Potassium and calcium channels in different nerve cells act as therapeutic targets in neurological disorders

The central nervous system, information integration center of the body, is mainly composed of neurons and glial cells. The neuron is one of the most basic and important structural and functional units of the central nervous system, with sensory stimulation and excitation conduction functions. Astrocytes and microglia belong to the glial cell family, which is the main source of cytokines and represents the main defense system of the central nervous system. Nerve cells undergo neurotransmission or gliotransmission, which regulates neuronal activity via the ion channels, receptors, or transporters expressed on nerve cell membranes. Ion channels, composed of large transmembrane proteins, play crucial roles in maintaining nerve cell homeostasis. These channels are also important for control of the membrane potential and in the secretion of neurotransmitters. A variety of cellular functions and life activities, including functional regulation of the central nervous system, the generation and conduction of nerve excitation, the occurrence of receptor potential, heart pulsation, smooth muscle peristalsis, skeletal muscle contraction, and hormone secretion, are closely related to ion channels associated with passive transmembrane transport. Two types of ion channels in the central nervous system, potassium channels and calcium channels, are closely related to various neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy. Accordingly, various drugs that can affect these ion channels have been explored deeply to provide new directions for the treatment of these neurological disorders. In this review, we focus on the functions of potassium and calcium ion channels in different nerve cells and their involvement in neurological disorders such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism, and rare disorders. We also describe several clinical drugs that target potassium or calcium channels in nerve cells and could be used to treat these disorders. We concluded that there are few clinical drugs that can improve the pathology these diseases by acting on potassium or calcium ions. Although a few novel ion-channelspecific modulators have been discovered, meaningful therapies have largely not yet been realized. The lack of target-specific drugs, their requirement to cross the blood–brain barrier, and their exact underlying mechanisms all need further attention. This review aims to explain the urgent problems that need research progress and provide comprehensive information aiming to arouse the research community's interest in the development of ion channel-targeting drugs and the identification of new therapeutic targets for that can increase the cure rate of nervous system diseases and reduce the occurrence of adverse reactions in other systems.

Calcium signaling and T-type calcium channels in cancer cell cycling

Regulation of intracellular calcium is an important signaling mechanism for cell proliferation in both normal and cancerous cells. In normal epithelial cells, free calcium concentration is essential for cells to enter and accomplish the S phase and the M phase of the cell cycle. In contrast, cancerous cells can pass these phases of the cell cycle with much lower cytoplasmic free calcium concentrations, indicating an alternative mechanism has developed for fulfilling the intracellular calcium requirement for an increased rate of DNA synthesis and mitosis of fast replicating cancerous cells. The detailed mechanism underlying the altered calcium loading pathway remains unclear; however, there is a growing body of evidence that suggests the T-type Ca2+ channel is abnormally expressed in cancerous cells and that blockade of these channels may reduce cell proliferation in addition to inducing apoptosis. Recent studies also show that the expression of T-type Ca2+ channels in breast cancer cells is proliferation state dependent, i.e. the channels are expressed at higher levels during the fast-replication period, and once the cells are in a non-proliferation state, expression of this channel isminimal. Therefore, selectively blocking calcium entry into cancerous cells may be a valuable approach for preventing tumor growth. Since T-type Ca2+ channels are not expressed in epithelial cells, selective T-type Ca2+ channel blockers may be useful in the treatment of certain types of cancers.

The opening of maitotoxin-sensitive calcium channels induces the acrosome reaction in human spermatozoa： differences from the zona pellucida

The acrosome reaction （AR）, an absolute requirement for spermatozoa and egg fusion, requires the influx of Ca2＋ into the spermatozoa through voltage-dependent Ca2＋ channels and store-operated channels. Maitotoxin （MTx）, a Ca2＋-mobilizing agent, has been shown to be a potent inducer of the mouse sperm AR, with a pharmacology similar to that of the zona pellucida （ZP）, possibly suggesting a common pathway for both inducers. Using recombinant human ZP3 （rhZP3）, mouse ZP and two MTx channel blockers （U73122 and U73343）, we investigated and compared the MTx- and ZP-induced ARs in human and mouse spermatozoa. Herein, we report that MTx induced AR and elevated intracellular Ca2＋ （[Ca2＋]~） in human spermatozoa, both of which were blocked by U73122 and U73343. These two compounds also inhibited the MTx-induced AR in mouse spermatozoa. In disagreement with our previous proposal, the AR triggered by rhZP3 or mouse ZP was not blocked by U73343, indicating that in human and mouse spermatozoa, the AR induction by the physiological ligands or by MTx occurred through distinct pathways. U73122, but not U73343 （inactive analogue）, can block phospholipase C （PLC）. Another PLC inhibitor, edelfosine, also blocked the rhZP3- and ZP-induced ARs. These findings confirmed the participation of a PLC-dependent signalling pathway in human and mouse zona protein-induced AR. Notably, edelfosine also inhibited the MTx-induced mouse sperm AR but not that of the human, suggesting that toxin-induced AR is PLC-dependent in mice and PLC-independent in humans.

Types of voltage-dependent calcium channels involved in high potassium depolarization-induced amylase secretion in the exocrine pancreatic tumour cell line AR4-2J

In the perifused fura-2 loaded exocrine pancreatic acinar cell line AR4-2J pulses of high potassium induced repetitive increases in intracellular calcium. Attached cells when stimulated with high potassium secreted large amount of amylase. High potassium-induced secretion was dependent both on the concentration of potassium and duration of stimulation. High potassium induced increases in intracellular calcium were inhibited by voltage-dependent calcium channel antagonists with an order of potency as follows: nifedipine > ω-agatoxin IVA > ω-conotoxin GVIA. In contrast, the L-type calcium channel antagonist nifedipine almost completely inhibited potassium-induced amylase secretion, whereas the N-type channel antagonist ω-conotoxin GVIA was without effect. The P-type channel antagonist ω-agatoxin IVA had a small inhibitory effect, but this inhibition was not significant at the level of amylase secretion. In conclusion, the AR4-2J cell line possesses different voltage-dependent calcium channels (L, P,N) with the L-type predominantly involved in depolarization induced amylase secretion.

Argemone mexicana extract alleviates gastrointestinal disorders by stimulating muscarinic receptors and blocking voltage-gated L-type calcium channels

Objective:To investigate the pharmacological potential of Argemone mexicana in treating constipation and emesis by using in vitro and in vivo models.Methods:The spasmogenic and spasmolytic effects were evaluated on isolated rabbit jejunum fragments loaded in a tissue organ bath.The response was recorded with an isotonic transducer attached with Power Lab Data Acquisition System.The laxative and antiemetic activities were assessed in BALB-c mice and poultry chicks challenged with carbamylcholine and copper sulphate stimulated emesis,respectively.Results:The total phenolic and total flavonoids contents of the extract were(267.75±5.77)mg GAE/g and(73.86±6.01)mg QE/g,respectively.Argemone mexicana extract exerted spasmogenic effect on isolated rabbit jejunum segments with an EC_(50)value of 0.016 mg/m L,which was blocked by atropine(0.3μM).Argemone mexicana extract exerted spasmolytic effect in atropine treated jejunum fragments with an EC_(50)value of 2.185 mg/mL.Furthermore,Argemone mexicana extract relaxed potassium(80 mM)-induced contractions(EC_(50):9.07 mg/mL),similar to a standard drug verapamil.The calcium channel blocker activity was confirmed by a rightward shift of concentration-response curve of calcium in the presence of Argemone mexicana extract(1-5 mg/mL)and verapamil(0.1-1μM).In addition,the extract increased the distance travelled by a charcoal in the gastrointestinal tract and exhibited antiemetic effect on copper sulphate induced emesis in chicks.Conclusions:Argemone mexicana shows cholinergic agonist and calcium channel blocker activities,as well as antiemetic effect.It may be used as a potential agent for treating gastrointestinal disorders.

Blocking Effect of Salvianolic Acid A on Calcium Channels in Isolated Rat Ventricular Myocytes

Objective： To study the effect of salvianolic acid A （SAA） on L-type calcium current （I-CaL） in isolated ventdcular myocytes of Sprague-Dawley rats. Methods： SPA powder was dissolved in normal Tyrode＇s solution to reach the concentrations of 1, 10, 100, and 1000 μmol/L. The traditional whole-cell patch-clamp recording technique was employed to evaluate the effects of SAA on I-CaL in single ventricular myocytes which were prepared by Langendorff perfusion apparatus from Sprague-Dawley rats. Results： SPA （1, 10, 100, and 1000 μmol/L） inhibited I-CaL peak value by 16.23%± 1.3% （n=6, P〈0.05）, 22.9% ± 3.6% （n=6, P〈0.05）, 53.4% ± 3.0% （n=8, P〈0.01）, and 62.26% ± 2.9% （n=8, P〈0.01）, respectively. SAA reversibly inhibited I-CaL in a dose-dependent manner and with a half-blocking concentration （IC50） of 38.3 μmol/L. SAA at 100 μmol/L elevated the I-V curve obviously, and shifted the half-active voltage （V0.5） from （-15.78± 0.86） mV to （-11.24 ± 0.77） mV （n=6, P〈0.05） and the slope （K） from 5.33 ±0.74 to 4.35±0.74 （n=6, P〉0.05）. However, it did not alter the shapes of I-V curve, steady-state inactivation curve, or recovery from inactivation curve. Conclusions： SAA inhibited I-CaL in a dose-dependent manner. It shifted the steady-state activation curve to a more positive voltage, which indicated that the drug affected the activated state of calcium channels, and suggested that the Ca2. antagonistic effect of SPA be beneficial in the treatment of myocardial ischemia reperfusion injury.

Formaldehyde increases intracellular calcium concentration in primary cultured hippocampal neurons partly through NMDA receptors and T-type calcium channels

Objective Formaldehyde at high concentrations is a contributor to air pollution. It is also an endogenous metabolic product in cells, and when beyond physiological concentrations, has pathological effects on neurons. Formaldehyde induces mis-folding and aggregation of neuronal tau protein, hippocampal neuronal apoptosis, cognitive impairment and loss of memory functions, as well as excitation of peripheral nociceptive neurons in cancer pain models. Intracellular calcium （[Ca2＋]i） is an important intracellular messenger, and plays a key role in many pathological processes. The present study aimed to investigate the effect of formaldehyde on [Ca2＋]i and the possible involvement of N-methyl-D-aspartate receptors （NMDARs） and T-type Ca2＋ channels on the cell membrane. Methods Using primary cultured hippocampal neurons as a model, changes of [Ca2＋]i in the presence of formaldehyde at a low concentration were detected by confocal laser scanning microscopy. Results Formaldehyde at 1 mmol/L approximately doubled [Ca2＋]i. （2R）-amino-5-phosphonopentanoate （AP5, 25 μmol/L, an NMDAR antagonist） and mibefradil （MIB, 1 μmol/L, a T-type Ca2＋ channel blocker）, given 5 min after formaldehyde perfusion, each partly inhibited the formaldehyde-induced increase of [Ca：＋]i, and this inhibitory effect was reinforced by combined application of AP5 and MIB. When applied 3 min before formaldehyde perfusion, AP5 （even at 50μmol/L） did not inhibit the formaldehyde-induced increase of [Ca2＋]i, but MIB （1 μmol/L） significantly inhibited this increase by 70%. Conclusion These results suggest that formaldehyde at a low concentration increases [Ca2＋]i in cultured hippocampal neurons; NMDARs and T-type Ca2＋ channels may be involved in this process.

CLOFILIUM, A POTENT BLOCKER OF SODIUM AND CALCIUM CHANNELS IN GUINEA-PIG VENTRICULAR MYOCYTES

The unsatisfactory results of clinical trials with class-Ⅰ antiarrhythmic drugs have prompted a renaissance of interest in compounds with class-Ⅲ antiarrhythmic action. In the present, we have reevaluated the class-Ⅲ antiarrhythmic ef-

VASORELAXANT DITERPENES: FROM TRADITIONNAL MEDICINE TO NEW INHIBITORS OF VOLTAGE-DEPENDANT CALCIUM CHANNELS

Croton zambezicus Muell.Arg.(Euphorbiaceae)(Syn.C.amabilis Muell.Arg.,C.gratissimus Burch.)is a shrub or small tree reaching 10 m in height.The leaf decoction is used in Benin as anti-hypertensive,anti-microbial(urinary infections)and to treat fever associated with malaria.We analysed the in vitro and in vivo vasorelaxant activity

A novel ω-conotoxin Bu8 inhibiting N-type voltage-gated calcium channels displays potent analgesic activity

ω-Conotoxins inhibit N-type voltage-gated calcium(Ca_(v)2.2)channels and exhibit efficacy in attenuating neuropathic pain but have a low therapeutic index.Here,we synthesized and characterized a novelω-conotoxin,Bu8 from Conus bullatus,which consists of 25 amino acid residues and three disulfide bridges.Bu8 selectively and potently inhibits depolarization-activated Ba^(2+ )currents mediated by rat Ca_(v)2.2 expressed in HEK293 T cells(IC_(50)=89 nmol/L).Bu8 is two-fold more potent thanω-conotoxin MVIIA,aω-conotoxin currently used for the treatment of severe chronic pain.It also displays potent analgesic activity in animal pain models of hot plate and acetic acid writhing but has fewer side effects on mouse motor function and lower toxicity in goldfish.Its lower side effects may be attributed to its faster binding rate and higher recovery ratios.The NMR structure demonstrates that Bu8 contains a small irregular tripleβ-strand.The structure-activity relationships of Bu8 Ala mutants and Bu8/MVIIA hybrid mutants demonstrate that the binding mode of Ca_(v)2.2 with the amino acid residues in loop 1 and loop 2 of Bu8 is different from that of MVIIA.This study characterizes a novel,more potentω-conotoxin and provides new insights for designing Ca_(v)2.2 antagonists.

Role of T-type Calcium Channels in Generating Hyperexcitatory Behaviors during Emergence from Sevoflurane Anesthesia in Neonatal Rats

In the current study,we sought to investigate whether T-type Ca^(2+)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 days16-18)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.

Design, Synthesis and Structure-activity of N-Glycosyl-l-pyridyl-lH-pyrazole-5-carboxamide as Inhibitors of Calcium Channels

Carbohydrates, with broad-spectrum structures and biological functions, are key organic compounds in nature, along with nucleic acids and proteins. As part of our ongoing efforts to develop a new class of pesticides with novel mechanism of action, a series of novel N-glycosyl-l-pyridyl-lH-pyrazole-5-carboxamide was designed and synthesized via the reactions of glycosyl methanamides and pyridyl-pyrazole acid. The compounds were characte- rized by IH NMR and 13C NMR. The bioassay results indicate that some of these compounds exhibit moderate insec- ticidal activities and assessed as potential inhibitors of calcium channels. The modulation of voltage-gated calcium channels by compounds 4a and 5a in the central neurons isolated from the third instar larvae of Spodoptera exigua was studied by whole-cell patch-clamp technique. In addition, compound 5a inhibits the recorded calcium currents reversible on washout. Experimental results also indicate that compound 5a did not release stored calcium from the Endoplasmic Reticulum. The present work demonstrates that N-glycosyl-l-pyridyl-lH-pyrazole-5-carboxamides cannot be used as possible inhibitors of calcium channels for developing novel pesticides.

The Effect of Levobunolol Hydrochloride on the Calcium andPotassium Channels in Isolated Ventricular Myocytes of Guinea Pig

The effects of levobunolol hydrochlorid (Bun) on the type L calciumchannel currents (Ica) and delayed rectifier potassium channel currents (Ik) in isolated ventricular myocytes of guinea pig were studied by using patch clamp wholecell recording techniques. The results were showed that: 1) Bun caused a dosedependent decrease in Ica and a dose-dependent increase in Ik of the ventricular myocytes.The threshold concentrations of Bun for Ica and Ik were 10-8 mol/L and10-7 mol/L respectively. The maximum effective concentration of Bun for both Ica and Ik was 3 × 10-5 mol/L, and half-maximal concentration was 3 × 10-6 mol/L;2 ) Ik was blocked by 2× 10-6mol/L tetraethylammonium (TEA). A concentration of 3 × 10-6 mol/L Bun showed a decreasing effect on the Ica as revealed by the current-voltage relationship curve, i. e., Bun caused an elevation of the curve; 3)When Ica was blocked by 2 × 10-6 mol/L Isoptin (Verapamil), at a concentrationof 3 × 106- mol/L Bun showed an increasing effect on Ik and the effect could be blocked by TEA. The above-mentioned results indicated that Bun had an inhibito-ry effect on Ica and a fascilitatory effect on Ik The results suggested that themolecular mechanisms of antihypertensive, heart rate slowing and β-receptorblocking effects of Bun might be due to decrease of Ica and increase of Ik.

Brain-derived neurotrophic factor signaling in the neuromuscular junction during developmental axonal competition and synapse elimination

During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.

Antineoplastic Effect of Calcium Channel Blocker-Verapamil and 5-Fluorouracil Intraperitoneal Chemotherapy on Hepatocarcinoma-Bearing Rats

Objective To study the antineoplastic effect of the calcium channel blocker verapamil and 5-fluorouracil intraperitoneal chemotherapy onhepatocarcinoma-bearing rats, and examine the action between calcium channel blockers and cytotoxic drugs.Methods We adopted the method of subcapsular implantation of carcinoma tissues of walker-256 in the left liver lobe as a model of livercarcinoma-bearing rats. All experimental animals were divided into four groups. On the sixth day post implantation, in group A (controlgroup) 6 ml of saline was injected intraperitoneally once a day for 3 days. In group B (single chemotherapy group) 6 ml of 5-Fu 75 mg/kg was injected intraperitoneally once a day for 3 days. In group C (combination of treatment group) both 5-Fu (75 mg/kg) and verapamil(25 mg/kg) were administered simultaneously as in A and B. In group D (simple verapamil group) only 6 ml of verapamil (25 mg/kg)was administered as above.Results Compared with groups A, B and D, The volume of cancer and the contents of liver cancer DNA and protein were significantlyreduced. The rates of inhibiting cancer (89.9% in group C and 35.4% in group B) were significantly increased in group C. Group C hadsignificantly long survival time compared to groups A, B and D ( P < 0.05) . By light microscopy, a number of focal necroses were foundin cancer tissue in group C.Conclusion Calcium channel blockers can enhance the antineoplastic effect of 5-Fu intraperitoneal chemotherapy to liver cancer ; Theuse of verapamil can not increase the toxicity of 5-Fu.

Pharmacological Investigation of Voltage-dependent Ca^(2+) Channels in Human Ejaculatory Sperm in vitro

The types of the voltage-dependent calcium channels （VDCCs） in human ejaculatory sperm and the effects of calcium channel blocker （CCB） on human sperm motility parameters in vitro were investigated. The human sperm motility parameters in vitro in response to the pharmacological agents nifedipine （NIF, inhibitor of L-type VDCC） and ω-conotoxin （GVIA, inhibitor of N-type VDCC） were compared and analyzed statistically. The results showed that NIF （1, 5, 10 μmol/L） could not only significantly affect human sperm＇s shape but also spermatozoa motility after incubated at least 10 rain in vitro （P〈0.001）. GVIA （0.1, 0.5 and 1 μmol/L） could just only significantly affect human sperm＇s progressive motility （a %＋b %） after incubated for 20 min in vitro （P〈0.01）, but they both could not significantly affect spermic abnormality rate. It is suggested that L-type VDCC, non L-type VDCCs and isoform of L-type VDCC exist in the cell membrane of human sperm solely or together, and they participate in the spermic physiological processes especially the spermic motility.

Effects of Tetrandrine on Cytosolic Free Calcium in Cultured Bovine Aortic Smooth Muscle Cells

\ The effects of tetrandrine (Tet) on cytosolic free calcium ([Ca2+]i) in subcultured bovine aortic smooth muscle cells (SMC) were studied by Fura2 and ARCMMIC cation measurement system. Tet (1～100 μmol·L-1) had no effect on the resting [Ca2+]i, but had inhibitory effects on [Ca2+]i elevation induced by high K+, 5HT, ATP, Ang II and NE in the presence of extracellular Ca2+. High concentration of Tet also inhibited Pheinduced [Ca2+]i elevation in absence of extracellular Ca2+. Tet (1～100 μmol·L-1) inhibited KCl (60 mmol·L-1) induced [Ca2+]i elevation in dosedependent manner, the IC50 value was 9.2 (95% confidence limits: 5.7～14.9) mmol·L-1. The results suggested that Tet had blocking effects on both VOC and ROC in bovine aortic SMC. It appears that the mechanisms of blocking effect of Tet on ROC might be primarily due to its Ca2+ entry blocking effects.

Calcium Signaling is Involved in Negative Phototropism of Rice Seminal Roots

Calcium ions （Ca2＋） act as an intracellular second messenger and affect nearly all aspects of cellular life. They are functioned by interacting with polar auxin transport, and the negative phototropism of plant roots is caused by the transport of auxin from the irradiated side to the shaded side of the roots. To clarify the role of calcium signaling in the modulation of rice root negative phototropism, as well as the relationship between polar auxin transport and calcium signaling, calcium signaling reagents were used to treat rice seminal roots which were cultivated in hydroculture and unilaterally illuminated at an intensity of 100-200 pmol/（m2.s） for 24 h. Negative phototropism curvature and growth rate of rice roots were both promoted by exogenous CaCI2 lower than 100 pmol/L, but inhibited by calcium channel blockers （verapamil and LaCI3）, calcineurin inhibitor （chlorpromazine, CPZ）, and polar auxin transport inhibitor （N-l-naphthylphthalamic acid, NPA）. Roots stopped growing and negative phototropism disappeared when the concentrations increased to 100 pmol/L verapamil, 12.500 ~Jmol/L LaCI3, 60 pmol/L CPZ, and 6 pmol/L NPA. Moreover, 100 pmol/L CaCI2 could relieve the inhibition of LaCI3, verapamil and NPA. The enhanced negative phototropism curvature was caused by the transportation of more auxin from the irradiated side to the shaded side in the presence of exogenous Ca2＋. Calcium signaling plays a key role as a second messenger in the process of light signal regulation of rice root growth and negative phototropism.

Ligustrazine inhibits high voltage-gated Ca^(2+) and TTX-resistant Na^+ channels of primary sensory neuron and thermal nociception in the rat:a study on peripheral mechanism

Objective Ligustrazine, also named as tetramethylpyrazine, is a compound purified from Ligusticum chuanxiong hort and has ever been testified to be a calcium antagonist. The present investigation was to determine the antinociceptive effect of ligustrazine and, if any, the peripheral ionic mechanism involved. Methods Paw withdrawal Latency （PWL） to noxious heating was measured in vivo and whole-cell patch recording was performed on small dorsal root ganglion （DRG） neurons. Results Intraplantar injection of ligustrazine （0.5 mg in 25 μl） significantly prolonged the withdrawal latency of ipsilateral hindpaw to noxious heating in the rat. Ligustrazine not only reversibly inhibited high-voltage gated calcium current of dorsal root ganglion （DRG） neuron in dose-dependent manner with IC50 of 1.89 mmol/L, but also decreased tetrodotoxin （TTX） -resistant sodium current in relatively selective and dose-dependent manner with IC50 of 2.49 mmol/L. Conclusion The results suggested that ligustrazine could elevate the threshold of thermal nociception through inhibiting the high-voltage gated calcium current and TTX-resistant sodium current of DRG neuron .in the rat.

Voltage gated calcium channel antibody-related neurological diseases

Voltage gated calcium channel(VGCC) antibodies are generally associated with Lambert-Eaton myasthenic syndrome. However the presence of this antibody has been associated with paraneoplastic as well as nonparaneoplastic cerebellar degeneration. Most patients with VGCC-antibody-positivity have small cell lung cancer(SCLC). Lambert-Eaton myasthenic syndrome(LEMS)is an autoimmune disease of the presynaptic part of the neuromuscular junction. Its classical clinical triadis proximal muscle weakness, areflexia and autonomic dysfunction. Fifty to sixty percent of LEMS patients have a neoplasia, usually SCLC. The co-occurrence of SCLC and LEMS causes more severe and progressive disease and shorter survival than non-paraneoplastic LEMS. Treatment includes 3,4 diaminopyridine for symptomatic purposes and immunotherapy with prednisolone, azathioprine or intravenous immunoglobulin in patients unresponsive to 3,4 diaminopyridine. Paraneoplastic cerebellar degeneration(PCD) is a syndrome characterized with severe, subacute pancerebellar dysfunction. Serum is positive for VGCC antibody in 41%-44% of patients, usually with the co-occurrence of SCLC. Clinical and electrophysiological features of LEMS are also present in 20%-40% of these patients. Unfortunately, PCD symptoms do not improve with immunotherapy. The role of VGCC antibody in the immunopathogenesis of LEMS is well known whereas its role in PCD is still unclear. All patients presenting with LEMS or PCD must be investigated for SCLC.