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In most non-excited cells, voltage-gated T-type calcium channels present three properties of activation, inactivation and slow inactivation, thus contribute to cellular calcium signaling and membrane potential. By which T-type calcium channels play an important role in many cancer cellular processes such as cell proliferation, differentiation, apoptosis, invasion, and metastasis. Inhibiting T-type calcium channels by drugs or genetic tools can change the related cellular currents and the intracellular Ca 2+ , thereby regulating the biological tumorigenesis. This article reviews the electrophysiological of T-type calcium channels during tumor progression, aims to provide a scientific basis for the study and treatment in cancer.
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Objective To evaluate the role of T?type calcium channels in up?regulation of spinal Ca2+∕calmodulin?dependent protein kinase Ⅱ ( CaMKⅡ) expression in rats with neuropathic pain. Meth?ods Forty?eight male Sprague?Dawley rats, weighing 230-270 g, in which intrathecal catheters were suc?cessfully implanted, were divided into 4 groups ( n=12 each) using a random number table: sham opera?tion group (group S), neuropathic pain group (group NP), normal saline group (group NS), and T?type calcium channel blocker mibefradil group ( group M ) . The model of neuropathic pain was established by chronic compression of the dorsal root ganglion ( DRG) . Normal saline 20μl and mibefradil 200μg ( dilu?ted to 20μl in normal saline) were injected intrathecally at 5 days after compression of the DRG in NS and M groups, respectively. Before intrathecal catheter implantation ( T1 ) , before compression of the DRG ( T2 ) , at 5 days after compression of the DRG and before intrathecal administration ( T3 ) , and at 30, 60, 120 and 240 min after intrathecal administration ( T4?7 ) , the mechanical paw withdrawal threshold ( MWT) and thermal paw withdrawal latency ( TWL) were measured. The rats were sacrificed after the last measure?ment of the pain threshold at T7 , and the lumbar enlargement segments of the spinal cord were harvested for determination of CaMKⅡ expression by Western blot. Results Compared with group S, the MWT was significantly decreased, and TWL was significantly shortened at T3?7 , and the expression of spinal CaMKⅡ was significantly up?regulated in NP and M groups (P0.05). Conclusion T?type calcium channels are opened, the intra?cellular free calcium ion concentrations are increased, and activated spinal CaMKⅡ is involved in the de?velopment of neuropathic pain in rats.
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Objective To investigate the effect of nesfatin-1 (NSF-1) on T-type Ca2+ channel currents in adult mouse dorsal root ganglion (DRG) neurons and possible signal transduction mechanisms involved.Methods We measured the expression of melanocortin 4 receptors(MC4-R)in mouse DRG by using western blotting analysis.The whole-cell patch clamp technique was used to record the effects of NSF 1 on T-type Ca2+ channel currents in small DRG neurons and several ligands were experimented to further clarify relevant signaling pathways.Results MC4-Rs were abundantly expressed in DRG neurons.NSF-1 enhanced T-type calcium channel currents in a dose-dependent manner in small DRG neurons in mice.NSF-1 mediated increment of T-type calcium channel currents was blocked by the MC4-R antagonist HS024,phosphokinase C antagonists GF109203X,and chelerythrine chloride,while the blockade of phospohokinase A PKI 6-22 elicited no such effects.Conclusions NSF-1 can enhance T type calcium channel currents in small DRG neurons through an MC4-R-dependent PKC signaling pathway.
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ObjectiveTo investigate the role of T-type calcium channel in the spinal neurotoxicity of intrathecal (IT) lidocaine in rats.MethodsForty-eight adult male SD rats in which IT catheter was successfully implanted,weighing 230-270 g,were randomly divided into 4 groups ( n =12 each):dimethyl sulfoxide (DMSO)group (group D),lidocaine group (group L),mibefradil + lidocaine group (group M),normal saline + lidocaine group (group N).Another 12 rats served as control group (group C).DMSO and 10％ lidocaine 20μl were injected intrathecally in groups D and L respectively.After mibefradil 200 μg/10μl and normal saline 10 μl were injected intrathecally in groups M and N respectively,10％ lidocaine 20 μl was injected intrathecally in the two groups.The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured before IT injection and at 2,4,8 and 12 h and 1,2,3,4 and 5 d after IT injection (T0-9).Four rats were sacrificed at T6 in each group and their lumbar enlargements were removed for microscopic examination.ResultsCompared with group C,no significant change in MWT and TWL was found at each time point in group D,MWT was significantly increased at T1-8 and TWL was significantly prolonged at T1-7 in groups L and N,and MWT was significantly increased at T1-6 and TWL was significantly prolonged at T1-6 in group M ( P ＜ 0.05 ).Compared with groups L and N,MWT was significantly decreased at T1-4 and TWL was significantly shortened at T1-4 in group M ( P ＜ 0.05).Pathological injury was significantly reduced in group M as compared with groups L and N.ConclusionT-type calcium channel is involved in the spinal neurotoxicity of IT lidocaine in rats.
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Expression of the T-type Ca2 + channels has been reported in numerous types of tumors due to their unique activation/inactivation properties. In some cancer cells, the expression of T-type Ca2+ channels is proliferation state dependent. T-type channel blockers or interfering the α1 subunit of this channel via siRNA decrease proliferation of these cells. Since T-type Ca2+ channels are not expressed in epithelial cells, selective T-type Ca2 + channel blockers maybe serve as a potential therapeutic approach in the treatment of certain types of cancers.
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Objective To investigate the effect of intrathecal(IT)mibefradil on the mechanical and thermal hyperalgesia following chronic compression of dorsal mot ganglion(CCD)in rats,trying to elucidate the role of T-type calcium channels in the nociceptive signal transmission at spinal level.Methods Forty-eight male SD rats weighing 230-250 g were randomly divided into 6 groups(n=8 each):group Ⅰ sham operation;group Ⅱ CCD;group Ⅲ CCD+normal saline(N.S.)and group Ⅳ,Ⅴ,Ⅵ CCD+mibefradil 50 ?g(Ⅳ),100 ?g (Ⅴ),200 ?g(Ⅵ).The animals were anesthetized with intraperitoneal(IP)1% pentobarbital 40 mg?kg~(-1). Intrathecal catheter was placed according to the technique described by Yaksh et al.Five days after IT catheter placement L_4 and I_5 dorsal root ganglion(DRG)compression(CCD)was performed in group Ⅱ-Ⅵ.In sham operation group(Ⅰ)only L_(4-5) transverse processes and intervertebral foramina were exposed but DRGs were not compressed.In group Ⅳ,Ⅴ,and Ⅵ 5 days after CCD model was established a bolus of mibefradil 50,100 and 200 ?g in 10 ?l NS was given IT.In group Ⅲ NS 10 ?l was given IT instead of mibefradil.Mechanical withdrawal threshold(MWT)using Von Frey filament and thermal withdrawal latency(TWL)using radiant heat applied to the plantar surface were measured before CCD(baseline)and 1,3,5,7,14 and 21 days after CCD in group Ⅰ and Ⅱ and before and 30,60,120,240 and 480 min after IT mibefradil in group Ⅲ-Ⅵ.Results The animals in group Ⅱ(CCD group)developed mechanical and thermal hyperalgesia from the 1st day after operation to the end of the experiment.IT mibefradil 50,100 and 200 ?g can all attenuate both mechanical and thermal hyperalgesia induced by CCD.Conclusion Spinal T-type calcium channel may play an important role in the pathogenesis of neuropathic pain.