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PLoS One ; 9(4): e94905, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24747296


In cardiomyocytes, Ca2+ entry through voltage-dependent Ca2+ channels (VDCCs) binds to and activates RyR2 channels, resulting in subsequent Ca2+ release from the sarcoplasmic reticulum (SR) and cardiac contraction. Previous research has documented the molecular coupling of small-conductance Ca2+-activated K+ channels (SK channels) to VDCCs in mouse cardiac muscle. Little is known regarding the role of RyRs-sensitive Ca2+ release in the SK channels in cardiac muscle. In this study, using whole-cell patch clamp techniques, we observed that a Ca2+-activated K+ current (IK,Ca) recorded from isolated adult C57B/L mouse atrial myocytes was significantly decreased by ryanodine, an inhibitor of ryanodine receptor type 2 (RyR2), or by the co-application of ryanodine and thapsigargin, an inhibitor of the sarcoplasmic reticulum calcium ATPase (SERCA) (p<0.05, p<0.01, respectively). The activation of RyR2 by caffeine increased the IK,Ca in the cardiac cells (p<0.05, p<0.01, respectively). We further analyzed the effect of RyR2 knockdown on IK,Ca and Ca2+ in isolated adult mouse cardiomyocytes using a whole-cell patch clamp technique and confocal imaging. RyR2 knockdown in mouse atrial cells transduced with lentivirus-mediated small hairpin interference RNA (shRNA) exhibited a significant decrease in IK,Ca (p<0.05) and [Ca2+]i fluorescence intensity (p<0.01). An immunoprecipitated complex of SK2 and RyR2 was identified in native cardiac tissue by co-immunoprecipitation assays. Our findings indicate that RyR2-mediated Ca2+ release is responsible for the activation and modulation of SK channels in cardiac myocytes.

Cálcio/metabolismo , Fenômenos Eletrofisiológicos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Potássio/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Sinalização do Cálcio , Técnicas de Silenciamento de Genes , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/deficiência , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo
Neurochem Res ; 33(10): 1979-89, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18461446


Neuropathic pain is induced by the injury to nervous systems and characterized by hyperalgesia, allodynia and spontaneous pain. The underlying mechanisms include peripheral and central sensitization resulted from neuronal hyperexcitability. A number of ion channels are considered to contribute to the neuronal hyperexcitability. Here, we particularly concentrate on an interesting ion channel, hyperpolarization-activated cyclic nucleotide gated (HCN) channels. We overview its biophysical properties, physiological functions, followed by focusing on the current progress in the study of its role in the development of neuropathic pain. We attempt to provide a comprehensive review of the potential valuable target, HCN channels, in the treatment of neuropathic pain.

Canais de Cátion Regulados por Nucleotídeos Cíclicos/fisiologia , Dor/fisiopatologia , Canais de Potássio/fisiologia , Animais , Axônios/fisiologia , Benzazepinas/farmacologia , Canais de Cátion Regulados por Nucleotídeos Cíclicos/efeitos dos fármacos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Ivabradina , Condução Nervosa/fisiologia , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Canais de Potássio/efeitos dos fármacos , Pirimidinas/farmacologia , Transmissão Sináptica/fisiologia
Pain ; 137(3): 495-506, 2008 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-18179873


Peripheral nerve injury causes neuropathic pain including mechanical allodynia and thermal hyperalgesia due to central and peripheral sensitization. Spontaneous ectopic discharges derived from dorsal root ganglion (DRG) neurons and from the sites of injury are a key factor in the initiation of this sensitization. Numerous studies have focused primarily on DRG neurons; however, the injured axons themselves likely play an equally important role. Previous studies of neuropathic pain rats with spinal nerve ligation (SNL) showed that the hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel in DRG neuronal bodies is important for the development of neuropathic pain. Here, we investigate the role of the axonal HCN channel in neuropathic pain rats. Using the chronic constriction injury (CCI) model, we found abundant axonal accumulation of HCN channel protein at the injured sites accompanied by a slight decrease in DRG neuronal bodies. The function of these accumulated channels was verified by local application of ZD7288, a specific HCN blocker, which significantly suppressed the ectopic discharges from injured nerve fibers with no effect on impulse conduction. Moreover, mechanical allodynia, but not thermal hyperalgesia, was relieved significantly by ZD7288. These results suggest that axonal HCN channel accumulation plays an important role in ectopic discharges from injured spinal nerves and contributes to the development of mechanical allodynia in neuropathic pain rats.

Axônios/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Gânglios Espinais/fisiopatologia , Hiperalgesia/fisiopatologia , Traumatismos dos Nervos Periféricos , Nervos Periféricos/fisiopatologia , Células do Corno Posterior/metabolismo , Tato , Animais , Ativação do Canal Iônico , Masculino , Potenciais da Membrana , Ratos , Ratos Sprague-Dawley
Exp Neurol ; 206(2): 269-79, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17628541


Several lines of evidence indicate that phosphatidylinositol 3-kinase (PI3K) and PI3K-protein kinase B/Akt (PKB/Akt) signal pathway mediate the pain hypersensitivity induced by intradermal injection of capsaicin or nerve growth factor. However, the role of PI3K and PI3K-PKB/Akt signal pathway activation in neuropathic pain is still unclear. Using L5 spinal nerve ligation (L5 SNL) and immunohistochemistry, we found that the numbers of phospho-PKB/Akt-immunoreactive (p-PKB/Akt IR) positive neurons were significantly increased in ipsilateral L5 dorsal root ganglia (DRG) and adjacent L4 DRG started at 12 h after surgery and maintained to the 3rd day. Meanwhile, L5 SNL also induced an increased expression of p-PKB/Akt in ipsilateral L5 spinal dorsal horn. Double immunofluorescence staining showed that p-PKB/Akt expressed entirely in DRG neurons, especially in IB4-positive neurons. Intrathecal injection of PI3K inhibitor wortmannin or LY294002 and PKB/Akt inhibitor Akt inhibitor IV or (-)-Deguelin, started before L5 SNL, reduced the behavioral signs of neuropathic pain. Intraperitoneal injection of wortmannin or (-)-Deguelin as above also reduced the pain hypersensitivity. Post-treatment with wortmannin, started at the 1st day or the 3rd day after L5 SNL, decreased abnormal pain behaviors. Whereas the inhibitory effect of Akt inhibitor IV on established neuropathic pain was observed only in those rats that received the drug treatment started at the 1st day. Immunohistochemistry revealed that intrathecal injection of wortmannin significantly inhibited the activation of PKB/Akt in L5 DRG and L5 spinal cord. The data suggested that PI3K and PI3K-PKB/Akt signal pathway activation might contribute to the development of neuropathic pain.

Gânglios Espinais/enzimologia , Doenças do Sistema Nervoso Periférico/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Medula Espinal/enzimologia , Animais , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Gânglios Espinais/fisiopatologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/enzimologia , Hiperalgesia/fisiopatologia , Imuno-Histoquímica , Ligadura/efeitos adversos , Masculino , Neuralgia/tratamento farmacológico , Neuralgia/enzimologia , Neuralgia/fisiopatologia , Neurônios Aferentes/enzimologia , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/fisiopatologia , Regulação para Cima/efeitos dos fármacos
Brain Res ; 1032(1-2): 63-9, 2005 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-15680942


Peripheral nerve injury causes ectopic discharges of different firing patterns, which may play an important role in the development of neuropathic pain. The molecular mechanisms underlying the generation of ectopic discharges are still unclear. In the present study, by using in vivo teased fiber recording technique we examined the effect of ZD7288, a specific blocker of hyperpolarization-activated current (I(h)), on the ectopic discharges in the dorsal root ganglion (DRG) neurons injured by spinal nerve ligation. We found that ectopic discharges of all three firing patterns (tonic, bursting and irregular) were dose- and time-dependently inhibited by local application of ZD7288. Interestingly, the extent of suppression was negatively related to frequency of firing prior to application of ZD7288. We also observed that ZD7288 could alter the firing patterns of the ectopic discharges. At 100 microM, tonic firing pattern was gradually transformed into bursting type whereas at 1 mM, it could be transformed to integer multiples firing. These results indicate that I(h) might play a role in the generation of various forms of ectopic discharges in the injured DRG neurons and may thus be a possible target for neuropathic pain treatment.

Potenciais de Ação/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Inibição Neural/efeitos dos fármacos , Neuralgia/fisiopatologia , Neurônios/efeitos dos fármacos , Pirimidinas/farmacologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Gânglios Espinais/patologia , Masculino , Neuralgia/patologia , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo