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At least 109 records · Page 6Linked to original sources
PubMed1991

Role of ion channels in lymphocytes.

Ion channels, and ion fluxes in general, appear to regulate a wide variety of processes important to lymphocyte function in normal and disease states. These include resting ionic homeostasis and the more complex signaling events involved in activation, proliferation, cytotoxic function, and volume regulation. The wider application of patch-clamp and microfluorimetry techniques to lymphocytes has helped to clarify some issues and raised many more. It seems likely that rapid progress will be made in our understanding of these areas through a combination of immunological, biochemical, and electrophysiological approaches.

Animals↗
PubMed2005

Potential analytical applications of gated artificial ion channels.

Biosensors based on natural ion channels combine a biological recognition mechanism with a physical transduction technique in a very selective and sensitive manner. This kind of molecular sensor will contribute to drug screening and environmental screening. Key information about channel gating, ion transport, and molecular mechanism is provided by the patch-clamp technique, commonly used for electrophysiological analysis. Here we report the synthesis of light-gated artificial ion channels, necessary constituents for construction of biosensors based on natural ion channels. The artificial gated ion channels described here are based on calix[4]resorcinarene. Opening and closing of the artificial ion channel is achieved by azo groups, which work like a lid. Azo groups alter their conformation on irradiation with light, and are chemically quite stable. Addition of a gate function will enhance the potential of synthetic channels to be used in sensors as molecular switches.

Azo Compounds↗
PubMed1991

Open channel block by gadolinium ion of the stretch-inactivated ion channel in mdx myotubes.

Currents flowing through single stretch-inactivated ion channels were recorded from cell-attached patches on myotubes from mdx mice. Adding micromolar concentrations of gadolinium to patch electrodes containing normal saline produced rapid transitions in the single-channel current between the fully open and closed states. The kinetics of the current fluctuations followed the predictions of a simple model of open channel block in which the transitions in the current arise from the entry and exit of Gd from the channel pore: histograms of the open and closed times were well fit with single exponentials, the blocking rate depended linearly on the concentration of gadolinium in the patch electrode, and the unblocking rate was independent of the concentration of gadolinium. Hyperpolarizing the patch increased the rate of unblocking (approximately e-fold per 85 mV), suggesting the charged blocking particle can exit the channel into the cell under the influence of the applied membrane field. The rate of blocking was rapid and was independent of the patch potential, consistent with the rate of ion entry into the pore being determined by its rate of diffusion in solution. When channel open probability was reduced by applying suction to the electrode, the blocking kinetics were independent of the extent of inactivation, suggesting that mechanosensitive gating does not modify the structure of the channel pore.

Animals↗
PubMed2001

pH alterations "reset" Ca2+ sensitivity of brain Na+ channel 2, a degenerin/epithelial Na+ ion channel, in planar lipid bilayers.

Members of the degenerin/epithelial Na(+) channel superfamily of ion channels subserve many functions, ranging from whole body sodium handling to mechanoelectrical transduction. We studied brain Na(+) channel 2 (BNaC-2) in planar lipid bilayers to examine its single channel properties and regulation by Ca(2+). Upon incorporation of vesicles made from membranes of oocytes expressing either wild-type (WT) BNaC-2 or BNaC-2 with a gain-of-function (GF) point mutation (G433F), functional channels with different properties were obtained. WT BNaC-2 resided in a closed state with short openings, whereas GF BNaC-2 was constitutively activated; a decrease in the pH in the trans compartment of the bilayer activated WT BNaC-2 and decreased its permeability for Na(+) over K(+). Moreover, these maneuvers made the WT channel more resistant to amiloride. In contrast, GF BNaC-2 did not respond to a decrease in pH, and its amiloride sensitivity and selectivity for Na(+) over K(+) were unaffected by this pH change. Buffering the bathing solutions with EGTA to reduce the free [Ca(2+)] to <10 nm increased WT single channel open probability 10-fold, but not that of GF BNaC-2. Ca(2+) blocked both WT and GF BNaC-2 in a dose- and voltage-dependent fashion; single channel conductances were unchanged. A drop in pH reduced the ability of Ca(2+) to inhibit these channels. These results show that BNaC-2 is an amiloride-sensitive sodium channel and suggest that pH activation of these channels could be, in part, a consequence of H(+) "interference" with channel regulation by Ca(2+).

Acid Sensing Ion Channels↗
PubMed2007

Thermodynamically equivalent silicon models of voltage-dependent ion channels.

We model ion channels in silicon by exploiting similarities between the thermodynamic principles that govern ion channels and those that govern transistors. Using just eight transistors, we replicate--for the first time in silicon--the sigmoidal voltage dependence of activation (or inactivation) and the bell-shaped voltage-dependence of its time constant. We derive equations describing the dynamics of our silicon analog and explore its flexibility by varying various parameters. In addition, we validate the design by implementing a channel with a single activation variable. The design's compactness allows tens of thousands of copies to be built on a single chip, facilitating the study of biologically realistic models of neural computation at the network level in silicon.

Animals↗
PubMed2003

[Ion channels and water channels--a prerequisite for living cells and electric signals in the brain].

Water channels and ion channels are membrane proteins that transport water and ions into and out of cells with high selectivity and efficiency. Peter Agre and Roderick MacKinnon were awarded the Nobel Prize in chemistry 2003 for their discoveries of the structure of water channels and ion channel proteins, thus explaining basal mechanisms that are fundamental to all forms of life and in particular to the electrical signalling in the brain. These scientific achievements answer questions that biophysicists and physiologists have discussed since the 19th century.

Aquaporins↗
PubMed2001

Ion channels and epilepsy.

Ion channels provide the basis for the regulation of excitability in the central nervous system and in other excitable tissues such as skeletal and heart muscle. Consequently, mutations in ion channel encoding genes are found in a variety of inherited diseases associated with hyper- or hypoexcitability of the affected tissue, the so-called 'channelopathies.' An increasing number of epileptic syndromes belongs to this group of rare disorders: Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in a neuronal nicotinic acetylcholine receptor (affected genes: CHRNA4, CHRNB2), benign familial neonatal convulsions by mutations in potassium channels constituting the M-current (KCNQ2, KCNQ3), generalized epilepsy with febrile seizures plus by mutations in subunits of the voltage-gated sodium channel or the GABA(A) receptor (SCN1B, SCN1A, GABRG2), and episodic ataxia type 1-which is associated with epilepsy in a few patients--by mutations within another voltage-gated potassium channel (KCNA1). These rare disorders provide interesting models to study the etiology and pathophysiology of disturbed excitability in molecular detail. On the basis of genetic and electrophysiologic studies of the channelopathies, novel therapeutic strategies can be developed, as has been shown recently for the antiepileptic drug retigabine activating neuronal KCNQ potassium channels.

Ataxia↗
PubMed2002

Regulation of ion channels by integrins.

Ion channels are regulated by protein phosphorylation and dephosphorylation of serine, threonine, and tyrosine residues. Evidence for regulation of channels by tyrosine phosphorylation comes primarily from investigations of the effects of growth factors, which act through receptor tyrosine kinases. The purpose of the present work is to summarize evidence for the regulation of ion channels by integrins, through their downstream, nonreceptor tyrosine kinases. We review both direct and indirect evidence for this regulation, with particular emphasis on Ca2+-activated K+ and voltage-gated Ca2+ channels. We then discuss the critical roles that cytoskeletal, focal-adhesion, and channel-associated scaffolding proteins may play in localizing nonreceptor tyrosine kinases to the vicinity of ion channels. We conclude by speculating on the physiological significance of these regulatory pathways.

Animals↗
PubMed2003

Flux assays in high throughput screening of ion channels in drug discovery.

Ion channels have been identified as therapeutic targets in various disorders, such as cardiovascular disease, neurological disease, and cystic fibrosis. Flux assays to detect functional ionic flux through ion channels are becoming increasingly popular as tools for screening compounds. In an optimized flux assay, modulation of ion channel activity may produce readily detectable changes in radiolabeled or nonradiolabeled ionic flux. Technologies based on flux assays are currently available in a fully automated high throughput format for efficient screening. This application offers sensitive, precise, and reproducible measurements giving accurate drug rank orders matching those of patch clamp data. Conveniently, the flux assay is amenable to adaptation for different ion channels, such as potassium, sodium, calcium, and chloride channels, by using suitable tracer ions. The nonradiolabeled rubidium-based flux assay coupled with the ion channel reader (ICR) technology has become very successful in ion channel activity analysis and is emerging as a popular technique in modern drug discovery.

Animals↗
PubMed2006

Structure of the N-terminal ankyrin repeat domain of the TRPV2 ion channel.

The TRPV ion channels mediate responses to many sensory stimuli including heat, low pH, neuropeptides, and chemical ligands. All TRPV subfamily members contain an intracellular N-terminal ankyrin repeat domain (ARD), a prevalent protein interaction motif. The 1.6-A crystal structure of the TRPV2-ARD, with six ankyrin repeats, reveals several atypical structural features. Repeats one through three display unusually long and flexible fingers with a large number of exposed aromatic residues, whereas repeats five and six have unusually long outer helices. Furthermore, a large counterclockwise twist observed in the stacking of repeats four and five breaks the regularity of the domain, altering the shape of surfaces available for interactions with proteins or other cellular ligands. Both solution studies and crystal packing interactions indicate that the TRPV2-ARD does not form homo-oligomers, suggesting that the ARD of TRPV ion channels may be used for interactions with regulatory factors rather than in promoting tetrameric assembly of the ion channels.

Amino Acid Motifs↗
PubMed2001

Ion channels involved in stroke.

Ion channels are membrane proteins that flicker open and shut to regulate the flow of ions down their electrochemical gradient across the membrane and consequently regulate cellular excitability. Every living cell expresses ion channels, as they are critical life-sustaining proteins. Ion channels are generally either activated by voltage or by ligand interaction. For each group of ion channels the channels' molecular biology and biophysics will be introduced and the pharmacology of that group of channels will be reviewed. The in vitro and in vivo literature will be reviewed and, for ion channel groups in which clinical trials have been conducted, the efficacy and therapeutic potential of the neuroprotective compounds will be reviewed. A large part of this article will deal with glutamate receptors, focusing specifically on N-methyl-D-aspartate (NMDA) receptors. Although the outcome of clinical trials for NMDA receptor antagonists as therapeutics for acute stroke is disappointing, the culmination of these failed trials was preceded by a decade of efforts to develop these agents. Sodium and calcium channel antagonists will be reviewed and the newly emerging efforts to develop therapeutics targeting potassium channels will be discussed. The future development of stroke therapeutics targeting ion channels will be discussed in the context of the failures of the last decade in hopes that this decade will yield successful stroke therapeutics.

Journal Article↗
PubMed2004

Activation of protein kinase C reverses capsaicin-induced calcium-dependent desensitization of TRPV1 ion channels.

Ca2+ selective ion channels of vanilloid receptor subtype-1 (TRPV1) in capsaicin-sensitive dorsal root ganglion (DRG) neurons and TRPV1 transfected Chinese hamster ovarian (CHO) cells are desensitized following calcium-dependent tachyphylaxis induced by successive applications of 100 nM capsaicin. Tachyphylaxis of TRPV1 to 100 nM capsaicin stimuli was not observed in the absence of extracellular calcium. Capsaicin sensitivity of desensitized TRPV1 ion channels recovered on application of phorbol-12-myristate-13-acetate (PMA). PMA-induced recovery of desensitized TRPV1 was primarily due to influx of extracellular calcium observed during re-application of capsaicin following desensitization. Capsazepine blocked the re-sensitization to capsaicin by PMA. Protein kinase C (PKC) inhibitory peptide PKC fragment 19-36 also inhibited re-sensitization to capsaicin by PMA. Reversal of capsaicin-induced desensitization by PMA was prevented by a mutation of TRPV1 where phosphorylation sites serine502 and serine800 were replaced with alanine. This study provides evidence for a role of PKC in reversing capsaicin-induced calcium-dependent desensitization of TRPV1 ion channels.

Amino Acid Substitution↗
PubMed2005

Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels.

Acid Sensing Ion Channels (ASICs) are a group of sodium-selective ion channels that are activated by low extracellular pH. The role of ASIC in disease states remains unclear partly due to the lack of selective pharmacological agents. In this report, we describe the effects of A-317567, a novel non-amiloride blocker, on three distinct types of native ASIC currents evoked in acutely dissociated adult rat dorsal root ganglion (DRG) neurons. A-317567 produced concentration-dependent inhibition of all pH 4.5-evoked ASIC currents with an IC50 ranging between 2 and 30muM, depending upon the type of ASIC current activated. Unlike amiloride, A-317567 equipotently blocked the sustained phase of ASIC3-like current, a biphasic current akin to cloned ASIC3, which is predominant in DRG. When evaluated in the rat Complete Freud's Adjuvant (CFA)-induced inflammatory thermal hyperalgesia model, A-317567 was fully efficacious at a dose 10-fold lower than amiloride. A-317567 was also potent and fully efficacious when tested in the skin incision model of post-operative pain. A-317567 was entirely devoid of any diuresis or natriuresis activity and showed minimal brain penetration. In summary, A-317567 is the first reported small molecule non-amiloride blocker of ASIC that is peripherally active and is more potent than amiloride in vitro and in vivo pain models. The discovery of A-317567 will greatly help to enhance our understanding of the physiological and pathophysiological role of ASICs.

Acid Sensing Ion Channels↗
PubMed2000

Inherited ion channel disorders.

UNLABELLED: The inherited ion channel disorders (channelopathies) are a group of disorders caused by mutations in genes encoding ion channels. Ion channel disorders can affect any tissue, but the majority affect skeletal muscle or the central nervous system. These disorders include skeletal muscle sodium channelopathies causing hyperkalaemic periodic paralysis, paramyotonia congenita and potassium-aggravated myotonia. Skeletal muscle calcium channelopathies can cause hypokalaemic periodic paralysis, malignant hyperthermia and central core disease. Skeletal muscle chloride channelopathies can cause Thomsen and Becker myotonia. A neuronal sodium channelopathy causes the generalised epilepsy febrile seizures plus syndrome. Neuronal potassium channelopathies can cause familial benign neonatal convulsions and episodic ataxia type 1. Finally, neuronal calcium channelopathies can cause episodic ataxia type 2, familial hemiplegic migraine and spinocerebellar ataxia type 6. CONCLUSION: The clinical features, aetiology and pathogenesis of inherited voltage-gated ion channel disorders affecting muscle and the central nervous system are reviewed here.

Ataxia↗
PubMed2005

Ion channels and cancer.

Membrane ion channels are essential for cell proliferation and appear to have a role in the development of cancer. This has initially been demonstrated for potassium channels and is meanwhile also suggested for other cation channels and Cl- channels. For some of these channels, like voltage-gated ether à go-go and Ca2+-dependent potassium channels as well as calcium and chloride channels, a cell cycle-dependent function has been demonstrated. Along with other membrane conductances, these channels control the membrane voltage and Ca2+ signaling in proliferating cells. Homeostatic parameters, such as the intracellular ion concentration, cytosolic pH and cell volume, are also governed by the activity of ion channels. Thus it will be an essential task for future studies to unravel cell cycle-specific effects of ion channels and non-specific homeostatic functions. When studying the role of ion channels in cancer cells, it is indispensable to choose experimental conditions that come close to the in vivo situation. Thus, environmental parameters, such as low oxygen pressure, acidosis and exposure to serum proteins, have to be taken into account. In order to achieve clinical application, more studies on the original cancer tissue are required, and improved animal models. Finally, it will be essential to generate more potent and specific inhibitors of ion channels to overcome the shortcomings of some of the current approaches.

Animals↗
PubMed2005

Natural products as tools for studies of ligand-gated ion channels.

Ligand-gated ion channels, or ionotropic receptors, constitute a group of membrane-bound proteins that regulate the flux of ions across the cell membrane. In the brain, ligand-gated ion channels mediate fast neurotransmission. They are crucial for normal brain function and involved in many diseases in the brain. Historically, natural products have been used extensively in biomedical studies and ultimately as drugs or leads for drug design. In studies of ligand-gated ion channels, natural products have been essential for the understanding of their structure and function. In the following a short survey of natural products and their use in studies of ligand-gated ion channels is given.

Animals↗