The Role of Post-Translational Modifications of Cav3. 2 in Neuropathic Pain / 中国生物化学与分子生物学报

Neuropathic pain is a common chronic pain that affects human health worldwide. As an important mediator of excitatory conduction in neurons, ion channels are important targets for mechanism research and drug research in this field. T-type calcium channel(Cav3) can be activated transiently when neurons are close to the resting potential of -70 mV, resulting in a transient Ca

Mibefradil improves skeletal muscle mass, function and structure in obese mice / 南方医科大学学报

OBJECTIVE@#To observe the effect of mibefradil on skeletal muscle mass, function and structure in obese mice.@*METHODS@#Fifteen 6-week-old C57BL/6 mice were randomized equally into normal diet group (control group), high-fat diet (HFD) group and high-fat diet +mibefradil intervention group (HFD +Mibe group). The grip strength of the mice was measured using an electronic grip strength meter, and the muscle content of the hindlimb was analyzed by X-ray absorptiometry (DXA). Triglyceride (TG) and total cholesterol (TC) levels of the mice were measured with GPO-PAP method. The cross-sectional area of the muscle fibers was observed with HE staining. The changes in the level of autophagy in the muscles were detected by Western blotting and immunofluorescence assay, and the activation of the Akt/mTOR signaling pathway was detected with Western blotting.@*RESULTS@#Compared with those in the control group, the mice in HFD group had a significantly greater body weight, lower relative grip strength, smaller average cross sectional area of the muscle fibers, and a lower hindlimb muscle ratio (P < 0.05). Immunofluorescence assay revealed a homogenous distribution of LC3 emitting light red fluorescence in the cytoplasm in the muscle cells in HFD group and HFD+Mibe group, while bright spots of red fluorescence were detected in HFD group. In HFD group, the muscular tissues of the mice showed an increased expression level of LC3 II protein with lowered expressions of p62 protein and phosphorylated AKT and mTOR (P < 0.05). Mibefradil treatment significantly reduced body weight of the mice, lowered the expression level of p62 protein, and increased forelimb grip strength, hindlimb muscle ratio, cross-sectional area of the muscle fibers, and the expression levels of LC3 II protein and phosphorylated AKT and mTOR (P < 0.05).@*CONCLUSION@#Mibefradil treatment can moderate high-fat diet-induced weight gain and improve muscle mass and function in obese mice possibly by activating AKT/mTOR signal pathway to improve lipid metabolism and inhibit obesityinduced autophagy.

Role of T-type Calcium Channels in Generating Hyperexcitatory Behaviors during Emergence from Sevoflurane Anesthesia in Neonatal Rats / 神经科学通报·英文版

In the current study, we sought to investigate whether T-type Ca channels (TCCs) in the brain are involved in generating post-anesthetic hyperexcitatory behaviors (PAHBs). We found that younger rat pups (postnatal days 9-11) had a higher incidence of PAHBs and higher PAHB scores than older pups (postnatal days 16-18) during emergence from sevoflurane anesthesia. The power spectrum of the theta oscillations (4 Hz-8 Hz) in the prefrontal cortex was significantly enhanced in younger pups when PAHBs occurred, while there were no significant changes in older pups. Both the power of theta oscillations and the level of PAHBs were significantly reduced by the administration of TCC inhibitors. Moreover, the sensitivity of TCCs in the medial dorsal thalamic nucleus to sevoflurane was found to increase with age by investigating the kinetic properties of TCCs in vitro. TCCs were activated by potentiated GABAergic depolarization with a sub-anesthetic dose of sevoflurane (1%). These data suggest that (1) TCCs in the brain contribute to the generation of PAHBs and the concomitant electroencephalographic changes; (2) the stronger inhibitory effect of sevoflurane contributes to the lack of PAHBs in older rats; and (3) the contribution of TCCs to PAHBs is not mediated by a direct effect of sevoflurane on TCCs.

T-Type Calcium Channels Are Required to Maintain Viability of Neural Progenitor Cells

T-type calcium channels are low voltage-activated calcium channels that evoke small and transient calcium currents. Recently, T-type calcium channels have been implicated in neurodevelopmental disorders such as autism spectrum disorder and neural tube defects. However, their function during embryonic development is largely unknown. Here, we investigated the function and expression of T-type calcium channels in embryonic neural progenitor cells (NPCs). First, we compared the expression of T-type calcium channel subtypes (CaV3.1, 3.2, and 3.3) in NPCs and differentiated neural cells (neurons and astrocytes). We detected all subtypes in neurons but not in astrocytes. In NPCs, CaV3.1 was the dominant subtype, whereas CaV3.2 was weakly expressed, and CaV3.3 was not detected. Next, we determined CaV3.1 expression levels in the cortex during early brain development. Expression levels of CaV3.1 in the embryonic period were transiently decreased during the perinatal period and increased at postnatal day 11. We then pharmacologically blocked T-type calcium channels to determine the effects in neuronal cells. The blockade of T-type calcium channels reduced cell viability, and induced apoptotic cell death in NPCs but not in differentiated astrocytes. Furthermore, blocking T-type calcium channels rapidly reduced AKT-phosphorylation (Ser473) and GSK3β-phosphorylation (Ser9). Our results suggest that T-type calcium channels play essential roles in maintaining NPC viability, and T-type calcium channel blockers are toxic to embryonic neural cells, and may potentially be responsible for neurodevelopmental disorders.

T type calciumchannel activated by brain injury induces neural stem cell proliferation / 西安交通大学学报(医学版)

ABSTRACT:Objective To investigate the mechanism and induction of T type calcium channel on neural stem cells after brain injury .Methods Adult mice brain injury model was established and divided into control ,sham operation ,surgery ,and surgery+mebefradil groups .Neural stem cells were separated from the subventricular zone (SVZ) and identified .Moreover ,we analyzed the results using MTT and neural stem cell sphere counting after adding different doses of mibefradil in culture medium ,respectively .Then we calculated the half maximal inhibitory concentration (IC50) of mibefradil on neural stem cells .Finally ,we analyzed the expression of Cav3 .2 in SVZ and the protein expressions of Cav3 .2 ,Cyclin A and caspase‐3 in neural stem cells by Western blot .Results In vivo , neural stem cell proliferation was increased in surgery group compared with that in control and sham‐operation groups .The proliferation of neural stem cells in surgery + mibefradil groups was significantly decreased compared with that in surgery group after mibefradil‐induced inhibition of T type calcium channel protein . In vitro , the formation of neural stem cell sphere was significantly inhibited after adding mibefradil .The cell growth ratio was significantly decreased when the concentration of mibefradil was above 5μmol/L .A values in 5 μmol/L ,10 μmol/L and 20μmol/L groups were significantly lower than those in control group (P<0 .05) .IC50 was 8 .93μmol/L .The protein expressions of Cyclin A and Cav3 .2 were inhibited while that of caspase‐3 was increased after mibefradil treatment .Conclusion Neural stem cell proliferation was enhanced by activating T type calcium channel after brain injury .

A system review: the effects of T-type CCB or ACEI /ARB for hypertensive patients with chronic kidney disease / 中国药学杂志

OBJECTIVE: To evaluate whether T-type CCBs are equivalent with or superior to ACEIs/ARBs on renal outcomes in hupertensive patients with chronic kidney disease. METHODS: Cochrane Library, Pubmed, EMbase and CNKI were searched for relevant randomized controlled trials (RCTs) from inception to May 2012. The meta-analysis was performed by Revman 5.1 software. RESULTS: Five RCTs (563 subjects) were included in the present study. T-type CCBs performed a pooled improvement in creatinine clearance and glomerular filtration rate similar to ACEIs/ARBs but were inferior to ACEIs/ARBs on reducing proteinuria excretion (three RCTs, 389 subjects, WMD 0.26 g·d-1, 95% CI 0.10 to 0.43), although T-type CCBs and ACEIs/ARBs showed stable anti-hypertensive effect. CONCLUSION: Our findings suggest that despite T-type CCBs do offer salutary effects on kidney outcomes and hypertension can be applied to treat hypertensive patients with chronic kidney disease, ACEIs /ARBs might be better choice for pressure control in this target population especially when proteinuria is the main issue of renal dysfunction.

Research progress of T-type calcium channels and the related drugs / 中国药理学通报

T-type calcium channels present in cardiovascular, neuronal and endocrine systems, and they are now receiving attention as novel therapeutic targets. It plays important roles in multiple cellular functions and genes those encode the T-type calcium channels have been recently reported. Many drugs and compounds non-specifically block T-type calcium channels. We review circumstances of the research of T- type calcium channels in the molecular structure, distribution, function, regulation and the related drugs.

The effect of mibefradil administered intrathecally and lateral ventricle to the pain threshold of the rats following chronic constriction injury(CCI) of the sciatic nerve / 中国药理学通报

Aim To investigate the role of T type calcium channel of spinal cord and supraspinal on the pain threthold of the rats following chronic constriction injury(CCI) of the sciatic nerve.Methods Intrathecal and lateral ventricle injection were employed in this study.With Von Frey hair and radiant thermal stimulator,we measured the mechanical withdrawal threshold(MWT) and thermal withdrawal latency(TWL)of the rats after injected mibefradil.Results The rats of CCI group formed steady mechanical and heat hyperaglsia from the third day after operation to the end of this study.Administered intrathecally mibefradil 50,100,200 ?g can increase the CCI rats MWT and TWL.However,mibefradil administered lateral ventricle can reduce the CCI rats MWT and TWL.Conclusion Blocking T type calcium channel of spinal can inhibit mechanical and heat hyperalgesia of the CCI rats,However,bloking the T type calcium channel of supraspinal can enhance the mechanical and heat hyperalgesia of the CCI rats.