the conscious rat. Results showed that the perfusion of 5-HT-moduline directly into this structure (1.25 mM) increased the striatal level of dopamine by two-fold (104% of the absolute basal release values, P = 0.0015) and that of 3-methoxytyramine by 3-fold (293%, P = 0.0001) without any change in the terminal metabolite concentrations. The intrastriatal administration of CP-93,129 induced a statistically significant, dose-dependent increase of dopamine levels (P < 0.0001). Coperfusion of 5-HT-moduline did not significantly alter the effect of CP-93,129 at 0.1 and 0.5 mM, but appeared to have an additive effect on the lowest dose (P = 0.0406). The results obtained show that 5-HT-moduline directly administered into the striatum increases the release of dopamine in this area. Presumably, this effect results from the desensitization of 5-HT1B receptors located on dopamine terminals. However, the fact that a 5-HT1B receptor agonist (CP-93,129) also increased the release of dopamine in the striatum and that 5-HT-moduline exhibited a slight additive effect with that of a low concentration of CP-93,129 suggests that the two substances interact with different mechanisms.

Animals↗
PubMed2002

GABAA receptors and benzodiazepines: a role for dendritic resident subunit mRNAs.

This review is designed to describe the evolution of the seminal observation made simultaneously in 1975 by Dr. W. Haefely's laboratory (Hoffman La Roche, Basel, Switzerland) and in the Laboratory of Preclinical Pharmacology (NIH, St. Elizabeths Hospital, Washington DC), that benzodiazepine action was mediated by a modulation of GABA action at GABA(A) receptors. In fact, our suggestion was that the benzodiazepine receptor was "a receptor on a receptor" and that this receptor was GABA(A). Needless to say, this suggestion created opposition, but we did not abandon the original idea, in fact, as shown in this review, there is now universal agreement with our hypothesis on the mode of action of benzodiazepines. Hence, this review deals with the allosteric modulation of GABA(A) receptors by benzodiazepines, the role of GABA(A) receptors and benzodiazepine structure diversities in this modulation, and describes the results of our attempts to establish a benzodiazepine (imidazenil) devoid of tolerance, withdrawal symptoms, and changes in the expression of GABA(A) receptor subunits during tolerance. It also deals with the idea that the synthesis of GABA(A) receptor subunits triggered by tolerance resides in dendrites and spines where mRNAs and the apparatus for this translation is located. New analytic procedures may foster progress in the understanding of tolerance to and withdrawal from benzodiazepines.

Allosteric Regulation↗