Calcium Channel Research Papers - Academia.edu (original) (raw)

Pathways through which glucose induces a rise in [Ca2]i of polymorphonuclear leukocytes of rats. Basal levels of [Ca2}i arc elevated in diabetes mellitus. Such an abnormality is most likely due to both increased calcium influx into cells and decreased efflux of this ion out of the cells. The present study examined the cellular pathways that are responsible for

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- Calcium, Glucose, Kidney, Diabetes mellitus

AMPA-type glutamate receptor (GluR) channels provide fast excitatory synaptic transmission in the CNS, but mediate also cytotoxic insults. It could be shown that AMPAtype GluR channel-mediated chronic excitotoxicity leads to an increased intracellular calcium concentration and plays an important role in neurodegenerative diseases like for example amyotrophic lateral sclerosis (ALS). As calcium is an important mediator of various processes in the cell and calcium signals have to be very precise in the temporospatial resolution, excessive intracellular calcium increases can seriously impair cell function. It is still unclear if AMPA-type receptors can directly interact with the intracellular calcium homeostasis or if other mechanisms are involved in this process. The objective of this study was therefore to investigate the calcium homeostasis in rat motoneurons under physiological stimulation of AMPA-type GluR channels using calcium imaging techniques and patch-clamp recordings simultaneously. It was found that spontaneous excitatory postsynaptic currents of cultured motoneurons did not elicit significant intracellular calcium transients. Large intracellular calcium transients occurred only when preceding fast sodium currents were observed. Pharmacological experiments showed that activation of AMPA-type GluR channels during synaptic transmission has a great functional impact on the calcium homeostasis in motoneurons as all kinds of activity was completely blocked by application of the selective kainateand AMPA-type GluR channel blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Furthermore we suggest from our experiments that calcium transients of several hundred milliseconds' duration result from release of calcium from the endoplasmic reticulum via activation of ryanodine receptors (calcium-induced calcium release, CICR). Our results help to understand the regulatory function of AMPA-type GluR channels in the intracellular calcium homeostasis which is known to be disturbed in neurodegenerative diseases.

- by K. Jahn and +1
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- Neuroscience, Psychology, Electrophysiology, Imaging

External calcium ion concentration is a major regulator of epidermal keratinocyte differentiation in vitro and probably also in vivo. Regulation of calcium-induced differentiation changes is proposed to occur via an external calcium-sensing, signaling pathway that utilizes increases in intracellular calcium ion concentration to activate differentiation-related gene expression. Calcium ion release from intracellular stores and calcium ion influx via storeoperated calcium-permeable channels are key elements in this proposed signaling pathway; however, the channels involved have not yet been identified. The present report shows that human gingival keratinocytes (HGKs) also undergo calcium-induced differentiation in vitro as indicated by involucrin expression and morphological changes. Moreover, TRPC1, which functions as a store-operated calcium channel in a number of cell types, including epidermal keratinocytes, is expressed in both proliferating and differentiating HGKs. Transfection of HGKs with TRPC1 siRNA disrupted expression of TRPC1 mRNA and protein com-pared with transfection with scrambled TRPC1 siRNA. Cells with disrupted TRPC1 expression showed decreased calcium-induced differentiation as measured by involucrin expression or morphological changes, as well as decreased thapsigargin-induced calcium ion influx, and a decreased rate of store calcium release. These results indicate that TRPC1 is involved in calcium-induced differentiation of HGKs likely by supporting a store-operated calcium ion influx.

- by Richard Presland
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- Physiology, Calcium, Gene expression, RNA interference

The venom of the Brazilian spider Phoneutria nigriventer possesses several neurotoxic polypeptidic fractions. Previous work has established that one of the toxic components, PhTx 3, inhibited Ca2÷-dependent glutamate release and the increase in cytosolic free Ca 2÷ in response to membrane depolarization. In the present work, we investigated the effect of PhTx 3 on the release of acetylcholine (ACh) from brain and peripheral neurons. PhTx 3 decreased the release of [3H]-ACh induced by tityustoxin and KC1 in brain cortical slices and myenteric plexus. The inhibitory effect of myenteric plexus had the same magnitude as that obtained in the absence of extraceUular Ca 2+. However, in brain PhTx 3 was less efficient at decreasing the evoked release of ACh. These experiments suggest that the target of PhTx 3 is coupled to the process of release of ACh in brain and autonomic nervous system.

- by T. Moraes-santos
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- Psychology, Cognitive Science, Autonomic Nervous System, Cerebral Cortex

CARRASCO, M., M. DEL RIO, A. HERNANZ AND M. DE LA FUENTE. Inhibition of human neutrophil functions by sulfated and nonsulfated cholecystokinin octapeptides. PEPTIDES 18(3) [415][416][417][418][419][420][421] 1997.-The effects of CCK-8s and desulfated CCK-8 at concentrations ranging from 10 014 to 10 06 M were studied in vitro on several functions of human peripheral neutrophils: adherence to substrate, mobility (spontaneous and directed by a chemical gradient or chemotaxis), ingestion of inert particles (latex beads) or cells ( Candida albicans), and production of superoxide anion measured by the nitroblue tetrazolium reduction test. The effect of CCK-8s on intracellular levels of cAMP was investigated as well as the implication of calcium in the action of CCK-8s on phagocytic function using stimulants and inhibitors of both intracellular and extracellular calcium channels. The two peptides, at concentrations from 10 012 to 10 08 M , inhibited significantly both mobility and ingestion capacities and increased adherence to substrate. A dose-response relationship was observed with a maximum inhibition of neutrophil functions at 10 010 M. CCK-8s and desulfated CCK-8 induced in these cells a significant, but transient, increase of cAMP levels at 60 s. Moreover, CCK-8s was found to inhibit completely the stimulation of latex bead phagocytosis in neutrophils produced by the calcium ionophore A23187. These results suggest that CCK-8 is a negative modulator of several neutrophil functions and that the inhibition of these activities could be carried out through an increase of the intracellular cAMP levels and a decrease of the extracellular calcium input. ᭧ 1997 Elsevier Science Inc.

- by Angel Hernanz
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- Physiology, Calcium, Cell Adhesion, Caffeine

Objective: To determine the prevalence and factors associated with Diabetic Retinopathy (DR) of type 1 diabetes mellitus in Thailand. Material and Method: A cross-sectional, multicenter, hospital-based study was carried out from April to December 2003. Diabetic patients in diabetic clinics of 11 tertiary centers were registered. Retinopathy was evaluated by the ophthalmologists. Results: Seven thousand one hundred and nineteen diabetic patients received retinal examination. The number of patients with type 1 diabetes was 347. The prevalence of DR in type 1 diabetes was 21.6% (75). This consisted of Non-Proliferative DR (NPDR) 10.9% (38) and Proliferative DR (PDR) 10.7%. Patients with DR were significantly older, predominantly female, longer duration of diabetes, had higher BMI, systolic Blood Pressure (BP), diastolic BP, serum creatinine, and TriGlycerides (TG) levels than those without DR. Both groups of patients were not different in term of plasma glucose and glycosylated hemoglobin levels. Although the patients with DR had a higher percentage of overt proteinuria than those without DR, there was no difference in percentage of patients with positive microalbuminuria in both groups. This may be explained by limitation of data (only 16% had results of microalbuminuria and 19% had results of proteinuria). After adjusted for duration of diabetes, serum creatinine and smoking status, factors (adjusted odds ratio [95% confidence interval]) associated with DR were duration of diabetes 5-9.9 years (4.0 [1.49-10.91]), 10-14.9 years (6.86 [2.45-19.20]), 15-19.9 years (21.13 [7.22-61.78]), ≥ 20 years (22.15 [7.32-66.99]) when compared with duration of diabetes less than 5 years, serum creatinine > 2 mg/dl (6.0 [2.09-17.22]) when compared with creatinine less than 2 mg/dl. From the presented model, age, gender, systolic BP > 140 mmHg, diastolic BP > 90 mmHg, serum TG and smoking status were not factors associated with DR. Conclusion: Diabetic retinopathy affects about one fifth of type 1 diabetic patients in our study. The authors found the factors associated with DR in type 1 DM were duration of diabetes and serum creatinine. Regular screening for DR and more aggressive management of metabolic factors should be done to reduce the prevalence of DR.

- by Chardpraorn Ngarmukos
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- Program Evaluation, Thailand, Treatment Outcome, Adolescent

The present study was undertaken to elucidate the mode of action of methanol extract from aerial parts of L. caulescens (TC-MELc) as spasmolytic agent on in vitro rat ileum test, and investigate the possible antibacterial activity of... more

Cannabinoids modulate nociceptive processing in models of acute, inflammatory and neuropathic pain. We have investigated the location and function of cannabinoid receptors on cultured neonatal dorsal root ganglion (DRG) neurones and F-11 cells, a dorsal root ganglion×neuroblastoma hybridoma which displays several of the features of authentic DRG neurones. CB 1 receptor immunolabelling was observed on the cell bodies and as fine puncta on processes of both cultured DRG neurones and F-11 cells. Additionally, fluorescence-activated cell sorting (FACS) analysis provided evidence that both CB 1 and CB 2 receptors are expressed on populations of cells within the cultured DRG and F-11 cells. The cannabinoid receptor agonist (+)-WIN55212 (10 and 100 nM) inhibited the mean voltage-activated Ca 2+ current in DRG neurones by 21% and 30%, respectively. The isomer, (Ϫ)-WIN55212 (10 and 100 nM) produced significantly less inhibition of 6% and 10% respectively. The CB 1 selective receptor antagonist SR141716A (100 nM) enhanced the peak high voltage-activated Ca 2+ current by 24% and simultaneous application of SR141716A (100 nM) and (+)-WIN55212 (100 nM) resulted in a significant attenuation of the inhibition obtained with (+)-WIN55212 alone. These data give functional evidence for the hypothesis that the analgesic actions of cannabinoids may be mediated by presynaptic inhibition of transmitter release in sensory neurones.

- by Andrew Irving
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- Psychology, Fluorescence, Neuropharmacology, Immunohistochemistry

Calcium (Ca 2+ ) entry in cells is crucial for development and physiology of virtually all cell types. It acts as an intracellular (second) messenger to regulate a diverse array of cellular functions, from cell division and differentiation to cell death. Among candidates for Ca 2+ entry in cells are-voltage-dependant Ca 2+ channels (VDCCs), transient receptor potential (TRP)-related Ca 2+ channels and store-operated Ca 2+ (SOC) channels. Plasma membrane Ca 2+ -ATPases (PMCA) and Na + /Ca 2+ exchanger (NCX) are mainly responsible for Ca 2+ extrusion. These different Ca 2+ channels/transporters and exchangers exhibit specific distribution and physiological properties. During pregnancy, the syncytiotrophoblast layer of the human placenta transfers as much as 30 g of Ca 2+ from the mother to the fetus, especially in late gestation where Ca 2+ transport through different channels must increase in response to the demands of accelerating bone mineralization of the fetus. The identification and characterization of the different Ca 2+ channels/transporters and exchangers on the brush-border membrane (BBM) facing the maternal circulation, and the basal plasma membrane (BPM) facing the fetal circulation; placental membrane of the syncytiotrophoblasts have been the focus of numerous studies. This review discusses current views in this field regarding localization and functions during transcellular Ca 2+ entry and extrusion from cells particularly in the placenta.

- by Louiza Belkacemi
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- Physiology, Cell Division, Fetal development, Pregnancy

ABSTRACT: Inhibitory and excitatory connecblockers (MgCl 2 and nifedipine) to the high-KCl metions of remarkably precise topographic order are dium reduced organotypicity drastically, indicating characteristic features of the mammalian auditory that a depolarization-induced increase of intracellular system, particularly within the superior olivary comcalcium is indispensable. Furthermore, the temporal plex (SOC). Little is known about the requirements course of the expression of the calcium-binding profor the correct development of these specific connectein parvalbumin in culture under high KCl mimics tions. Previous in vivo experiments have demonstrated that in vivo, demonstrating developmental processes a high expression of calcium-binding proteins in this during incubation. The need for calcium influx into system during development, pointing to the need for neurons of this auditory network in vitro (which is precise calcium regulation. Here, we have employed not seen in other slice culture systems) strengthens an organotypic slice culture from the above neuronal the hypothesis that an optimal calcium concentration network and analyzed the requirements for the mainis exceptionally important in auditory neurons. The tenance and development of this system in vitro. When effect of KCl in the slice cultures may substitute for slices from neonatal rats were incubated in standard input activity regulating intracellular calcium in audiculture medium for up to 7 days, we found no organotory neurons in vivo. ᭧ 1998 John Wiley & Sons, Inc. J typic features. Only if 25 mM KCl was added to the Neurobiol 34: 97-112, 1998

- by Eckhard Friauf
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- Cognitive Science, Calcium, Neurobiology, Calcium Channel

We have previously reported the multifunctional profile of N-(3-chloro-10H-phenothiazin-10-yl)-3-(dimethylamino)propanamide (1) as an effective neuroprotectant and selective butyrylcholinesterase inhibitor. In this paper, we have developed a series of N-acylaminophenothiazines obtained from our compound library or newly synthesised. At micro- and sub-micromolar concentrations, these compounds selectively inhibited butyrylcholinesterase (BuChE), protected neurons against damage caused by both exogenous and mitochondrial free radicals, showed low toxicity, and could penetrate into the CNS. In addition, N-(3-chloro-10H-phenothiazin-10-yl)-2-(pyrrolidin-1-yl)acetamide (11) modulated the cytosolic calcium concentration and protected human neuroblastoma cells against several toxics, such as calcium overload induced by an l-type Ca2+-channel agonist, tau-hyperphosphorylation induced by okadaic acid and Aβ peptide.► N-acylaminophenothiazines are a new family of multifunctional neuroprotective agents. ► Selective inhibition of BuChE vs. AChE. ► Good CNS penetration by PAMPA-BBB assay. ► Neuroprotection vs. oxidative stress, calcium overload, okadaic acid and beta-amyloid. ► Calcium channel modulating activity.

- by Javier Egea
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- Organic Chemistry, Calcium, Neuroprotection, Free Radical

Spider venoms are complex mixtures of neurotoxic peptides, proteins and low molecular mass organic molecules. Their neurotoxic activity is due to the interaction of the venom components with cellular receptors, in particular ion channels. Spider venoms have proven to be a rich source of highly specific peptide ligands for selected subtypes of potassium, sodium and calcium channels, and these toxins have been used to elucidate the structure and physiological roles of the channels in excitable and non-excitable cells. Spider peptides show great variability in their pharmacological activity and primary structure but relative homogeneity in their secondary structure. Following diverse molecular evolution mechanisms, and in particular selective hypermutation, short spider peptides appear to have functionally diversified while retaining a conserved molecular scaffold. This paper reviews the composition and pharmacology of spider venoms with emphasis on polypeptide toxin structure, mode of action and molecular evolution. © 2000 Société française de biochimie et biologie moléculaire / Éditions scientifiques et médicales Elsevier SAS spiders / neurotoxins / peptides / ion channels / structure / pharmacology * Correspondence and reprints.

- by Gerardo Corzo
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- Pharmacology, Structure, Molecular Evolution, Calcium

Metabotropic glutamate receptors (mGluRs) can increase intracellular Ca2+ concentration via Ins(1,4,5)P3- and ryanodine-sensitive Ca2+ stores in neurons. Both types of store are coupled functionally to Ca2+-permeable channels found in the plasma membrane. The mGluR-mediated increase in intracellular Ca2+ concentration can activate Ca2+-sensitive K+ channels and Ca2+-dependent nonselective cationic channels. These mGluR-mediated effects often result from mobilization of Ca2+ from ryanodine-sensitive, rather than Ins(1,4,5)P3-sensitive, Ca2+ stores, suggesting that close functional interactions exist between mGluRs, intracellular Ca2+ stores and Ca2+-sensitive ion channels in the membrane.

- by Joel Bockaert
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- Neuroscience, Cognitive Science, Calcium, Ion Channels
- by Bruce K. Cassels
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- Life Sciences, Cerebral Cortex, Calcium Channel, Rats

Tunicamycin effect on thapsigargin-induced store-operated calcium entry was investigated. Ca 2+ influx was stimulated by 50% upon exposure of Jurkat cells to tunicamycin. Moreover, tunicamycin efficiently prevented the inhibition of store-operated calcium entry caused by dissipation of mitochondrial membrane potential. Protective action of tunicamycin on store-operated Ca 2+ entry was also partially preserved in Jurkat cells depleted of ATP, while Ca 2+ entry into ATP-deprived cells grown in tunicamycinfree medium was almost completely inhibited. Tunicamycin-evoked changes in cellular Ca 2+ fluxes coincided with decreased glycosylation of STIM1 protein. Although the latter observation is correlative and needs additional confirmation it may suggest that deglycosylation of STIM1 protein deprives store-operated calcium entry system of an important regulatory mechanism. This study suggests a novel mechanism of modulation of the activity of store-operated calcium channels in lymphoidal cells.

- by Krzysztof Zabłocki
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- Calcium, Membrane Proteins, Calcium channels, Tunicamycin

This study was carried out to provide scientific basis for the medicinal use of turmeric (Curcuma longa) in gastrointestinal and respiratory disorders. The crude extract of turmeric (Cl.Cr), relaxed the spontaneous and K + (80 mM)-induced contractions in isolated rabbit jejunum as well as shifted the CaCl 2 concentration-response curves. In rabbit tracheal preparation, Cl.Cr inhibited carbachol and K + -induced contractions. In anesthetized rats, Cl.Cr produced variable responses on blood pressure with a mixture of weak hypertensive and hypotensive actions. In rabbit aorta, Cl.Cr caused a weak vasoconstrictor and a vasodilator effect on K + and phenylephrine-induced contractions. In guinea-pig atria, Cl.Cr inhibited spontaneous rate and force of contractions at 14-24 times higher concentrations. Activity directed fractionation revealed that the vasodilator and vasoconstrictor activities are widely distributed in the plant with no clear separation into the polar or non-polar fractions. When used for comparison, both curcumin and verapamil caused similar inhibitory effects in all smooth muscle preparations with relatively more effect against K + -induced contractions and that both were devoid of any vasoconstrictor effect and curcumin had no effect on atria. These data suggest that the inhibitory effects of Cl.Cr are mediated primarily through calcium channel blockade, though additional mechanism cannot be ruled out and this study forms the basis for the traditional use of turmeric in hyperactive states of the gut and airways. Furthermore, curcumin, the main active principle, does not share all effects of turmeric. D

- by Anwar Gilani
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- Life Sciences, Phytotherapy, Smooth muscle, Blood Pressure

In the present work we investigated the mechanism involved in the vasodilator effect induced by euxanthone in rat small mesenteric arteries. We observed that euxanthone induced concentrationdependent vasodilatation in arteries by a mechanism independent on the release of endothelial factors, such as nitric oxide (NO) and cyclooxygenase-derived factors. In addition our results also suggest that euxanthone induced its vasodilator effect through inhibition of calcium-sensitive mechanisms activated by protein kinase C, rather than by inhibition of contractions dependent on the release of the intracellular calcium stores or by inhibition of voltage-operated calcium channels.

Acute arterial hypertension is one of the major concerns in many clinical settings including but not limited to operating room, intensive care and emergency care units. Perioperative hypertension is one of the major reasons for cancellation of elective surgeries, and also increases the perioperative morbidity. We would like to discuss pathophysiology, evaluation of the patients with acute hypertension, management of these patients and future considerations of the current intravenous antihypertensive medications. Key Words: Acute Hypertension; Intravenous; Anti-Hypertensive Medications; Calcium Channel Blockers; Dihydropyridine; Clevidipine.

- by Sergio D Bergese
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- Anesthesiology, Hypertension, Calcium Channel, Intravenous

The Ca 2+ homeostasis within cells controls a diversity of cellular processes including gene transcription, proliferation and apoptosis. Perturbance of Ca 2+ signaling may induce deregulation of cell proliferation and suppression of cell death providing the basis for cancer development. In human prostate cancer, a correlation between the mRNA expression of the Ca 2+ channel TRPV6 and the staging of the cancer has been described. We have analyzed the influence of TRPV6 on cell proliferation within HEK-293 cells. We show that TRPV6 increases cell proliferation of HEK-293 cells in a Ca 2+ dependent manner. The increased proliferation correlates with slightly increased intracellular Ca 2+ levels without interfering with the intrinsic Ca 2+ dependence of HEK-293 cell proliferation. Low doses of econazole inhibit both, TRPV6 dependent Ca 2+ signals and cell proliferation while BTP2, a potent inhibitor of Ca 2+ signals and cell proliferation in T-cells, neither influences TRPV6 dependent Ca 2+ signals nor cell proliferation of HEK-293 cells. Our data demonstrate that TRPV6 increases the rate of Ca 2+ dependent cell proliferation which is a prerequisite for its potential role in tumor progression.

- by Markus Hoth and +3
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- Physiology, Prostate Cancer, Gene expression, Cell line
- by Theophile Godfraind
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- Calcium, Multidisciplinary, Ion Channels, Smooth muscle

Histamine-releasing neurons are located exclusively in the TM of the hypothalamus, from where they project to practically all brain regions, with ventral areas (hypothalamus, basal forebrain, amygdala) receiving a particularly strong innervation. The intrinsic electrophysiological properties of TM neurons (slow spontaneous firing, broad action potentials, deep afterhyperpolarisations, etc.) are extremely similar to other aminergic neurons. Their firing rate varies across the sleep-wake cycle, being highest during waking and lowest during rapid-eye movement sleep. In contrast to other aminergic neurons somatodendritic autoreceptors (H 3 ) do not activate an inwardly rectifying potassium channel but instead control firing by inhibiting voltage-dependent calcium channels. Histamine release is enhanced under extreme conditions such as dehydration or hypoglycemia or by a variety of stressors. Histamine activates four types of receptors. H 1 receptors are mainly postsynaptically located and are coupled positively to phospholipase C. High densities are found especially in the hypothalamus and other limbic regions. Activation of these receptors causes large depolarisations via blockade of a leak potassium conductance, activation of a non-specific cation channel or activation of a sodium-calcium exchanger. H 2 receptors are also mainly postsynaptically located and are coupled positively to adenylyl cyclase. High densities are found in hippocampus, amygdala and basal ganglia. Activation of these receptors also leads to mainly excitatory effects through blockade of calcium-dependent potassium channels and modulation of the hyperpolarisationactivated cation channel. H 3 receptors are exclusively presynaptically located and are negatively coupled to adenylyl cyclase. High densities are found in the basal ganglia. These receptors mediated presynaptic inhibition of histamine release and the release of other neurotransmitters, most likely via inhibition of presynaptic calcium channels. Finally, histamine modulates the glutamate NMDA receptor via an action at the polyamine binding site. The central histamine system is involved in many central nervous system functions: arousal; anxiety; activation of the sympathetic nervous system; the stress-related release of hormones from the pituitary and of central aminergic neurotransmitters; antinociception; water retention and suppression of eating. A role for the neuronal histamine system as a danger response system is proposed.

- by Helmut Haas and +1
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- Cognitive Science, Ion Channels, Histamine, Cerebrospinal Fluid

Patients with neuropathic pain (NP) are challenging to manage and evidence-based clinical recommendations for pharmacologic management are needed. Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated at a consensus meeting. Medications were considered for recommendation if their efficacy was supported by at least one methodologically-sound, randomized clinical trial (RCT) demonstrating superiority to placebo or a relevant comparison treatment. Recommendations were based on the amount and consistency of evidence, degree of efficacy, safety, and clinical experience of the authors. Available RCTs typically evaluated chronic NP of moderate to severe intensity. Recommended first-line treatments include certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel a2-d ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol are recommended as generally second-line treatments that can be considered for first-line use in select clinical circumstances. Other medications that would generally be used as third-line treatments but that could also be used as second-line treatments in some circumstances include certain antiepileptic and antidepressant medications, mexiletine, N-methyl-D-aspartate receptor antagonists, and topical capsaicin. Medication selection should be individualized, considering side effects, potential beneficial or deleterious effects on comorbidities, and whether prompt onset of pain relief is necessary. To date, no medications have demonstrated efficacy in lumbosacral radiculopathy, which is probably the most common type of NP. Long-term studies, head-to-head comparisons between medications, studies

- by John Farrar
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- Pain, Evidence Based Medicine, Serotonin, Systematic Literature Review

The rocker mice are hereditary ataxic mutants that carry a point mutation in the gene encoding the Ca V 2.1 (P ⁄ Q-type) Ca 2+ channel a 1 subunit, and show the mildest symptoms among the reported Ca V 2.1 mutant mice. We studied the basic characteristics of the rocker mutant Ca 2+ channel and their impacts on excitatory synaptic transmission in cerebellar Purkinje cells (PCs). In acutely dissociated PC somas, the rocker mutant channel showed a moderate reduction in Ca 2+ channel current density, whereas its kinetics and voltage dependency of gating remained nearly normal. Despite the small changes in channel function, synaptic transmission in the parallel fiber (PF)-PC synapses was severely impaired. The climbing fiber inputs onto PCs showed a moderate impairment but could elicit normal complex spikes. Presynaptic function of the PF-PC synapses, however, was unexpectedly almost normal in terms of paired-pulse facilitation, sensitivity to extracellular Ca 2+ concentration and glutamate concentration in synaptic clefts. Electron microscopic analyses including freeze-fracture replica labeling revealed that both the number and density of postsynaptic a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors substantially decreased without gross structural changes of the PF-PC synapses. We also observed an abnormal arborization of PC dendrites in young adult rocker mice ( 1 month old). These lines of evidence suggest that even a moderate dysfunction of Ca V 2.1 Ca 2+ channel can cause substantial changes in postsynaptic molecular composition of the PF-PC synapses and dendritic structure of PCs.

- by Elek Molnar
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- Psychology, Cognitive Science, Calcium, Patch-clamp and imaging techniques

Gamma-aminobutyric acid (GABA), one of the main inhibitory neurotransmitters in the brain, interacts with three types of receptors for GABA--GABA(A), GABA(B) and GABA(C). GABA(A) receptors, associated with binding sites for benzodiazepines and barbiturates in the form of a receptor complex, control opening of the chloride channel. When GABA binds to the receptor complex, the channel is opened and chloride anions enter the neuron, which is finally hyperpolarized. GABA(B) receptors are metabotropic, linked to a cascade of second messengers whilst the physiological meaning of ionotropic GABA(C) receptors, mainly located in the retina, is generally unknown. Novel antiepileptic drugs acting selectively through the GABA-ergic system are tiagabine and vigabatrin. The former inhibits neuronal and glial uptake of GABA whilst the latter increases the synaptic concentration of GABA by inhibition of GABA-aminotransferase. Gabapentin, designed as a precursor of GABA easily entering the brain, was shown to increase brain synaptic GABA. This antiepileptic drug also decreases influx of calcium ions into neurons via a specific subunit of voltage-dependent calcium channels. Conventional antiepileptics generally inhibit sodium currents (carbamazepine, phenobarbital, phenytoin, valproate) or enhance GABA-ergic inhibition (benzodiazepines, phenobarbital, valproate). Ethosuximide, mainly controlling absences, reduces calcium currents via T-type calcium channels. Novel antiepileptic drugs, mainly associated with an inhibition of voltage-dependent sodium channels are lamotrigine and oxcarbazepine. Since glutamate-mediated excitation is involved in the generation of seizure activity, some antiepileptics are targeting glutamatergic receptors--for instance, felbamate, phenobarbital, and topiramate. Besides, they also inhibit sodium currents. Zonisamide, apparently sharing this common mechanism, also reduces the concentration of free radicals. Novel antiepileptic drugs are better tolerated by epileptic patients and practically are devoid of important pharmacokinetic drug interactions.

- by Jeffrey Britton
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- Epilepsy, Neurobiology, Free Radical, Glutamate
- by Hartmut Porzig
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- Calcium, Multidisciplinary, Ion Channels, Heart

In adherent and motile neutrophils NAD(P)H concentration, flavoprotein redox potential, and production of reactive oxygen species and nitric oxide, are all periodic and exhibit defined phase relationships to an underlying metabolic oscillation of ;20 s. Utilizing fluorescence microscopy, we have shown in real-time, on the single cell level, that the system is sensitive to externally applied periodically pulsed weak magnetic fields matched in frequency to the metabolic oscillation. Depending upon the phase relationship of the magnetic pulses to the metabolic oscillation, the magnetic pulses serve to either increase the amplitude of the NAD(P)H and flavoprotein oscillations, and the rate of production of reactive oxygen species and nitric oxide or, alternatively, collapse the metabolic oscillations and curtail production of reactive oxygen species and nitric oxide. Significantly, we demonstrate that the cells do not directly respond to the magnetic fields, but instead are sensitive to the electric fields which the pulsed magnetic fields induce. These weak electric fields likely tap into an endogenous signaling pathway involving calcium channels in the plasma membrane. We estimate that the threshold which induced electric fields must attain to influence cell metabolism is of the order of 10 ÿ4 V/m.

- by Allen Rosenspire
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- Biophysics, Fluorescence Microscopy, Calcium, Biophysical Chemistry
- by Myra Weiner and +2
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- Behavior, Toxicology, Risk assessment, Ion Channels

Pregabalin (Lyrica) is a new antiepileptic drug that is active in animal seizure models. Pregabalin is approved in US and Europe for adjunctive therapy of partial seizures in adults, and also has been approved for the treatment of pain from diabetic neuropathy or post-herpetic neuralgia in adults. Recently, it has been approved for treatment of anxiety disorders in Europe. Pregabalin is structurally related to the antiepileptic drug gabapentin and the site of action of both drugs is similar, the alpha2-delta (alpha2-delta) protein, an auxiliary subunit of voltage-gated calcium channels. Pregabalin subtly reduces the synaptic release of several neurotransmitters, apparently by binding to alpha2-delta subunits, and possibly accounting for its actions in vivo to reduce neuronal excitability and seizures. Several studies indicate that the pharmacology of pregabalin requires binding to alpha2-delta subunits, including structure-activity analyses of compounds binding to alpha2-delta subunits and pharmacology in mice deficient in binding at the alpha2-delta Type 1 protein. The preclinical findings to date are consistent with a mechanism that may entail reduction of abnormal neuronal excitability through reduced neurotransmitter release. This review addresses the preclinical pharmacology of pregabalin, and also the biology of the high affinity binding site, and presumed site of action.

- by Eric Fauman
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- Epilepsy, Glutamate, Amines, Calcium channels

A PubMed search of the years 1965 to 2003 found only 30 articles that were directly related to modeling seizures or epilepsy in aged animals. This lack of research is disturbing but explainable because of the high cost of aged animals and their increasing infirmity. Many changes occur in the older brain: cell loss in the hippocampal formation, changes in long-term potentiation maintenance, alteration in kindling, increased susceptibility to status epilepticus, and neuronal damage from stroke. The effect of aging on voltage-gated sodium and calcium channels has not been studied sufficiently. With increasing numbers of elderly persons with epilepsy needing appropriate treatment, the need to better understand the basic mechanisms of epilepsy is crucial.

- by gary mathern
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- Long Term Potentiation, Aging, Epilepsy, Electroencephalography

This article reviews our knowledge about a specific subgroup of chronic CNS-related side effects of antiepileptic drugs (AED) treatment, i.e., the effects of AEDs on mood. In line with a recent hypothesis, using the experience of AED treatment in psychiatry, we examined whether mood effects are related to the known anticonvulsant mechanisms of action of the AEDs. Specifically we examined whether AEDs, acting through potentiation of GABAergic neurotransmitter release, have ''sedating'' effects on mood, whereas AEDs that act through the reduction of excitatory glutamate neurotransmitter release have ''activating'' effects on mood. The results of this review yield evidence that there are relationships between the known anticonvulsant mechanisms of action of the AEDs and mood effects. Mood effects occur especially when the drugs have a sustained effect on neuronal mechanisms, in particular when the inhibitory or excitatory neurotransmitter release is altered. Drugs with ''use-dependent'' impact on sodium or calcium channels probably have a more transient impact and do not lead to interictal stable mood effects. Drugs with multiple mechanisms of action seem to combine a favorable efficacy profile with an increased risk of severe mood problems. The quality of the evidence, however, is not conclusive and there are many paradoxical results. One reason for this lack of ''fit'' may be the use in this review of a simplified classification, based only on the predominant mechanism of action to classify a drug. Only a limited number of AEDs (ethosuximide, tiagabine) are characterized by a single anticonvulsant mechanism of action. Probably more detailed coupling of mechanisms of action (e.g., inspecting the type and route of impact on GABA release) and mood effects may give less confusing results. The use of magnetic resonance imaging techniques such as spectroscopy may provide interesting results.

- by Bettina Schmitz
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- Epilepsy, Affect, Glutamate, Cerebral Cortex

The antidiarrhoeal activity of six Egyptian medicinal plant extracts (200 and 400 mg kg −1 ) and their effect on motility of isolated rabbit's duodenum was investigated. Phytochemical screening of the plant extracts for their active constituents was also carried out by TLC. Oral administration of methanol extract from Conyza dioscoridis (CD) or Alhagi maurorum (AM) in a 200 mg kg −1 dose exhibits a significant antidiarrhoeal effect against castor oil-induced diarrhoea, while Mentha microphylla (MM), Convolvulus arvensis (CA), Conyza linifolia (CL) produced no significant effect. In a dose of 400 mg kg −1 , Mentha microphylla, Conyza dioscoridis, Alhagi maurorum, Zygophyllum album (ZA), and Conyza linifolia produced a significant (P < 0.01) effect, while Convolvulus arvensis produced no antidiarrhoeal effect in rats. Methanol extract of Mentha microphylla, Conyza dioscoridis, Zygophyllum album, and Convolvulus arvensis induced a dose-dependent (0.4-2.8 mg ml −1 ) relaxation of rabbit's duodenal smooth muscle. Alhagi maurorum and Conyza linifolia increased the contractile force in concentrations between 0.4 and 1.6 mg ml −1 . Higher concentrations (>3.2 mg ml −1 ) caused a rapid depressant effect. The depressant effect induced by Alhagi maurorum (in a higher dose) and Zygophyllum album appeared to be due to calcium channel blocking effect, since CaCl 2 could not restore the contractile response of the tissue impregnated in calcium free-medium. However, a ganglionic blocking effect appeared to be a possible mechanism of action of Mentha microphylla and Conyza dioscoridis since a stimulant dose of nicotine could not restore the contractile response of the tissue. The effect of Convolvulus arvensis and Conyza linifolia was not through any of the common mediators. Phytochemical screening revealed the presence of tannins, flavonoids, unsaturated sterols/triterpenes, carbohydrates, lactones and proteins/amino acids as major constituents.

- by attia atta
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- Complementary and Alternative Medicine, Plant Biology, Egypt, Ethnopharmacology

Objectives: Amlodipine is a calcium channel blocker (CCB) known to stimulate nitric oxide production from endothelial cells. Whether this ancillary property can be related to the capacity of amlodipine to concentrate and alter the structure of cholesterol-containing membrane bilayers is a matter of investigation. Here, we reasoned that since the endothelial nitric oxide synthase is, in part, expressed in cholesterol-rich plasmalemmal microdomains (e.g., caveolae and rafts), amlodipine could interfere with this specific locale of the enzyme and thereby modulate NO production in endothelial cells. Methods and results: Using a method combining lubrol-based extraction and subcellular fractionation on sucrose gradient, we found that amlodipine, but not verapamil or nifedipine, induced the segregation of endothelial NO synthase (eNOS) from caveolin-enriched low-density membranes (8 T 2% vs. 42 T 3% in untreated condition; P < 0.01). We then performed co-immunoprecipitation experiments and found that amlodipine dose-dependently disrupted the caveolin/eNOS interaction contrary to other calcium channel blockers, and potentiated the stimulation of NO production by agonists such as bradykinin and vascular endothelial growth factor (VEGF) (+ 138 T 28% and + 183 T 27% over values obtained with the agonist alone, respectively; P < 0.01). Interestingly, we also documented that the dissociation of the caveolin/ eNOS heterocomplex induced by amlodipine was not mediated by the traditional calcium-dependent calmodulin binding to eNOS and that recombinant caveolin expression could compete with the stimulatory effects of amlodipine on eNOS activity. Finally, we showed that the amlodipine-triggered, caveolin-dependent mechanism of eNOS activation was independent of other pleiotropic effects of the CCB such as superoxide anion scavenging and angiotensin-converting enzyme (ACE) inhibition. Conclusions: This study unravels the modulatory effects of amlodipine on caveolar integrity and the capacity of caveolin to maintain eNOS in its vicinity in the absence of any detectable changes in intracellular calcium levels. The resulting increase in caveolin-free eNOS potentiates the NO production in response to agonists including VEGF and bradykinin. More generally, this work opens new avenues of treatment for drugs able to structurally alter signaling pathways concentrated in caveolae.

- by Theophile Godfraind
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- Cardiovascular, Signal Transduction, Nitric oxide, Vascular endothelium

The fusion construct pEGFP-PTXS1 was assembled by ligating cDNA encoding the S1 subunit of Bordetella pertussis toxin (PTX) into the plasmid pEGFP-C1 (which codes for enhanced green¯uorescent protein). Microinjection of pEGFP-PTXS1 (1±100 ng/ml) into the nucleus of dissociated rat sympathetic ganglion neurons resulted in functional expression as determined from the diffuse green¯uorescence and disruption of norepinephrine-mediated N-type Ca 21 channel modulation. The heterologously expressed toxin retained speci®city for Ga i/o -dependent pathways as VIP-mediated modulation of N-type Ca 21 channels and muscarine-mediated inhibition of M-type K 1 channels persisted in pEGFP-PTXS1 expressing neurons. These data demonstrate that the S1 subunit of PTX is readily expressed in mammalian neurons and remains functional following fusion to the C-terminus of another protein. q

- by Paul Kammermeier
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- Neuroscience, Psychology, Cognitive Science, Gene expression

In dissociated neurons of rat superior cervical ganglion (SCG), noradrenaline (NA) and acetylcholine (ACh) suppressed Ca 2÷ currents elicited by depolarizations to 0 mV from -60 mV. With GTPw-S in patch electrodes, ACh and NA caused persistent inhibition of Ca -'+ currents. Pretreatment of SCG cells with pertussis toxin abolished the action of ACh but not of NA. The results suggest that ACh and NA reduce the Ca 2+ currents in SCG cells through different G proteins.

- by Shiro Konishi
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- Cognitive Science, Brain, Calcium channels, Calcium Channel

One of the most consistent genetic findings to have emerged from bipolar disorder genome wide association studies (GWAS) is with CACNA1C, a gene that codes for the α(1C) subunit of the Ca(v)1.2 voltage-dependent L-type calcium channel (LTCC). Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders, as well as changes in brain function and structure in control subjects who have no diagnosable psychiatric illness. These data are consistent with a continuum of shared neurobiological vulnerability between diverse-Diagnostic and Statistical Manual (DSM) defined-neuropsychiatric diseases. While involved in numerous cellular functions, Ca(v)1.2 is most frequently implicated in coupling of cell membrane depolarization to transient increase of the membrane permeability for calcium, leading to activation and, potentially, changes in intracellular signaling pathway activity, gene transcription, and synaptic plasticity. Ca(v)1.2 is involv...

- by Michal Arad
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- Cognitive Science, Depression, Schizophrenia, Psychiatric Genetics

In order to assess the role of L-type voltage-gated calcium channels in electrical stimulation-mediated neuroprotection in vivo, we assessed survival of primary auditory afferents (spiral ganglion cells) in systemically deafened guinea pigs following chronic electrical stimulation with or without intracochlear infusion of verapamil, an L-type voltage-gated calcium channel antagonist. Continuous  intracochlear drug delivery (0.5 ml / h) was provided using a delivery system developed previously in our laboratory using Alzet mini-osmotic pumps. In the absence of chronic stimulation, spiral ganglion cell survival was relatively symmetric in animals treated unilaterally with either artificial perilymph or verapamil (50 mg / ml). In the presence of unilateral chronic electrical stimulation, spiral ganglion cell survival was significantly greater in stimulated, perilymph-infused ears, relative to the contralateral ear. In contrast, spiral ganglion cell survival was bilaterally symmetric in chronically stimulated, verapamil-infused animals. The difference in symmetry of spiral ganglion cell survival between the two groups was statistically significant. In vitro, passive depolarization has been demonstrated to enhance survival of cultured neurons via activation of L-type calcium channels. The results of this study indicate that, as suggested by in vitro depolarization models, in vivo electrical stimulation-mediated neuroprotection requires the activation of L-type voltage-gated calcium channels. Chronic electrical stimulation of the deaf ear is an ideal preparation for further studies in which to extrapolate findings from in vitro depolarization models. 

- by Richard Altschuler and +1
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- Cognitive Science, Drug delivery, Brain, Cochlear Implant

Zn2+ increased the rate of spontaneous release of catecholamines from bovine adrenal glands. This effect was Ca2+ independent; in fact, in the absence of extracellular Ca2+, the secretory effects of Zn2+ were enhanced. At low concentrations (3–10 μM), Zn2+ enhanced the secretory responses to 10-s pulses of 100 μM 1,1-dimethyl-4-phenylpiperazinium (DMPP, a nicotinic receptor agonist) or 100 mM K+. In the presence of DMPP, secretion was increased 47% above controls and in high-K+ solutions, secretion increased 54% above control. These low concentrations of Zn2+ did not facilitate the whole-cell Ca2+ (I Ca) or Ba2+ (I Ba) currents in patch-clamped chromaffin cells. Higher Zn2+ concentrations inhibited the currents (IC50 values, 346 μM for I Ca and 91 μM for I Ba) and blocked DMPP- and K+-evoked secretion (IC50 values, 141 and 250 μM, respectively). Zn2+ permeated the Ca2+ channels of bovine chromaffin cells, although at a much slower rate than other divalent cations. Peak currents at 10 mM Ba2+, Ca2+, Sr2+ and Zn2+ were 991, 734, 330 and 7.4 pA, respectively. Zn2+ entry was also evidenced using the fluorescent Ca2+ probe fura-2. This was possible because Zn2+ causes an increase in fura-2 fluorescence at the isosbestic wavelength for Ca2+, i.e. 360 nm. There was a slow resting entry of Zn2+ which was accelerated by stimulation with DMPP or high-K+ solution. The entry of Zn2+ was concentration dependent, slightly antagonized by 1 mM Ca2+ and completely blocked by 5 mM Ni2+. The entry of Ca2+ evoked by depolarization with high-K+ solution was antagonized by Zn2+. We conclude that inhibition by Zn2+ of evoked catecholamine secretion is associated with blockade of Ca2+ entry through Ca2+ channels recruited by DMPP or K+. However, the facilitation of secretion observed at low Zn2+ concentrations, or in the absence of Ca2+, may be exerted at an intracellular site on the secretory machinery. This is plausible because Zn2+ permeates the bovine chromaffin cell Ca2+ channels and in this way gains access to the cytosol. In addition, we have established conditions for measuring Zn2+ transients in fura-2-loaded cells with a very high sensitivity, taking advantage of the high-affinity binding of Zn2+ to fura-2 and the modification of its fluorescence spectrum.

- by Carlos Villalobos
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- Physiology, Calcium, Strontium, Calcium channels

Organophosphorus (OP) used as pesticides and hydraulic fluids can produce acute poisoning known as OPinduced delayed neuropathy (OPIDN), whose effects take long time to recover. Thus a secure therapeutic strategy to prevent the most serious effects of this poisoning would be welcome. In this study, tri-ocresyl phosphate (TOCP, 500 mg/kg p.o.) was given to hens, followed or not by nimodipine (1 mg/kg i.m.) and calcium gluconate (Ca-glu 5 mg/kg i.v.). Six hours after TOCP intoxication, neuropathy target esterase (NTE) activity inhibition was observed, peaking after 24 h exceeding 80% inhibition. A fall in the plasmatic calcium levels was noted 12 h after TOCP was given and, in the sciatic nerve, Ca 2+ fell 56.4% 24 h later; at the same time calcium activated neutral protease (CANP) activity increased 308.7%, an effect that lasted 14 days. Any bird that received therapeutic treatment after TOCP intoxication presented significant signs of OPIDN. These results suggest that NTE may be implicated in the regulation of calcium entrance into cells being responsible for the maintenance of normal function of calcium channels, and that increasing CANP activity is responsible to triggering OPIDN. Thus, with one suitably adjusted dose of nimodipine as well as Ca-glu, we believe that this treatment strategy may be used in humans with acute poisoning by neuropathic OP.

- by Rosângela Peccinini
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- Calcium, Pesticides, Calcium channels, Muscles
- by Josef Flammer
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- Multiple sclerosis, Sickle Cell Anemia, Gene Therapy, Anorexia Nervosa

Episodic ataxia type 2 (EA 2) is a rare neurological disorder of autosomal dominant inheritance resulting from dysfunction of a voltage-gated calcium channel. It manifests with recurrent disabling attacks of imbalance, vertigo, and ataxia, and can be provoked by physical exertion or emotional stress. In the spell-free interval, patients present with central ocular motor dysfunction, mainly downbeat nystagmus. A slow progression of cerebellar signs accompanied by a slight atrophy of midline cerebellar structures is commonly observed during the course of the disease. EA 2 is caused most often by the loss of function mutations of the calcium channel gene CACNA1A, which encodes the Ca V 2.1 subunit of the P/Q-type calcium channel and is primarily expressed in Purkinje cells. To date, more than 30 mutations have been described. Two effective treatment options have been established for EA 2: acetazol-amide (ACTZ), which probably changes the intracellular pH and thereby the transmembraneous potential, and 4-aminopyridine (4-AP), a potassium channel blocker. Approximately 70% of all patients respond to treatment with ACTZ, but the effect is often only transient. In an open trial, 4-AP prevented attacks in five of six patients with EA 2, most likely by increasing the resting activity and excitability of the Purkinje cells. These findings were confirmed by experiments in animal models of EA 2. Many aspects of the pathophysiology (e.g., induction of the attacks) and treatment of EA 2 (e.g., mode of action of ACTZ and 4-AP) still remain unclear and need to be addressed in further animal and clinical studies.

- by Andreas Zwergal
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- Mutation, Calcium channels, Calcium Channel, Cerebellar ataxia

Calcium plays a key role in both apoptotic and necrotic cell death. Emptying of intracellular calcium stores and/or alteration in intracellular calcium levels can modulate cell death in almost all cell types. These calcium fluxes are determined by the activity of membrane channels normally under tight control. The channels may be ligand activated or voltage dependent as well as being under the control of affector molecules such as calmodulin. It has become increasingly apparent that many calcium channels are affected by reactive oxygen or reactive nitrogen species; ROS/RNS. This may be part of the normal signaling pathways in the cell or by the action of exogenously generated ROS or RNS often by toxins. This review covers the recent literature on the activity of these redox active channels as related to cell death.

- by Paul Waring
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- Mitochondria, Apoptosis, Reactive Oxygen Species, Glutamate receptors

Background: The vestibular system provides the primary input of our sense of balance and spatial orientation. Dysfunction of the vestibular system can severely affect a person's quality of life. Therefore, understanding the molecular basis of vestibular neuron survival, maintenance, and innervation of the target sensory epithelia is fundamental.

- by Bernd Fritzsch
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- Animal Behavior, Quality of life, Signal Transduction, Vestibular System

Cellular actions of nociceptin/orphanin FQ (N/OFQ) resemble those of -, ␦-, and -opioids, i.e. activation of inwardly rectifying K ϩ conductance, inhibition of high-voltage-activated Ca 2ϩ channel currents, and impediment of neurotransmitter release. Differences in ORL 1 and -receptor distribution lead to: 1) more widespread actions of N/OFQ on periaqueductal gray neurons than opioids and 2) differential effects of N/OFQ and opioids in the brainstem. Also, unlike opioids, N/OFQ inhibits T-type Ca 2ϩ channel current in sensory neurons. Opioids and N/OFQ may modulate glutamate responses in different ways, and certain actions of N/OFQ are potentiated following nerve injury whereas those of -opioids are attenuated. Agonists at ORL 1 receptors may therefore be of clinical interest in the management of neuropathic pain.

- by peter smith
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- Physiology, Electrophysiology, Calcium, Xenopus

La6andula stoechas L. (Lamiaceae) has been used for a long time in traditional medicine as an anticonvulsant and antispasmodic. The aqueous-methanolic extract of L. stoechas flowers (LS) was studied for its possible anticonvulsant and antispasmodic activities. When tested in mice, LS (600 mg/kg) significantly reduced the severity and increased the latency of convulsions induced by pentylene tetrazole (PTZ). LS likewise reduced PTZ's lethality. LS up to a dose of 600 mg/kg was found devoid of any hypnotic effect in mice, however, animals were found to be dull, calm and relaxed. The sedative effect of the plant extract was confirmed, as it prolonged the pentobarbital sleeping time in mice similar to that of diazepam. In isolated rabbit jejunum preparations, LS caused a dose-dependent (0.1 -1.0 mg/ml) relaxation of spontaneous contractions. LS also inhibited K + -induced contractions in a similar dose range, thereby suggesting calcium channel blockade. This effect was confirmed when pretreatment of the jejunum preparation with LS produced a dose-dependent shift of the Ca 2 + dose-response curve to the right, similar to the effect of verapamil, a standard calcium channel blocker. These data indicate that the plant extract exhibits anticonvulsant and antispasmodic activities. Its calcium channel blocking property may be mechanistically related to these activities. Its usefulness in folk medicine appears thus to be based on a sound mechanistic background.

Lanthanides, also called rare-earth elements, are an interesting group of 15 chemically active, mainly trivalent, f-electronic, silvery-white metals. In fact, lanthanides are not as rare as the name implies, except for promethium, a radioactive artificial element not found in nature. The mean concentrations of lanthanides in the earth's crust are comparable to those of life-important elements like iodine, cobalt and selenium. Many lanthanide compounds show particular magnetic, catalytic and optic properties, and that is why their technical applications are so extensive. Numerous industrial sources enable lanthanides to penetrate into the human body and therefore detailed toxicological studies of these metals are necessary. In the liver, gadolinium selectively inhibits secretion by Kupffer cells and it decreases cytochrome P450 activity in hepatocytes, thereby protecting liver cells against toxic products of xenobiotic biotransformation. Praseodymium ion (Pr3+) produces the same ...

- by Artur Pałasz and +1
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- Tissue culture, Interest Groups, Human Body, Calcium Channel

Antimuscarinics are the mainstay of the medical therapy for overactive bladder, but their side effects and often modest success have prompted studies on novel pharmacological approaches. In this paper, we give a systematic literature review of peer-reviewed papers on the subject. Effective nonantimuscarinic treatments are currently scarce, but many new promising compounds are emerging, which target key molecular pathways involved in micturition control. The most promising potential therapeutic targets include: nervous GABAergic, glycinergic, dopaminergic, and serotonergic systems; b-adrenoceptors and cAMP metabolism; nonadrenergic-noncholinergic mechanisms such as purinergic and neuropeptidergic systems; vanilloid receptors; bladder afferent nerves; nonneuronal bladder signaling systems including urothelium and interstitial cells; prostanoids; Rho-kinase; and different subtypes of potassium and calcium channels. Despite the enormous amount of new biologic insight, very few drugs with mechanism of action other than antimuscarinics have passed as yet the proof-ofconcept stage. Further preclinical and clinical studies are urgently needed in this rapidly moving field.

- by Emilio Sacco
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- Peer Review, Urinary incontinence, Systematic Literature Review, Urogynecology

Hypokalaemic periodic paralysis (HypoKPP) is a skeletal muscle channelopathy caused by mutations in calcium (CACNA1S) and sodium (SCN4A) channel subunits. A small number of causative mutations have been found in European and Asian patients, but not in African patients yet. We have identified a large Beninese family in which HypoKPP segregated over five generations and was caused by the CACNA1S R1239H mutation. We report on the clinical and histopathological spectrum of the disorder in this family. A later age at onset (15.8+/-8.8years), and particular triggering factors due to specific African life conditions seem to be characteristic of our observation.

- by Dismand Houinato and +1
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- Genetics, Skeletal muscle biology, Africa, Transmission Electron Microscopy