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1.
Eur J Pharmacol ; 899: 174026, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33722592

RESUMEN

Riluzole is an anticonvulsant drug also used to treat the amyotrophic lateral sclerosis and major depressive disorder. This compound has antiglutamatergic activity and is an important multichannel blocker. However, little is known about its actions on the Kv4.2 channels, the molecular correlate of the A-type K+ current (IA) and the fast transient outward current (Itof). Here, we investigated the effects of riluzole on Kv4.2 channels transiently expressed in HEK-293 cells. Riluzole inhibited Kv4.2 channels with an IC50 of 190 ± 14 µM and the effect was voltage- and frequency-independent. The activation rate of the current (at +50 mV) was not affected by the drug, nor the voltage dependence of channel activation, but the inactivation rate was accelerated by 100 and 300 µM riluzole. When Kv4.2 channels were maintained at the closed state, riluzole incubation induced a tonic current inhibition. In addition, riluzole significantly shifted the voltage dependence of inactivation to hyperpolarized potentials without affecting the recovery from inactivation. In the presence of the drug, the closed-state inactivation was significantly accelerated, and the percentage of inactivated channels was increased. Altogether, our findings indicate that riluzole inhibits Kv4.2 channels mainly affecting the closed and closed-inactivated states.


Asunto(s)
Bloqueadores de los Canales de Potasio/farmacología , Riluzol/farmacología , Canales de Potasio Shal/antagonistas & inhibidores , Células HEK293 , Humanos , Activación del Canal Iónico , Potenciales de la Membrana , Canales de Potasio Shal/genética , Canales de Potasio Shal/metabolismo , Factores de Tiempo
2.
J. Venom. Anim. Toxins incl. Trop. Dis. ; 26: e20190043, May 29, 2020. ilus, tab, graf
Artículo en Inglés | VETINDEX | ID: vti-29965

RESUMEN

Background:The tarantula Chilobrachys jingzhao is one of the largest venomous spiders in China. In previous studies, we purified and characterized at least eight peptides from C. jingzhao venom. In this report, we describe the purification and characterization of Jingzhaotoxin-X (JZTX-X), which selectively blocks Kv4.2 and Kv4.3 potassium channels.Methods:JZTX-X was purified using a combination of cation-exchange HPLC and reverse-phase HPLC. The amino-acid sequence was determined by automated Edman degradation and confirmed by mass spectrometry (MS). Voltage-gated ion channel currents were recorded in HEK293t cells transiently transfected with a variety of ion channel constructs. In addition, the hyperalgesic activity of JZTX-X and the toxin´s effect on motor function were assessed in mice.Results:JZTX-X contained 31 amino acids, with six cysteine residues that formed three disulfide bonds within an inhibitory cysteine knot (ICK) topology. In whole-cell voltage-clamp experiments, JZTX-X inhibited Kv4.2 and Kv4.3 potassium channels in a concentration- and voltage-dependent manner, without affecting other ion channels (Kv1.1, 1.2, 1.3, 2.1, delayed rectifier potassium channels, high- and low-voltage-activated Ca2+ channels, and voltage-gated sodium channels Nav1.5 and 1.7). JZTX-X also shifted the voltage-dependent channel activation to more depolarized potentials, whereas extreme depolarization caused reversible toxin binding to Kv4.2 channels. JZTX-X shifted the Kv4.2 and Kv4.3 activities towards a resting state, since at the resting potential the toxin...(AU)


Asunto(s)
Animales , Canales de Potasio Shal/antagonistas & inhibidores , Canales de Potasio Shal/análisis , Venenos de Araña/aislamiento & purificación , Técnicas de Placa-Clamp
3.
Toxicon ; 119: 244-52, 2016 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-27346450

RESUMEN

The venom from the scorpion Tityus serrulatus (Ts) has been extensively studied mainly because of its rich cocktail of neurotoxins. Neurotoxins are the major and the most known components based on their modulation of voltage-gated ion channels. Until now, electrophysiological studies demonstrated that the Ts venom comprises toxins that affect Nav and Kv channels. However, although many studies have been conducted in this field, many peptides from Ts venom await further studies, including Ts8 toxin. Here we report the isolation and electrophysiological study of Ts8. The toxin Ts19 Frag-II was used as negative control. Ts8 demonstrates, among 20 tested channels, to be a selective modulator of Kv4.2 channels. Based on studies investigating the involvement of Kv4.2 on controlling nociception, we further investigated the modulation of pain by Ts8. Using intraplantar injections, Ts8 induced overt nociception (licking and lifting behaviors) and decreased the mechanical nociceptive threshold (hyperalgesia). Furthermore, the hyperalgesia was prolonged when intrathecal injections were performed. Independent of the severity, most of the victims stung by Ts scorpions report an intense and persistent pain as the major manifestation. The new role of Ts8 on nociception could explain, at least partially, this phenomenon. Additionally, our study also stresses the involvement of toxins specific to Nav channels and inflammatory mediators on the Ts painful sting. This work provides useful insights for a better understanding of the prolonged and intense pain associated with Ts envenoming for the development of specific therapies.


Asunto(s)
Bloqueadores de los Canales de Potasio/toxicidad , Venenos de Escorpión/química , Canales de Potasio Shal/antagonistas & inhibidores , Toxinas Biológicas/toxicidad , Secuencia de Aminoácidos , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Nocicepción/efectos de los fármacos , Venenos de Escorpión/aislamiento & purificación , Homología de Secuencia de Aminoácido , Toxinas Biológicas/química
4.
Toxicol Appl Pharmacol ; 288(2): 203-12, 2015 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-26216464

RESUMEN

The antimalarial drug mefloquine, is known to be a potassium channel blocker, although its mechanism of action has not being elucidated and its effects on the transient outward current (Ito) and the molecular correlate, the Kv4.3 channel has not being studied. Here, we describe the mefloquine-induced inhibition of the rat ventricular Ito and of CHO cells co-transfected with human Kv4.3 and its accessory subunit hKChIP2C by whole-cell voltage-clamp. Mefloquine inhibited rat Ito and hKv4.3+KChIP2C currents in a concentration-dependent manner with a limited voltage dependence and similar potencies (IC50=8.9µM and 10.5µM for cardiac myocytes and Kv4.3 channels, respectively). In addition, mefloquine did not affect the activation of either current but significantly modified the hKv4.3 steady-state inactivation and recovery from inactivation. The effects of this drug was compared with that of 4-aminopyridine (4-AP), a well-known potassium channel blocker and its binding site does not seem to overlap with that of 4-AP.


Asunto(s)
Potenciales de Acción/efectos de los fármacos , Antimaláricos/toxicidad , Activación del Canal Iónico/efectos de los fármacos , Mefloquina/toxicidad , Miocitos Cardíacos/efectos de los fármacos , Bloqueadores de los Canales de Potasio/toxicidad , Canales de Potasio Shal/antagonistas & inhibidores , 4-Aminopiridina/farmacología , Animales , Antimaláricos/metabolismo , Sitios de Unión , Células CHO , Cricetulus , Relación Dosis-Respuesta a Droga , Femenino , Proteínas de Interacción con los Canales Kv/genética , Proteínas de Interacción con los Canales Kv/metabolismo , Mefloquina/metabolismo , Simulación del Acoplamiento Molecular , Miocitos Cardíacos/metabolismo , Potasio/metabolismo , Bloqueadores de los Canales de Potasio/metabolismo , Unión Proteica , Ratas Wistar , Canales de Potasio Shal/genética , Canales de Potasio Shal/metabolismo , Factores de Tiempo , Transfección
5.
Neurosci Lett ; 414(2): 150-4, 2007 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-17197081

RESUMEN

Field recordings were used to determine the influence of delta-opioid receptor activation on corticostriatal synaptic transmission. Application of the selective delta-opioid receptor agonist, [Tyr-D-Pen-Gly-Phe-D-Pen]-enkephalin (DPDPE, 1 microM), decreased the amplitude of the field-excitatory synaptic potential and at the same time increased the paired pulse ratio (PPR) suggesting a presynaptic site of action. This response reversed rapidly when DPDPE was washed and blocked by 1 nM of the selective delta-receptor antagonist naltrindole. Neither omega-conotoxin GVIA (1 microM) nor omega-agatoxin TK (400 nM), blockers of N- and P/Q-type Ca2+-channels, respectively, nor TEA (1 mM), blocker of some classes of K+-channels, occluded the effects of DPDPE. Instead, 1 mM 4-AP or 400 microM Ba2+ occluded completely the effects of DPDPE. Therefore, the results suggest that the modulation by delta opioids at corticostriatal terminals is mediated by transient (KV4) K+-conductances.


Asunto(s)
Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Encefalina D-Penicilamina (2,5)/farmacología , Vías Nerviosas/metabolismo , Neurotransmisores/metabolismo , Receptores Opioides delta/agonistas , Canales de Potasio Shal/agonistas , Analgésicos Opioides/farmacología , Animales , Bloqueadores de los Canales de Calcio/farmacología , Corteza Cerebral/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Masculino , Antagonistas de Narcóticos/farmacología , Vías Nerviosas/efectos de los fármacos , Péptidos Opioides/metabolismo , Técnicas de Cultivo de Órganos , Bloqueadores de los Canales de Potasio/farmacología , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Ratas , Ratas Wistar , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides delta/metabolismo , Canales de Potasio Shal/antagonistas & inhibidores , Canales de Potasio Shal/metabolismo , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología
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