The Experts below are selected from a list of 132 Experts worldwide ranked by ideXlab platform
Kety Mirković - One of the best experts on this subject based on the ideXlab platform.
-
Swim stress alters the behavioural response of mice to GABA-related and some GABA-unrelated Convulsants.
Epilepsy research, 2001Co-Authors: Danka Peričić, Maja Jazvinšćak, Dubravka Švob, Kety MirkovićAbstract:Abstract To elucidate the relationship between stress and seizures, the effect of a single swim stress on the convulsive signs and death produced by several GABA-related and GABA-unrelated Convulsants, and the effect of repeated swim stress on picrotoxin-induced convulsions was studied. Mice were subjected to swim stress (10 min swimming at 18–19°C), and the i.v. infusion of Convulsants started 15 min thereafter. The latency to the onset of several Convulsant signs and death was measured, and the doses of Convulsants producing convulsions and death were calculated. Additional experiments included mice swimming at room temperature, and those which were stressed repeatedly (twice a day for four consecutive days, plus one stressful procedure on the fifth day). Swim stress increased the dose needed to produce Convulsant signs and death after bicuculline, picrotoxin, pentylenetetrazole, strychnine and 4-aminopyridine, while kainic acid-induced convulsions were not affected. Using picrotoxin infusion, the effect of swimming in room temperature water was less than the effect of swimming in 18–19°C water. In addition, the effect of repeated stress was less than the effect of acute stress on picrotoxin-induced convulsions. The results demonstrate that acute swim stress lowers the convulsive potency of GABA-related and some GABA-unrelated Convulsants. Repeatedly stressed animals develop tolerance to anticonvulsive effect of swim stress.
Jonathan B Cohen - One of the best experts on this subject based on the ideXlab platform.
-
positive and negative allosteric modulation of an α1β3γ2 γ aminobutyric acid type a gabaa receptor by binding to a site in the transmembrane domain at the γ β interface
Journal of Biological Chemistry, 2015Co-Authors: Selwyn S Jayakar, Rooma Desai, Pavel Y Savechenkov, Karol S Bruzik, Keith W Miller, Xiaojuan Zhou, David C Chiara, Jonathan B CohenAbstract:Abstract In the process of developing safer general anesthetics, isomers of anesthetic ethers and barbiturates have been discovered that act as Convulsants and inhibitors of γ-aminobutyric acid type A receptors (GABAARs) rather than potentiators. It is unknown whether these Convulsants act as negative allosteric modulators by binding to the intersubunit anesthetic binding sites in the GABAAR transmembrane domain (Chiara et al., J. Biol. Chem. 288: 19434-19357 (2013)) or to known Convulsant sites in the ion channel or extracellular domains. Here we show that S-mTFD-MPPB (S-1-methyl-5-propyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid), a photoreactive analog of the Convulsant barbiturate S-MPPB, inhibits α1β3γ2 but potentiates α1β3 GABAAR responses. In the α1β3γ2 GABAAR, S-mTFD-MPPB binds with high affinity to the γ+-β- subunit interface site with negative energetic coupling to GABA binding in the extracellular domain at the β+-α- subunit interfaces. GABA inhibits [3H]S-mTFD-MPPB photolabeling of γ2Ser-280 (γM2-15') in this site. In contrast, within the same site GABA enhances photolabeling of β3Met-227 in βM1 by an anesthetic barbiturate, [3H]R-mTFD-MPAB, which differs from S-mTFD-MPPB in structure only by chirality and two hydrogens (propyl vs. allyl). S-mTFD-MPPB and R-mTFD-MPAB are predicted to bind in different orientations at the γ+-β- site, based upon the distance in GABAAR homology models between γ2Ser-280 and β3Met-227. These results provide an explanation for S-mTFD-MPPB inhibition of α1β3γ2 GABAAR function and provide a first demonstration that an intersubunit binding site in the GABAAR transmembrane domain binds negative and positive allosteric modulators.
-
positive and negative allosteric modulation of an α1β3γ2 γ aminobutyric acid type a gabaa receptor by binding to a site in the transmembrane domain at the γ β interface
Journal of Biological Chemistry, 2015Co-Authors: Selwyn S Jayakar, Rooma Desai, Pavel Y Savechenkov, Karol S Bruzik, Keith W Miller, Xiaojuan Zhou, David C Chiara, Jonathan B CohenAbstract:In the process of developing safer general anesthetics, isomers of anesthetic ethers and barbiturates have been discovered that act as Convulsants and inhibitors of γ-aminobutyric acid type A receptors (GABAARs) rather than potentiators. It is unknown whether these Convulsants act as negative allosteric modulators by binding to the intersubunit anesthetic-binding sites in the GABAAR transmembrane domain (Chiara, D. C., Jayakar, S. S., Zhou, X., Zhang, X., Savechenkov, P. Y., Bruzik, K. S., Miller, K. W., and Cohen, J. B. (2013) J. Biol. Chem. 288, 19343-19357) or to known Convulsant sites in the ion channel or extracellular domains. Here, we show that S-1-methyl-5-propyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid (S-mTFD-MPPB), a photoreactive analog of the Convulsant barbiturate S-MPPB, inhibits α1β3γ2 but potentiates α1β3 GABAAR responses. In the α1β3γ2 GABAAR, S-mTFD-MPPB binds in the transmembrane domain with high affinity to the γ(+)-β(-) subunit interface site with negative energetic coupling to GABA binding in the extracellular domain at the β(+)-α(-) subunit interfaces. GABA inhibits S-[(3)H]mTFD-MPPB photolabeling of γ2Ser-280 (γM2-15') in this site. In contrast, within the same site GABA enhances photolabeling of β3Met-227 in βM1 by an anesthetic barbiturate, R-[(3)H]methyl-5-allyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (mTFD-MPAB), which differs from S-mTFD-MPPB in structure only by chirality and two hydrogens (propyl versus allyl). S-mTFD-MPPB and R-mTFD-MPAB are predicted to bind in different orientations at the γ(+)-β(-) site, based upon the distance in GABAAR homology models between γ2Ser-280 and β3Met-227. These results provide an explanation for S-mTFD-MPPB inhibition of α1β3γ2 GABAAR function and provide a first demonstration that an intersubunit-binding site in the GABAAR transmembrane domain binds negative and positive allosteric modulators.
Danka Peričić - One of the best experts on this subject based on the ideXlab platform.
-
Swim stress alters the behavioural response of mice to GABA-related and some GABA-unrelated Convulsants.
Epilepsy research, 2001Co-Authors: Danka Peričić, Maja Jazvinšćak, Dubravka Švob, Kety MirkovićAbstract:Abstract To elucidate the relationship between stress and seizures, the effect of a single swim stress on the convulsive signs and death produced by several GABA-related and GABA-unrelated Convulsants, and the effect of repeated swim stress on picrotoxin-induced convulsions was studied. Mice were subjected to swim stress (10 min swimming at 18–19°C), and the i.v. infusion of Convulsants started 15 min thereafter. The latency to the onset of several Convulsant signs and death was measured, and the doses of Convulsants producing convulsions and death were calculated. Additional experiments included mice swimming at room temperature, and those which were stressed repeatedly (twice a day for four consecutive days, plus one stressful procedure on the fifth day). Swim stress increased the dose needed to produce Convulsant signs and death after bicuculline, picrotoxin, pentylenetetrazole, strychnine and 4-aminopyridine, while kainic acid-induced convulsions were not affected. Using picrotoxin infusion, the effect of swimming in room temperature water was less than the effect of swimming in 18–19°C water. In addition, the effect of repeated stress was less than the effect of acute stress on picrotoxin-induced convulsions. The results demonstrate that acute swim stress lowers the convulsive potency of GABA-related and some GABA-unrelated Convulsants. Repeatedly stressed animals develop tolerance to anticonvulsive effect of swim stress.
Keith W Miller - One of the best experts on this subject based on the ideXlab platform.
-
contrasting actions of a Convulsant barbiturate and its antiConvulsant enantiomer on the α1β3γ2l gabaa receptor account for their in vivo effects
The Journal of Physiology, 2015Co-Authors: Rooma Desai, Pavel Y Savechenkov, Dorota Zolkowska, Ri Le Ge, Michael A Rogawski, Karol S Bruzik, Stuart A Forman, Douglas E Raines, Keith W MillerAbstract:Key Points Most barbiturates are anaesthetics but unexpectedly a few are Convulsants whose mechanism of action is poorly understood. We synthesized and characterized a novel pair of chiral barbiturates that are capable of photolabelling their binding sites on GABAA receptors. In mice the S-enantiomer is a Convulsant, but the R-enantiomer is an antiConvulsant. The Convulsant S-enantiomer binds solely at an inhibitory site. It is both an open state inhibitor and a resting state inhibitor. Its action is pH independent, suggesting the pyrimidine ring plays little part in binding. The inhibitory site is not enantioselective because the R-enantiomer inhibits with equal affinity. In contrast, only the antiConvulsant R-enantiomer binds to the enhancing site on open channels, causing them to stay open longer. The enhancing site is enantioselective. The in vivo actions of the Convulsant S-enantiomer are accounted for by its interactions with GABAA receptors. Abstract Most barbiturates are anaesthetics but a few unexpectedly are Convulsants. We recently located the anaesthetic sites on GABAA receptors (GABAARs) by photolabelling with an anaesthetic barbiturate. To apply the same strategy to locate the Convulsant sites requires the creation and mechanistic characterization of a suitable agent. We synthesized enantiomers of a novel, photoactivable barbiturate, 1-methyl-5-propyly-5-(m-trifluoromethyldiazirinyl) phenyl barbituric acid (mTFD-MPPB). In mice, S-mTFD-MPPB acted as a Convulsant, whereas R-mTFD-MPPB acted as an antiConvulsant. Using patch clamp electrophysiology and fast solution exchange on recombinant human α1β3γ2L GABAARs expressed in HEK cells, we found that S-mTFD-MPPB inhibited GABA-induced currents, whereas R-mTFD-MPPB enhanced them. S-mTFD-MPPB caused inhibition by binding to either of two inhibitory sites on open channels with bimolecular kinetics. It also inhibited closed, resting state receptors at similar concentrations, decreasing the channel opening rate and shifting the GABA concentration–response curve to the right. R-mTFD-MPPB, like most anaesthetics, enhanced receptor gating by rapidly binding to allosteric sites on open channels, initiating a rate-limiting conformation change to stabilized open channel states. These states had slower closing rates, thus shifting the GABA concentration–response curve to the left. Under conditions when most GABAARs were open, an inhibitory action of R-mTFD-MPPB was revealed that had a similar IC50 to that of S-mTFD-MPPB. Thus, the inhibitory sites are not enantioselective, and the Convulsant action of S-mTFD-MPPB results from its negligible affinity for the enhancing, anaesthetic sites. Interactions with these two classes of barbiturate binding sites on GABAARs underlie the enantiomers’ different pharmacological activities in mice.
-
positive and negative allosteric modulation of an α1β3γ2 γ aminobutyric acid type a gabaa receptor by binding to a site in the transmembrane domain at the γ β interface
Journal of Biological Chemistry, 2015Co-Authors: Selwyn S Jayakar, Rooma Desai, Pavel Y Savechenkov, Karol S Bruzik, Keith W Miller, Xiaojuan Zhou, David C Chiara, Jonathan B CohenAbstract:Abstract In the process of developing safer general anesthetics, isomers of anesthetic ethers and barbiturates have been discovered that act as Convulsants and inhibitors of γ-aminobutyric acid type A receptors (GABAARs) rather than potentiators. It is unknown whether these Convulsants act as negative allosteric modulators by binding to the intersubunit anesthetic binding sites in the GABAAR transmembrane domain (Chiara et al., J. Biol. Chem. 288: 19434-19357 (2013)) or to known Convulsant sites in the ion channel or extracellular domains. Here we show that S-mTFD-MPPB (S-1-methyl-5-propyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid), a photoreactive analog of the Convulsant barbiturate S-MPPB, inhibits α1β3γ2 but potentiates α1β3 GABAAR responses. In the α1β3γ2 GABAAR, S-mTFD-MPPB binds with high affinity to the γ+-β- subunit interface site with negative energetic coupling to GABA binding in the extracellular domain at the β+-α- subunit interfaces. GABA inhibits [3H]S-mTFD-MPPB photolabeling of γ2Ser-280 (γM2-15') in this site. In contrast, within the same site GABA enhances photolabeling of β3Met-227 in βM1 by an anesthetic barbiturate, [3H]R-mTFD-MPAB, which differs from S-mTFD-MPPB in structure only by chirality and two hydrogens (propyl vs. allyl). S-mTFD-MPPB and R-mTFD-MPAB are predicted to bind in different orientations at the γ+-β- site, based upon the distance in GABAAR homology models between γ2Ser-280 and β3Met-227. These results provide an explanation for S-mTFD-MPPB inhibition of α1β3γ2 GABAAR function and provide a first demonstration that an intersubunit binding site in the GABAAR transmembrane domain binds negative and positive allosteric modulators.
-
positive and negative allosteric modulation of an α1β3γ2 γ aminobutyric acid type a gabaa receptor by binding to a site in the transmembrane domain at the γ β interface
Journal of Biological Chemistry, 2015Co-Authors: Selwyn S Jayakar, Rooma Desai, Pavel Y Savechenkov, Karol S Bruzik, Keith W Miller, Xiaojuan Zhou, David C Chiara, Jonathan B CohenAbstract:In the process of developing safer general anesthetics, isomers of anesthetic ethers and barbiturates have been discovered that act as Convulsants and inhibitors of γ-aminobutyric acid type A receptors (GABAARs) rather than potentiators. It is unknown whether these Convulsants act as negative allosteric modulators by binding to the intersubunit anesthetic-binding sites in the GABAAR transmembrane domain (Chiara, D. C., Jayakar, S. S., Zhou, X., Zhang, X., Savechenkov, P. Y., Bruzik, K. S., Miller, K. W., and Cohen, J. B. (2013) J. Biol. Chem. 288, 19343-19357) or to known Convulsant sites in the ion channel or extracellular domains. Here, we show that S-1-methyl-5-propyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid (S-mTFD-MPPB), a photoreactive analog of the Convulsant barbiturate S-MPPB, inhibits α1β3γ2 but potentiates α1β3 GABAAR responses. In the α1β3γ2 GABAAR, S-mTFD-MPPB binds in the transmembrane domain with high affinity to the γ(+)-β(-) subunit interface site with negative energetic coupling to GABA binding in the extracellular domain at the β(+)-α(-) subunit interfaces. GABA inhibits S-[(3)H]mTFD-MPPB photolabeling of γ2Ser-280 (γM2-15') in this site. In contrast, within the same site GABA enhances photolabeling of β3Met-227 in βM1 by an anesthetic barbiturate, R-[(3)H]methyl-5-allyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (mTFD-MPAB), which differs from S-mTFD-MPPB in structure only by chirality and two hydrogens (propyl versus allyl). S-mTFD-MPPB and R-mTFD-MPAB are predicted to bind in different orientations at the γ(+)-β(-) site, based upon the distance in GABAAR homology models between γ2Ser-280 and β3Met-227. These results provide an explanation for S-mTFD-MPPB inhibition of α1β3γ2 GABAAR function and provide a first demonstration that an intersubunit-binding site in the GABAAR transmembrane domain binds negative and positive allosteric modulators.
Danka Pericic - One of the best experts on this subject based on the ideXlab platform.
-
swim stress inhibits 5 ht2a receptor mediated head twitch behaviour in mice
Psychopharmacology, 2003Co-Authors: Danka PericicAbstract:Rationale Several studies have shown that swim stress lowers the Convulsant potency of different Convulsants. The involvement of α2- adrenoceptors has been proposed. Drugs active at α2-adrenoceptors are known to modulate the head twitch response, the behaviour supposedly mediated by 5-HT2A receptors.