Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “allosteric modulation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 685 records · Page 38Linked to original sources
PubMed2003

The pharmacology of spontaneously open alpha 1 beta 3 epsilon GABA A receptor-ionophores.

Human alpha(1)beta(3) epsilon GABA(A) receptors were expressed in Xenopus oocytes and examined using the conventional two-electrode voltage-clamp technique and compared to alpha(1)beta(3)gamma(2) receptors. The effects of several GABA(A) agonists were studied, and the allosteric modulation of the channel by a number of GABAergic modulators investigated. The presence of the epsilon subunit increased the potency and efficacy of direct activation by partial GABA(A) agonists (piperidine-4-sulphonic acid and thio-4-PIOL), pentobarbital and neuro-steroids. Direct activation by 3-hydroxylated neurosteroids was restricted to 3alpha epimers, while chirality at C5 was indifferent. The 3beta-sulfate esters of pregnenolone and dehydroepiandrosterone inhibited the spontaneous currents with efficacies higher, while bicuculline methiodide and SR 95531 did so lower than picrotoxin and TBPS. Furosemide, fipronil, triphenylcyanoborate and Zn(2+) blocked the spontaneous currents of alpha(1)beta(3) epsilon receptors with different efficacies. Flunitrazepam and 4'-chlorodiazepam inhibited the spontaneous currents with micromolar potencies. In conclusion, spontaneously active alpha(1)beta(3) epsilon GABA(A) receptors can be potentiated and blocked by GABAergic agents within a broad range of efficacy.

Allosteric Regulation↗
PubMed2006

Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia.

This article describes recent progress towards validation of the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis of schizophrenia in preclinical models. Schizophrenia, a complex disease characterized by positive, negative and cognitive symptoms, affects 1% of the world population and requires lifelong, daily maintenance therapy. For the last several decades, thinking in this field has been dominated by the hypothesis that hyperfunction of dopamine pathways played a key role in schizophrenia. However, the therapeutic agents developed from this hypothesis have a slow onset of action and tend to improve only the positive symptoms of the disease. The NMDA receptor antagonist PCP has been shown to induce the positive, negative and cognitive symptoms of schizophrenia in healthy patients and cause a resurgence of symptoms in stable patients. These observations led to the NMDA receptor hypofunction hypothesis as an alternative theory for the underlying cause of schizophrenia. According to this hypothesis, any agent that can potentiate NMDA receptor currents has the potential to ameliorate the symptoms of schizophrenia. To date, NMDA receptor currents can be modulated by either direct action on modulatory sites on the NMDA receptor (i.e., the glycine co-agonist binding site) or indirectly by activation of G-protein coupled receptors (GPCRs) known to potentiate NMDA receptor function (i.e., mGluR5). This review will discuss the NMDA receptor hypofunction hypothesis, the NMDA receptor as an emerging target for the development of novel antipsychotic agents and progress towards in vivo target validation with GlyT1 inhibitors and mGluR5 positive allosteric modulators. Other potential targets for modulating NMDA receptor currents (polyamine sites, muscarinic receptors, etc...) will also be addressed briefly.

Allosteric Regulation↗
PubMed2005

Phenytoin differentially modulates the affinity of agonist and antagonist ligands for sigma 1 receptors of guinea pig brain.

We evaluated the effects of phenytoin (DPH) on the affinity for sigma-1 (sigma(1)) receptors of agonist or antagonist sigma(1) ligands in guinea pig brain. Heterologous competition experiments showed that DPH (250 microM and 1 mM) concentration-dependently increased the affinity of the sigma(1) agonists dextromethorphan, (+)-SKF-10,047, (+)-3-PPP, and PRE-084. However, neither DPH 250 microM nor 1 mM increased (in fact, they slightly decreased) the affinity of the sigma(1) receptor antagonists haloperidol, BD 1063, NE-100, progesterone, and BD 1047. These findings suggest that allosteric modulation by DPH of the affinity of sigma(1) receptor ligands depends on the agonist or antagonist characteristics of the ligand. Therefore, determining in vitro the differential modulation by DPH of sigma(1) ligand affinity appears to constitute a procedure that can predict the pharmacological profile of different sigma(1) ligands.

Allosteric Regulation↗
PubMed2002

Modulation of glycine receptor function: a novel approach for therapeutic intervention at inhibitory synapses?

Transmitter-gated ion channels mediate rapid synaptic transmission in the CNS and constitute important targets for many neuroactive drugs. Inhibitory glycine receptors (GlyRs) are members of the nicotinic acetylcholine receptor superfamily and inhibit neuronal firing by opening Cl(-) channels following agonist binding. In this article, we discuss recent developments in GlyR pharmacology, delineate the receptor domains that are involved in binding of agonists and allosteric modulators, and present a molecular model of the extracellular architecture of the receptor. The recent discovery of compounds that act preferentially on specific GlyR isoforms and the differential expression of these isoforms in distinct regions of the developing and adult CNS show considerable promise towards the development of drugs that act in defined glycine-mediated pathways. In particular, compounds that can potentiate GlyR function should provide leads for novel muscle relaxants in addition to sedative and analgesic agents.

Animals↗
PubMed1991

Competitive antagonism by recognized 5-HT2 receptor antagonists at 5-HT1C receptors in pig choroid plexus.

The effects of several antagonists, known to interact with 5-HT2 receptors (ritanserin, LY 53857, ICI 169,369, methysergide, mesulergine and ketanserin), were tested against 5-HT-stimulated production of inositol phosphate in pig choroid plexus, a 5-HT1C receptor model. These antagonists produced dextral shifts of the concentration response curve to 5-HT in a parallel manner, without depressing significantly the maximal response. The following pA2 values (in parentheses) were obtained: mesulergine (8.88), methysergide (8.85), LY 53857 (8.69), ritanserin (8.69), ICI 169,369 (7.86), and ketanserin (6.57). These pA2 values were in good agreement with the pKD values determined in radioligand binding studies performed in pig choroid plexus with [3H]mesulergine. The present data demonstrate that several drugs described as 5-HT2 receptor selective antagonists (e.g. ritanserin, LY 53857 and ICI 169,369) are also potent, competitive and surmountable antagonists at 5-HT1C receptors. Thus, the results provide further evidence for the pharmacological similarity of 5-HT1C and 5-HT2 receptors. However, in contrast to the situation described with methysergide, ritanserin and LY 53857 in several 5-HT2 receptor models, none of these antagonists acted in a non-competitive or unsurmountable fashion at 5-HT1C receptors. These results suggest, but do not firmly rule out, that at least in the presence of the drugs tested in the present study, 5-HT1C receptors in the choroid plexus do not undergo an allosteric modulation; these findings are apparently in contrast to a model proposed previously for 5-HT2 receptors (Kaumann and Frenken 1985, Naunyn-Schmiedeberg's Arch Pharmacol 328:295-300).

Allosteric Regulation↗
PubMed2003

Estradiol and testosterone modulate the anesthetic action of the GABA-A agonist THIP, but not of the neurosteroid 3alpha,5beta-pregnanolone in the rat.

RATIONALE: As sex steroids modify the number and distribution of brain gamma-aminobutyric acid (GABA)A receptor subunits, we investigated the potential modulation of anesthesia, induced by agents acting on the GABAA receptor, by estrogen and androgen. OBJECTIVES: To assess possible effects of sex and hormonal condition (i.e., intact vs castrate; estradiol vs testosterone treatment) on the anesthetic effect of a GABAA agonist, THIP (4,5,6,7-tetrahydroisoxazolo[5,4,-c]pyridin-3-ol hydrochloride), and an allosteric modulator of the GABAA receptor: 3alpha-hydroxy-5beta-pregnan-20-one (epipregnanolone). METHODS: The potencies of THIP and epipregnanolone for inducing loss of the righting response were compared between: (a) female and male rats; (b) intact and castrated animals of each sex; (c) untreated castrates and castrates given estradiol or testosterone. RESULTS: Sex and endocrine condition influenced sensitivity to i.v. THIP for the induction of anesthesia. ED50 values were: gonadectomized females, 80 mg/kg>intact males, 50 mg/kg>proestrous females, 35 mg/kg>gonadectomized males, 28 mg/kg. Estradiol benzoate (EB; 3 microg/day for 5 days) significantly increased THIP sensitivity in gonadectomized females: THIP+EB: ED50=26 mg/kg vs THIP+sesame oil: ED50=94 mg/kg, while testosterone propionate (TP; 10 mg injected 24 h before THIP) decreased THIP sensitivity in orchidectomized males when compared with vehicle-injected animals (ED50=72 mg/kg vs 22 mg/kg, respectively). CONCLUSIONS: Results suggest that estrogen increases the density or availability of GABAA receptor subtypes on which THIP acts, while testosterone exerts the opposite effect. Neither sex nor gonadal condition influenced the anesthetic action of epipregnanolone as a similar potency was found in intact and in gonadectomized males and females.

Anesthesia↗
PubMed1990

In situ cross-linking of human erythrocyte band 3 by bis(sulfosuccinimidyl)suberate. Evidence for ligand modulation of two alternate quaternary forms: covalent band 3 dimers and noncovalent tetramers formed by the association of two covalent dimers.

Treatment of intact human erythrocytes with bis(sulfosuccinimidyl)suberate converted band 3 to two species with lower electrophoretic mobility in sodium dodecyl sulfate (SDS). The presence of the noncovalent anion transport inhibitor, 4,4'-dinitrostilbene-2,2'-disulfonate, promoted the lowest mobility form, while a closely related analogue, 4,4'-diisothiocyano-2,2'-stilbenedisulfonate, did not. Ferguson analysis of the electrophoretic behavior of the two slowly migrating bands strongly suggested that they represented dimers and tetramers of band 3. Increasing the temperature of the SDS solution to greater than 60 degrees C quantitatively converted the tetrameric species to the dimeric form. We conclude that band 3 can be intermonomerically cross-linked by bis(sulfosuccinimidyl)suberate as covalent dimers within two alternate quaternary forms in a manner modulated by the ligand occupying the intramonomeric stilbenedisulfonate site. In one form, band 3 covalent dimers are noncovalently associated as a SDS-resistant tetramer, while in the other form, covalent dimers are not so associated. There is no obvious relationship between ligand stereochemistry and the resulting quaternary form, suggesting that the two forms reflect alternate allosterically modulated porter quaternary structures. The significance of these two quaternary states to the transport or the ankyrin binding functions of band 3 is unknown.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1989

Direct evidence for modulation of porter quaternary structure by transport site ligands.

The transport inhibitor DNDS (4,4'-dinitrostilbene-2,2'-disulfonate) changes the bis(sulfosuccinimidyl)suberate (BS3) crosslinking pattern of band 3 protein from a mixture of dimer-crosslinkable (DC) and tetramer-crosslinkable (TC) states to the TC-state as the exclusive crosslinked product for reactions occurring in membranes of intact human erythrocytes. Pretreatment of cells with DNDS followed by extensive washing restores the original DC to TC proportionality indicating that the two states are reversibly interconvertible. We suggest a model wherein band 3 transport site ligands allosterically modulate the global conformation of a tetrameric porter between two reversibly interconvertible quaternary structures. These transitions in quaternary structure may be important to transmembrane signaling of events between the exofacial ligand binding site and the sites on the porter extension which bind ankyrin and hemoglobin.

Allosteric Regulation↗
PubMed2001

Modulation of [3H]quinpirole binding at striatal D2 dopamine receptors by a monoamine oxidaseA-like site: evidence from radioligand binding studies and D2 receptor- and MAO(A)-deficient mice.

[3H]Quinpirole is a dopamine agonist with high affinity for the D2 and D3 dopamine receptors. A variety of monoamine oxidase inhibitors (MAOIs) inhibit equilibrium binding of [3H]quinpirole binding in rat striatal membranes suggesting that MAOIs interact with a novel binding site that is labeled by [3H]quinpirole or that allosterically modulates [3H]quinpirole binding. To determine whether the D2 receptor is essential for [3H]quinpirole binding and/or modulation of [3H]quinpirole binding by MAOIs, D2 receptor-deficient mice were studied. [3H]Quinpirole binding was decreased in D2 receptor-deficient mice to 3% of that observed in wild-type controls indicating that [3H]quinpirole binding is associated with the D2 dopamine receptors. Then, in an attempt to label the site mediating the modulation of [3H]quinpirole binding, binding of the MAOI [3H]Ro 41-1049 was characterized in rat striatal membranes. [3H]Ro-41-1049 labeled a single binding site with a pharmacological profile with respect to MAOIs that was similar to both [3H]quinpirole binding (Spearman r=0.976) and MAO(A) activity. To determine whether MAO(A) plays a role in the modulation of [3H]quinpirole binding by MAOIs, MAO(A)-deficient mice were examined. In these mice, [3H]Ro-41-1049 binding was decreased to 7% of wild-type control. [3H]Spiperone binding was unaltered. Spiperone-displaceable [3H]quinpirole binding was decreased to 43% of wild-type control; however, the remaining [3H]quinpirole binding in MAO(A)-deficient animals was inhibited by Ro 41-1049 similar to wild-type. [3H]Ro-41-1049 binding was not decreased in D2 receptor-deficient mice. These data suggest that [3H]Ro-41-1049 labels multiple sites and that MAOIs modulate [3H]quinpirole binding to the D2 receptor via interactions at a novel, non-MAO binding site with MAO(A)-like pharmacology.

Animals↗
PubMed1990

Comparison of crystal and solution hemoglobin binding of selected antigelling agents and allosteric modifiers.

This paper details comprehensive binding studies (solution and X-ray) of human hemoglobin A with a group of halogenated carboxylic acids that were investigated as potential antisickling agents. It is, to our knowledge, the first study to compare solution and crystal binding for a series of compounds under similar high-salt conditions used for cocrystallization. The compounds include [(3,4-dichlorobenzyl)oxy]acetic acid, [(p-bromobenzyl)oxy]acetic acid, clofibric acid, and bezafibrate. The location and stereochemistry of binding sites have been established by X-ray crystallography, while the number of binding sites and affinity constants were measured by using equilibrium dialysis. The solution binding studies were conducted with deoxygenated hemoglobin and carbonmonoxyhemoglobin with low (50 mM) and high (2 M) salt concentrations. It was concluded that the observed crystal structures are consistent with the binding observed in solution and that the number of binding sites is independent of salt concentration, while the binding constant increases with increasing salt concentration. The studies also reveal that relatively small changes in the chemical structure of a drug molecule can result in entirely different binding sites on the protein. Moreover, the X-ray studies provide a possible explanation for the multiplicity in function exhibited by these compounds as allosteric modulators and/or antisickling agents. Finally, the studies that these compounds bind differently to the R and T states of hemoglobin, an observation of special significance to the original design of these agents.

Allosteric Regulation↗
PubMed1993

Monoclonal antibody AE-2 modulates carbamate and organophosphate inhibition of fetal bovine serum acetylcholinesterase.

The monoclonal antibody AE-2, raised against the human erythrocyte acetylcholinesterase (AChE) dimer (acetylcholine acetylhydrolase, EC 3.1.1.7), binds to other mammalian AChEs, including the tetramer that occurs in fetal bovine serum (FBS). AE-2 partially inhibited the rate of hydrolysis of the charged substrate acetylthiocholine by FBS AChE, whereas it increased the rate of hydrolysis of the neutral substrate indophenyl acetate. Present results show that AE-2 decreases the rate of inhibition of FBS AChE by the positively charged organophosphate amiton-p-toluene sulfonate and the positively charged carbamates pyridostigmine and neostigmine but accelerates inhibition of FBS AChE by the neutral organophosphates paraoxon and diisopropylfluorophosphate. Results suggest that AE-2 may allosterically modulate an anionic site in the catalytic center of FBS AChE.

Acetylcholinesterase↗
PubMed1993

Interaction of La3+ with GABAA receptors in rat cerebrocortical membranes as detected with [35S]t-butylbicyclophosphorothionate binding.

Lanthanides at micromolar concentrations stimulated binding of [35S]t-butylbicyclophosphorothionate (TBPS), a highly sensitive marker for allosteric modulation of the chloride channel of GABAA receptors, to purified rat cerebrocortical synaptosomal membranes in the absence of GABA. This trivalent cation effect appeared to reflect a specific and direct interaction with GABAA receptors, and could not be mimicked by divalent metal ions including Ca2+, Cd2+, Co2+, Sr2+, Mg2+ and Mn2+. On the other hand, Zn2+, a known allosteric regulator of GABAA receptors, inhibited TBPS binding, but its presence could not prevent stimulation of TBPS binding by La3+. We further examined the lanthanide binding site by monitoring La3(+)-induced changes in TBPS binding. La3+ reduced the Kd for TBPS without affecting Bmax. Stimulation of TBPS by La3+ was not additive with the increased TBPS binding induced by other agonists, including GABA (at nanomolar concentrations), neurosteroids or benzodiazepines (in the absence of GABA). GABA at micromolar concentrations inhibited TBPS binding and its inhibitory effect was potentiated by neurosteroids and benzodiazepines, but not by La3+. Thus, GABA, in the presence of La3+, inhibited TBPS binding in a monophasic manner with a Hill coefficient of approximately 2 and an IC50 of 6 microM. In the absence of La3+, the dose-response profile for GABA became biphasic with an appearance of a stimulatory phase at concentrations of GABA lower than 1 microM. Analysis of the initial stimulation yielded a Hill coefficient of 1 and an EC50 of 88 nM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Evidence for allosteric linkage between exosites 1 and 2 of thrombin.

Investigations to date have demonstrated that ligand binding to exosites 1 or 2 on thrombin produces conformational changes at the active site. In this study, we directly compared the effect of ligand binding to exosites 1 and 2 on the structure and function of the active site of thrombin and investigated functional linkage between the two exosites. Binding studies were performed in solution with fluorescein-Phe-Pro-Arg-CH2Cl (FPR)-thrombin. Hirudin-(54-65) and sF2, a synthetic peptide corresponding to residues 63-116 of prothrombin fragment 2, were used as ligands for exosites 1 and 2 of thrombin, respectively. The two ligands produce diametric changes in the fluorescence of fluorescein-FPR-thrombin and also have opposing effects on the rate of thrombin hydrolysis of a number of chromogenic substrates. These results indicate that sF2 and hirudin-(54-65) differentially affect the conformation of the active site. Experiments then were performed to investigate whether both ligands can bind to thrombin simultaneously. When thrombin-bound fluorescein-sF2 is titrated with hirudin-(54-65), complete displacement of fluorescein-sF2 is observed. Likewise, when thrombin-bound fluorescein-hirudin-(54-65) is titrated with sF2, complete displacement occurs. Additional support for reciprocal binding was obtained in fluorescence experiments where both probes were labeled and in experiments monitoring ligand binding to agarose-immobilized thrombin. This mutually exclusive binding of either ligand can be explained by reciprocal, allosteric modulation of ligand affinity between the two exosites. Thus, not only do the two exosites differentially influence the active site, they also affect the binding properties of the opposing exosite.

Allosteric Regulation↗
PubMed1998

Allosteric activation of the Ca2+ receptor expressed in Xenopus laevis oocytes by NPS 467 or NPS 568.

The Ca2+ receptor is a G protein-coupled receptor that enables parathyroid cells and certain other cells in the body to respond to changes in the concentration of extracellular Ca2+. In this study, two novel phenylalkylamine compounds, NPS 467 and NPS 568, were examined for effects on Xenopus laevis oocytes expressing the bovine or human parathyroid Ca2+ receptors. Increases in chloride current (ICl) were elicited in oocytes expressing the bovine Ca2+ receptor when the extracellular Ca2+ concentration was raised above 1.5 mM, whereas Ca2+ concentrations > 3 mM were generally necessary to elicit responses in oocytes expressing the human Ca2+ receptor. NPS 467 and NPS 568 potentiated the activation of ICl by extracellular Ca2+ in oocytes expressing either Ca2+ receptor homolog, and this resulted in a leftward shift of the Ca2+ concentration-response curve. Neither compound was active in the absence of extracellular Ca2+. Certain inorganic and organic cations known to activate the Ca2+ receptor were substituted for elevated levels of extracellular Ca2+ to increase ICl and the effects of these agonists were also potentiated by NPS 568 or NPS 467. The effects of NPS 568 were stereoselective and the R-enantiomer was about 10-fold more potent than the corresponding S-enantiomer. Neither NPS 467 nor 568 affected ICl in water-injected oocytes or in oocytes expressing the substance K receptor or the metabotropic glutamate receptor 1a. These results provide compelling evidence that NPS 467 and NPS 568 act directly upon the parathyroid Ca2+ receptor to increase its sensitivity to activation by extracellular Ca2+. This activity suggests that these compounds are positive allosteric modulators of the Ca2+ receptor. As such, these compounds define a new class of pharmacological agents with potent and selective actions on the Ca2+ receptor.

Allosteric Regulation↗
PubMed2004

Vinburnine decelerates [3H]N-methylscopolamine binding to recombinant human muscarinic M1-M4 acetylcholine receptors.

The kinetics of [3H]N-methylscopolamine binding to membranes of Chinese hamster ovary (CHO) cells expressing muscarinic M(1)-M(4) acetylcholine receptors was studied. [3H]N-methylscopolamine dissociation was used for the "single-point" analysis of allosteric modulation by vinburnine (L-eburnamonine). [3H]N-methylscopolamine dissociation was decelerated by vinburnine with EC(50) values of 29.5, 4.1, 9.5 and 15.0 microM for muscarinic M(1)-M(4) receptors, respectively. Acetylcholine doubled the EC(50) of vinburnine for muscarinic M(3) receptors. These kinetic EC(50) values correlated with equilibrium binding constants, supporting the ternary allosteric model. Vinburnine also decelerated the association of [3H]N-methylscopolamine binding, resulting in opposite cooperativity for muscarinic M(1) and M(2) receptors.

Allosteric Regulation↗
PubMed1994

A scheme to account for the effects of Rb+ and K+ on inward rectifier K channels of bovine artery endothelial cells.

An electrochemical gating model is presented to account for the effects described in the companion paper by M. R. Silver, M. S. Shapiro, and T. E. DeCoursey (1994. Journal of General Physiology, 103:519-548) of Rb+ and Rb+/K+ mixtures on the kinetics and voltage dependence of an inwardly rectifying (IR) K+ channel. The model proposes that both Rb+ and K+ act as allosteric modulators of an intrinsically voltage dependent isomerization between open and closed states. Occupancy of binding sites on the outside of the channel promotes channel opening and stabilizes the open state. Rb+ binds to separate sites within the pore and plugs IR channels. Occupancy of the pore by Rb+ can modify the rates of isomerization and the affinity of the allosteric sites for activator ions. The model also incorporates the proposed triple-barreled nature of the IR channel (Matsuda, H., 1988. Journal of Physiology. 397:237-258.) by proposing that plugging of the channel is a cooperative process involving a single site in each of the three bores, 80% of the way through the membrane field. Interaction between bores during plugging and permeation is consistent with correlated flux models of the properties of the IR channel. Parallel bores multiply the number allosteric sites associated with the macromolecular channel and allow for steep voltage dependence without compromising the parallel shift of the half-activation potential with reversal potential. Our model proposes at least six and possibly 12 such allosteric binding sites for activator ions. We derive algebraic relations that permit derivation of parameters that define simple versions of our model from the data of Silver et al. (1994). Numerical simulations based on those parameters closely reproduce that data. The model reproduces the RS+ induced slowing of IR kinetics and the negative shift of the relation between the half-activation voltage (V1/2) and reversal potential when channel plugging is associated with (a) a slowing of the isomerization rates; (b) an increase in the affinity of allosteric sites on closed channels that promote opening; and (c) a decrease in the affinity of sites on open channels that slow closing. Rb+ also slows closing at positive potentials where open channel blockade is unlikely. Allowing Rb+ to be 1.5 times more potent than K+ as an activator in the model can account for this effect and improves the match between the predicted and observed relation between the Rb+ to K+ mole fraction and the opening rate at V1/2.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1999

Dual role of GABA in the neonatal rat hippocampus.

The effects of modulators of GABA-A receptors on neuronal network activity were studied in the neonatal (postnatal days 0-5) rat hippocampus in vitro. Under control conditions, the physiological pattern of activity of the neonatal hippocampal network was characterized by spontaneous network-driven giant depolarizing potentials (GDPs). The GABA-A receptor agonist isoguvacine (1-2 microM) and the allosteric modulator diazepam (2 microM) induced biphasic responses: initially the frequency of GDPs increased 3 to 4 fold followed by blockade of GDPs and desynchronization of the network activity. The GABA-A receptor antagonists bicuculline (10 microM) and picrotoxin (100 microM) blocked GDPs and induced glutamate (AMPA and NMDA)-receptor-mediated interictal- and ictal-like activities in the hippocampal slices and the intact hippocampus. These data suggest that at early postnatal ages GABA can exert a dual - both excitatory and inhibitory - action on the network activity.

Animals↗
PubMed1996

Intricate regulation of tyrosine hydroxylase activity and gene expression.

Tyrosine hydroxylase catalyzes the rate-limiting step in the biosynthesis of the catecholamines dopamine, norepinephrine, and epinephrine. Therefore, the regulation of tyrosine hydroxylase enzyme number and intrinsic enzyme activity represents the central means for controlling the synthesis of these important biogenic amines. An intricate scheme has evolved whereby tyrosine hydroxylase activity is modulated by nearly every documented form of regulation. Beginning with the genomic DNA, evidence exists for the transcriptional regulation of tyrosine hydroxylase mRNA levels, alternative RNA processing, and the regulation of RNA stability. There is also experimental support for the role of both translational control and enzyme stability in establishing steady-state levels of active tyrosine hydroxylase protein. Finally, mechanisms have been proposed for feedback inhibition of the enzyme by catecholamine products, allosteric modulation of enzyme activity, and phosphorylation-dependent activation of the enzyme by various different kinase systems. Given the growing literature suggesting that different tissues regulate tyrosine hydroxylase mRNA levels and activity in different ways, regulatory mechanisms provide not only redundancy but also diversity in the control of catecholamine biosynthesis.

Allosteric Regulation↗