RESUMO
Using the patch-clamp method in the whole cell configuration, it was shown that external potassium ions play an important role in the regulation of calcium-activated chloride channels (CaCCs). A clear dependence of the conductivity of the СаССs on the external potassium concentration was shown. The effect of external potassium in the range 0-15 mM on the conductivity of chloride channels was significantly greater than the effect it had on other ionic currents (sodium or potassium). There is reason to believe that these changes in the conductivity of CaCCs may contribute to the development of pathophysiological processes such as hypokalemia or hyperkalemia.
Assuntos
Canais de CloretoRESUMO
Using the patch-clamp method in the whole cell configuration, it was shown that new conjugates of 2-aminothiophene-3-carboxylic acid with adamantane derivatives exhibit the ability to modulate CaCC activity in the single Purkinje neurons of rat cerebellum. It was noted that, depending on the nature of the substitution in the thiophene fragment, the nature of the effect on CaCC varies from inhibition to potentiation of CaCC currents. The described compounds are also blockers of the NMDA receptor ifenprodile site, which may have an additional neuroprotective contribution to the spectrum of biological activity of these compounds.
Assuntos
Adamantano/farmacologia , Canais de Cloreto/antagonistas & inibidores , Potenciais da Membrana/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tiofenos/farmacologia , Animais , Células Cultivadas , Masculino , Neurônios/metabolismo , Neurônios/fisiologia , Técnicas de Patch-Clamp/métodos , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
A new derivative of 3,7-diazabicyclo[3.3.1]nonane, which showed a high activity as a positive allosteric modulator of AMPA receptors of the CNS, was studied in electrophysiological experiments. At doses of 0.01 mg/kg, this compound significantly improved the memory of experimental animals disturbed by maximal electric shock. The results indicate that this compound is a promising candidate for preclinical trials and clinical studies as a drug for treatment of a number of psychoneurological diseases.
Assuntos
Hipocampo/metabolismo , Transtornos Mentais , Doenças do Sistema Nervoso , Nootrópicos , Receptores de AMPA , Regulação Alostérica , Animais , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/metabolismo , Transtornos Mentais/patologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Nootrópicos/química , Nootrópicos/farmacologia , Ratos , Receptores de AMPA/agonistas , Receptores de AMPA/química , Receptores de AMPA/metabolismoRESUMO
Using the patch-clamp method in the whole-cell configuration, we showed that the new derivatives of 2-aminothiophene-3-carboxylic acid, which were synthesized by us earlier, can both block (compound 1) and potentiate (compound 2) calcium-activated chloride currents in single rat cerebellar Purkinje cells.
Assuntos
Canais de Cloreto/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Células de Purkinje/metabolismo , Toluidinas , Animais , Células Cultivadas , Ratos , Toluidinas/síntese química , Toluidinas/química , Toluidinas/farmacologiaRESUMO
The whole-cell voltage clamp technique was employed to record the total ionic currents in rat cerebellar Purkinje neurons. When intrapipette solution contained 120 mM KCl, replacement of the standard external physiological saline with Na-free solution resulted in appearance of inward tail current after the end of the depolarizing pulse. When intrapipette potassium ions were replaced for cesium ones, the tail currents were observed even in the presence of normal Na+ concentration (140 mM) in the external solution. Tail currents were not observed when external solution contained no Cl- and/or Ca2+ ions. Niflumic acid (25-100 µM) blocked these currents by 80-100%. Complete replacement of external Na+ for Tris ions pronouncedly augmented the amplitude and duration of the tail currents. These findings suggest that the tail transients in rat cerebellar Purkinje neurons are calcium-activated chloride currents whose amplitude and kinetics depend on ionic composition of the extracellular and intracellular solutions.
Assuntos
Cálcio/metabolismo , Cerebelo/metabolismo , Potenciais da Membrana/fisiologia , Células de Purkinje/metabolismo , Animais , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Transporte de Íons , Cinética , Potenciais da Membrana/efeitos dos fármacos , Ácido Niflúmico/farmacologia , Concentração Osmolar , Técnicas de Patch-Clamp , Potássio/metabolismo , Cultura Primária de Células , Células de Purkinje/citologia , Células de Purkinje/efeitos dos fármacos , Ratos , Ratos Wistar , Sódio/metabolismoRESUMO
A decrease in the external chloride ion concentration to 4 mM caused a decrease in the fast sodium current to 85-100% in rat cerebellum Purkinje neurons in the whole-cell configuration using the patchclamp method. This effect did not depend on the main cation from the internal side of the cell membrane (120 mM of potassium or cesium) and also appeared when Cl- was substituted with sulfate (SO2-4) or phosphate (H2PO4-) anion outside of the cell. The effect was reversible after washing out the low chloride by the standard saline.
Assuntos
Cloretos/metabolismo , Íons/metabolismo , Células de Purkinje/fisiologia , Canais de Sódio/metabolismo , Cloreto de Sódio/metabolismo , Cloreto de Sódio/farmacologia , Animais , Cloretos/farmacologia , Células de Purkinje/efeitos dos fármacos , Ratos , Canais de Sódio/efeitos dos fármacosRESUMO
Using patch-clamp method (whole cell configuration), it was shown that tetraethylammonium (TEA) and 4-aminopyridine (4-AP) block calcium-dependent chloride currents in the membrane of freshly isolated cerebellar Purkinje cells of rats (12-15 days). In the concentration range studied (50 µM-10 mM TEA and 100 µM-1 mM 4-AP), both compounds blocked the chloride current at IC50 130 µM for TEA and 110 µM for 4-AP. TEA blockade was reversible after washing. The effect of 4-AP at concentrations greater than 100 µM was irreversible: both outward and inward chloride currents were blocked even after the removal of 4-AP from the incubation medium.
Assuntos
4-Aminopiridina/farmacologia , Cetilpiridínio/metabolismo , Moduladores de Transporte de Membrana/farmacologia , Células de Purkinje/efeitos dos fármacos , Tetraetilamônio/farmacologia , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Masculino , Potenciais da Membrana/efeitos dos fármacos , Técnicas de Patch-Clamp , Células de Purkinje/metabolismo , Ratos WistarRESUMO
We have previously shown that neuropeptide cycloprolylglycine (CPG) increases the content of brain-derived neurotrophic factor (BDNF) in the culture of neuronal cells under normal conditions and in pathology. This is the first study to show that CPG at a physiological concentration of 10-6 M significantly enhances the transmembrane AMPA currents in rat cerebellar Purkinje cells. Thus, CPG is a positive endogenous modulator of AMPA receptors. It was assumed that the neuropsychotropic effects of CPG are implemented as a result of BDNF accumulation after the activation of AMPA receptors by this neuropeptide.
Assuntos
Fármacos Atuantes sobre Aminoácidos Excitatórios/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/metabolismo , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/fisiologia , Receptores de AMPA/metabolismo , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Ácido Caínico/administração & dosagem , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Técnicas de Patch-Clamp , Psicotrópicos/administração & dosagem , Ratos WistarAssuntos
Hormônio Adrenocorticotrópico/análogos & derivados , Neurotransmissores/farmacologia , Fragmentos de Peptídeos/farmacologia , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/fisiologia , Receptores de AMPA/metabolismo , Hormônio Adrenocorticotrópico/farmacologia , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Agonistas de Aminoácidos Excitatórios/farmacologia , Ácido Caínico/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Técnicas de Patch-Clamp , RatosRESUMO
The presence of calcium-dependent potential-activated chloride currents in the membranes of freshly isolated rat cerebellar Purkinje cells (12-15 days) was shown by the whole-cell patch clamp technique. Chloride currents appeared in a sodium-free external solution and reversibly disappeared in the absence of external chloride and calcium ions.
Assuntos
Potenciais de Ação , Cálcio/metabolismo , Membrana Celular/metabolismo , Cloretos/metabolismo , Células de Purkinje/metabolismo , Animais , Células Cultivadas , Canais de Cloreto/metabolismo , Masculino , Células de Purkinje/fisiologia , Ratos , Ratos WistarRESUMO
We studied the effect of somatostatin on presinaptic NMDA receptors and postsinaptic GABA, NMDA, and AMPA receptors in rat brain. It was shown that somatostatin inhibits NMDA-induced (45)Ca(2+) uptake into synaptosomes isolated from rat brain cortex (IC50=2.8×10(-11) M). Somatostatin potentiates AMPA receptors and inhibits hippocampal NMDA receptors in the entire range of examined concentrations (10(-14)-10(-7) M); it also potentiates or inhibits GABA receptor currents in a concentration-dependent manner. Our results suggest that somatostatin modulates the function of ionotropic glutamate and GABA receptors and is involved in cognitive and neurodegenerative processes in the mammalian brain.
Assuntos
Encéfalo/metabolismo , Transporte de Íons/efeitos dos fármacos , Neurônios/metabolismo , Receptores de AMPA/metabolismo , Receptores de GABA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Somatostatina/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Cálcio/metabolismo , Peptídeo da Parte Intermédia da Adeno-Hipófise Semelhante à Corticotropina/metabolismo , Sinergismo Farmacológico , Ácido Caínico/farmacologia , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Transmissão Sináptica/efeitos dos fármacos , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Ácido gama-Aminobutírico/farmacologiaAssuntos
Aorta/citologia , Cálcio/fisiologia , Calmodulina/antagonistas & inibidores , Músculo Liso Vascular/efeitos dos fármacos , Nicardipino/farmacologia , Canais de Potássio/efeitos dos fármacos , Quinina/farmacologia , Sulfonamidas/farmacologia , Trifluoperazina/farmacologia , Células Cultivadas , HumanosRESUMO
Using the patch-clamp technique the action of internal barium- and magnesium-ions on the calcium-dependent potassium channel in the membrane of vascular smooth muscle cells from the media layer of the human aorta was studied. Under symmetrical potassium conditions in excised inside-out patches bathed in the standard solution containing EGTA, the addition of barium as well as magnesium led to a concentration-dependent shift of the activation-curves to negative values of the membrane potential compared with the control, a block of single channel activity by barium, whereas no inhibitory effects by magnesium were registered. Thus, these results suggest that the process of channel activation of the calcium-dependent potassium channel of high conductance depends not merely on calcium but also on other divalent earthalkali ions.