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PubMed2006

Autonomic regulation of voltage-gated cardiac ion channels.

Altering voltage-gated ion channel currents, by changing channel number or voltage-dependent kinetics, regulates the propagation of action potentials along the plasma membrane of individual cells and from one cell to its neighbors. Functional increases in the number of cardiac sodium channels (Na(V)1.5) at the myocardial sarcolemma are accomplished by the regulation of caveolae by beta adrenergically stimulated G-proteins. We demonstrate that Na(V)1.5, Ca(V)1.2a, and K(V)1.5 channels specifically localize to isolated caveolar membranes, and to punctate regions of the sarcolemma labeled with caveolin-3. In addition, we show that Na(V)1.5, Ca(V)1.2a, and K(V)1.5 channel antibodies label the same subpopulation of isolated caveolae. Plasma membrane sheet assays demonstrate that Na(V)1.5, Ca(V)1.2a, and K(V)1.5 cluster with caveolin-3. This may have interesting implications for the way in which adrenergic pathways alter the cardiac action potential morphology and the velocity of the excitatory wave.

Action Potentials↗
PubMedDate not supplied

Control of Na+ spike backpropagation by intracellular signaling in the pyramidal neuron dendrites.

The integrative function of neurons depends on the somato-dendritic distribution and properties of voltage-gated ion channels. Sodium, potassium, calcium, and hyperpolarization-activated cyclic nucleotide-gated K+ (HCN) channels expressed in the dendrites can be modulated by a number of neurotransmitters and second-messenger systems. For example, activation of protein kinases leads to an increase in dendritic excitability by removing a slow inactivation of Na+ channels and decreasing the activity of transient K+ channels in the apical dendrites of hippocampal pyramidal neurons. Consequently, action potentials propagating along the dendrites can be modified significantly by a variety of neuromodulatory synaptic inputs.

Acetylcholine↗
PubMed2006

Modulation of h-channels in hippocampal pyramidal neurons by p38 mitogen-activated protein kinase.

Hyperpolarization-activated cyclic nucleotide-gated ion channels (h-channels; I(h); HCN) modulate intrinsic excitability in hippocampal and neocortical pyramidal neurons, among others. Whereas I(h) mediated by the HCN2 isoform is regulated by cAMP, there is little known about kinase modulation of I(h), especially for the HCN1 isoform predominant in pyramidal neurons. We used a computational method to identify a novel kinase modulator of h-channels, p38 mitogen-activated protein kinase (p38 MAPK). Inhibition of p38 MAPK in hippocampal pyramidal neurons caused a approximately 25 mV hyperpolarization of I(h) voltage-dependent activation. This downregulation of I(h) produced hyperpolarization of resting potential, along with increased input resistance and temporal summation of excitatory inputs. Activation of p38 MAPK caused a approximately 11 mV depolarizing shift in I(h) activation, along with depolarized resting potential, and decreased input resistance and temporal summation. Inhibition of related MAPKs, ERK1/2 (extracellular signal-related kinase 1/2) and JNK (c-Jun N-terminal kinase), produced no effect on I(h). These results show that p38 MAPK is a strong modulator of h-channel biophysical properties and may deserve additional exploration as a link between altered I(h) and pathological conditions such as epilepsy.

Adaptation, Physiological↗
PubMed1999

The pharmacology of ion channels: with particular reference to voltage-gated Ca2+ channels.

Ion channels are molecular machines that serve as principal integrating and regulatory devices for the control of cellular excitability. They are also major targets for drug action. The basic aspects of ion channel structure and pharmacological control are reviewed and illustrated with specific reference to a major class of therapeutic agents and molecular tools--the clinically available Ca2+ channel antagonists.

Animals↗
PubMed1996

Covalent activation of retinal rod cGMP-gated channels reveals a functional heterogeneity in the ligand binding sites.

Ion channels gated by the binding of multiple ligands play a critical role in synaptic transmission and sensory transduction. It has been difficult to resolve the contribution of individual binding events to channel gating because ligands are continuously binding and unbinding at each site. In examining the allosteric mechanism of retinal rod cGMP-gated channels, we have circumvented this problem by making use of a cGMP derivative, 8-p-azidophenacylthio-cGMP (APT-cGMP), that can be covalently tethered to the binding sites in the presence of long-wavelength UV light. In excised membrane patches, a population of channels was isolated that contained covalently-attached ligands at all but one site. Activation of these channels by cGMP revealed a previously unknown heterogeneity in the ligand-binding sites. The dose-response relations were much shallower than predicted by single-site activation models, but were well described by models in which there are two populations of sites, in roughly equal proportion, that bind cGMP with apparent affinities that differ by a factor of 25. The two apparent affinities, incorporated into a four-site model of the channel, provided an accurate description of the patch's original dose-response relation. A comparison of results on native and expressed channels suggests that the heterogeneity in the native channel arises at least in part from the presence of two different cGMP-binding subunits.

Ambystoma↗
PubMed1998

Structure of the MscL homolog from Mycobacterium tuberculosis: a gated mechanosensitive ion channel.

Mechanosensitive ion channels play a critical role in transducing physical stresses at the cell membrane into an electrochemical response. The MscL family of large-conductance mechanosensitive channels is widely distributed among prokaryotes and may participate in the regulation of osmotic pressure changes within the cell. In an effort to better understand the structural basis for the function of these channels, the structure of the MscL homolog from Mycobacterium tuberculosis was determined by x-ray crystallography to 3.5 angstroms resolution. This channel is organized as a homopentamer, with each subunit containing two transmembrane alpha helices and a third cytoplasmic alpha helix. From the extracellular side, a water-filled opening approximately 18 angstroms in diameter leads into a pore lined with hydrophilic residues which narrows at the cytoplasmic side to an occluded hydrophobic apex that may act as the channel gate. This structure may serve as a model for other mechanosensitive channels, as well as the broader class of pentameric ligand-gated ion channels exemplified by the nicotinic acetylcholine receptor.

Amino Acid Sequence↗
PubMed2004

Structural elements involved in activation of the gamma-aminobutyric acid type A (GABAA) receptor.

Ligand-gated ion channels function as rapid signal transducers, converting chemical signals (in the form of neurotransmitters) into electrical signals in the postsynaptic neuron. This is achieved by the recognition of neurotransmitter at its specific-binding sites, which then triggers the opening of an ion channel ('gating'). For this to occur rapidly (< 1 ms), there must be an efficient coupling between the agonist-binding site and the gate, located more than 30 angstroms (1 angstroms = 0.1 nm) away. Whereas a great deal of progress has been made in elucidating the structure and function of both the agonist-binding site and the ion permeation pathway in ligand-gated ion channels, our knowledge of the coupling mechanism between these domains has been limited. In this review, we summarize recent studies of the agonist-binding site and the ion channel in the gamma-aminobutyric acid type A receptor, and discuss those structural elements that may mediate coupling between them. We will also consider some possible molecular mechanisms of receptor activation.

Animals↗
PubMed2006

External ions are coactivators of kainate receptors.

The activation of ligand-gated ion channels is thought to depend solely on the binding of chemical neurotransmitters. In this study, we demonstrate that kainate (KA) ionotropic glutamate receptors (iGluRs) require not only the neurotransmitter L-glutamate (L-Glu) but also external sodium and chloride ions for activation. Removal of external ions traps KA receptors (KARs) in a novel inactive state that binds L-Glu with picomolar affinity. Moreover, occupancy of KARs by L-Glu precludes external ion binding, demonstrating crosstalk between ligand- and ion-binding sites. AMPA iGluRs function normally in the absence of external ions, revealing that even closely related iGluR subfamilies operate by distinct gating mechanisms. This behavior is interchangeable via a single amino acid residue that operates as a molecular switch to confer AMPA receptor behavior onto KARs. Our findings identify a novel allosteric site that singles out KARs from all other ligand-gated ion channels.

Animals↗
PubMed2002

Trapping the sensor.

Voltage-gated ion channels open in response to a change in membrane potential. The "sensor," or the channel's molecular entity responsible for the detection of voltage change, is formed by a transmembrane element, rich with basic residues, called the "voltage sensor" or the "S4 domain." The movement of the S4 drives a global conformational change leading to the opening of the permeation pathway and ion conduction. In this issue of Neuron, Schönherr and colleagues show that physical constrains of the "gating canal," or the crevice through which the S4 moves, determines whether voltage-gated potassium channels open quickly or slowly.

Animals↗
PubMed2004

Density-dependent changes of the pore properties of the P2X2 receptor channel.

Ligand-gated ion channels underlie and play important roles in synaptic transmission, and it is generally accepted that the ion channel pores have a rigid structure that enables strict regulation of ion permeation. One exception is the P2X ATP-gated channel. After application of ATP, the ion selectivity of the P2X2 channel time-dependently changes, i.e. permeability to large cations gradually increases, and there is significant cell-to-cell variation in the intensity of inward rectification. Here we show P2X2 channel properties are correlated with the expression level: increasing P2X2 expression level in oocytes increases permeability to large cations, decreases inward rectification and increases ligand sensitivity. We also observed that the inward rectification changed in a dose-dependent manner, i.e. when low concentration of ATP was applied to an oocyte with a high expression level, the intensity of inward rectification of the evoked current was weak. Taken together, these results show that the pore properties of P2X2 channel are not static but change dynamically depending on the open channel density. Furthermore, we identified by mutagenesis study that Ile328 located at the outer mouth of the pore is critical for the density-dependent changes of P2X2. Our findings suggest synaptic transmission can be modulated by the local density-dependent changes of channel properties caused, for example, by the presence of clustering molecules.

Adenosine Triphosphate↗
PubMed2002

Multimerization of the ligand binding domains of cyclic nucleotide-gated channels.

Cyclic nucleotide-gated (CNG) channels comprise four subunits and are activated by the direct binding of cyclic nucleotide to an intracellular domain on each subunit. This ligand binding domain is thought to contain a beta roll followed by two alpha helices, designated the B and C helices. To examine the quaternary structure of CNG channels and how it changes during ion channel gating, we introduced single cysteines along the C helix of each subunit in an otherwise cysteineless channel. We found that cysteines on the C helices could form intersubunit disulfide bonds, even between diagonal subunits. Disulfide bond formation occurred primarily in closed channels and inhibited channel opening. These data suggest that the C helices from all four channel subunits are in close proximity in the closed state and move apart during channel opening.

Animals↗
PubMed1997

Ion channels in neuroglial cells.

With the advent of the patch clamp technique, many different types of ion channels have been found in neuroglial cells, including voltage-sensitive ion channels (Na+, Ca2+, K+, and CI- channels), ligand-gated ion channels (glutamate receptor and GABAA receptor), and mechanosensitive ion channels. Most of these ion channels have also been found in excitable cells, and thus excitable and non-excitable cells in the nervous system share a similar repertoire of ion channel gene expression. Various factors, such as different developmental stage or different regions in the brain, are known to influence glial ion channel expression. In addition, glial ion channel expression is influenced by the presence of neurons, suggesting the existence of dynamic mechanism(s) for regulating ion channel expression via cell-to-cell signaling between neurons and glia. In this review, the current understanding of various types of ion channels found in neuroglial cells (i.e., astrocytes, oligodendrocytes, and Schwann cells) is summarized.

Animals↗
PubMed2006

A voltage-sensor water pore.

Voltage-sensor (VS) domains cause the pore of voltage-gated ion channels to open and close in response to changes in transmembrane potential. Recent experimental studies suggest that VS domains are independent structural units. This independence is revealed dramatically by a voltage-dependent proton-selective channel (Hv), which has a sequence homologous to the VS domains of voltage-gated potassium channels (Kv). Here we show by means of molecular dynamics simulations that the isolated open-state VS domain of the KvAP channel in a lipid membrane has a configuration consistent with a water channel, which we propose as a common feature underlying the conductance of protons, and perhaps other cations, through VS domains.

Animals↗
PubMed1995

The multi-ion nature of the cGMP-gated channel from vertebrate rods.

1. Native cGMP-gated channels were studied in rod outer segments of the larval tiger salamander, Ambystoma tigrinum. The alpha-subunit of the cGMP-gated channel, here referred to as the wild type (WT), and mutant channels were heterologously expressed in Xenopus laevis oocytes. These channels were studied in excised membrane patches in the inside-out configuration and were activated by the addition of 100 or 500 microM cGMP. The current carried by monovalent cations was measured under voltage-clamp conditions. 2. In the presence of 110 mM Na+ in the extracellular medium and different amounts of Na+ in the intracellular medium, the I-V relations of the native channel could be described by a single-site model with a profile of Gibbs free energy with two barriers and a well. A similar result was obtained in the presence of 110 mM Li+ in the extracellular medium and different amounts of Li+ in the intracellular medium. The well depth was 1.4RT (where R is the gas constant and T is the absolute temperature) for both Li+ and Na+. 3. The I-V relations of the native channel in the presence of 110 mM Na+ on one side of the membrane and 110 mM Li+ on the other side could not be described by the same single-site model with identical values of barriers and well obtained in the presence of Li+ or Na+ alone: the well for Li+ had to be at least 4RT. 4. In the presence of mixtures of 110 mM Li+ and Cs+ on the cytoplasmic side of the membrane, an anomalous mole fraction effect was observed both in the native and the WT channel. No anomalous behaviour was seen in the presence of Li(+)-Na+ and Li(+)-NH4+ mixtures. 5. The anomalous mole fraction effect with mixtures of Li+ and Cs+ was not observed in the channel where glutamate 363 was mutated to a glutamine (E363Q) or an asparagine (E363N). When glutamate 363 was mutated to an aspartate (E363D), the anomalous mole fraction effect with mixtures of Li+ and Cs+ was still observed, although significantly reduced. 6. When lysine 346, arginine 369, aspartate 370 and glutamate 372 were neutralized by mutation to glutamine, the ion permeation through the mutant channels and the WT channel had largely similar properties.(ABSTRACT TRUNCATED AT 400 WORDS)

Ambystoma↗
PubMed2003

A single ring of charged amino acids at one end of the pore can control ion selectivity in the 5-HT3 receptor.

1. To determine the mechanisms by which cation- or anion-specific channels select between these ions, we have examined the role of electrostatic factors in a typical ligand-gated ion channel, the 5-hydroxytryptamine3 (5-HT3) receptor, by removal and/or insertion of rings of conserved charged residues at either end of the pore. 2. Neutralization of the negatively charged ring at the intracellular end of the channel (E-1'A) results in a nonselective channel (PNa/PCl=0.89). 3. Insertion of positively charged residues at the extracellular end of the pore either results in a nonfunctional receptor (A24'K) or one that remains cation-selective (PNa/PCl=110; S19'R). 4. Combining the removal of a negatively charged ring (E-1'A) with the insertion of a positively charged ring (S19'R), however, results in a channel that is predominantly anion-selective (PNa/PCl=0.37). 5. The data suggest that for the cation-selective 5-HT3 receptor, the control of selectivity exerted by charged rings at either end of the pore is dominated by the ring of negatively charged residues at the intracellular side of the channel. As changing the charge at this position has also been shown to change ionic selectivity in anion-selective receptors, these data suggest that electrostatic factors can control selectivity in the whole Cys-loop family.

Amino Acid Sequence↗
PubMed1996

Two alternatively spliced forms of the cGMP-gated channel alpha-subunit from cone photoreceptor are expressed in the chick pineal organ.

Light sensitivity of the pineal has been retained in most vertebrates, except mammals. Retinal photoreceptors and pinealocytes share common components of light-dependent signaling pathways. In particular, an ion channel gated by cGMP has been electrophysiologically identified in chick pinealocytes; however, the physiological function of a light-sensitive enzyme cascade is not known, and primary structures of only a few pineal components have been determined. By PCR analysis and cloning of the respective cDNA, we show that the chick pineal expresses the alpha-subunit of the cyclic nucleotide-gated (CNG) channel of rod photoreceptors and two short forms of the cone CNG channel. Analysis of the chick cone CNG channel gene reveals that these forms are produced by alternative splicing, which removes either one or two exons from the transcript. The shorter splice variant is functional when heterologously expressed, and it is approximately twofold more sensitive to activation by cGMP than the cone CNG channel. The chick cone CNG channel and the pineal splice form are both modulated by Ca2+/calmodulin (CaM). The CaM sensitivity might be mediated by a putative CaM-binding site in an N-terminal segment encoded by exon 4. This exon is missing in the gene for the rod CNG channel alpha-subunit. Pineal CNG channels are candidates for receptor-mediated Ca2+ entry into pinealocytes and may be an important element of signaling pathways that control the light response and secretion of the pineal hormone melatonin.

Alternative Splicing↗
PubMed2005

Ligand-gated channels.

Ligand-gated ion channels (LGICs) are fast-responding channels in which the receptor, which binds the activating molecule (the ligand), and the ion channel are part of the same nanomolecular protein complex. This paper will describe the properties and functions of the nicotinic acetylcholine LGIC superfamily, which plays a critical role in the fast chemical transmission of electrical signals between nerve cells and between nerve and muscle cells. The superfamily will mainly be exemplified by the excitatory nicotinic acetylcholine receptor (nAChR) and the inhibitory glycine receptor (GlyR) channels.

Animals↗
PubMed2003

Muscle biopsy and cell cultures: potential diagnostic tools in hereditary skeletal muscle channelopathies.

Hereditary muscle channelopathies are caused by dominant mutations in the genes encoding for subunits of muscle voltage-gated ion channels. Point mutations on the human skeletal muscle Na+ channel (Nav1.4) give rise to hyperkalemic periodic paralysis, potassium aggravated myotonia, paramyotonia congenita and hypokalemic periodic paralysis type 2. Point mutations on the human skeletal muscle Ca2+ channel give rise to hypokalemic periodic paralysis and malignant hyperthermia. Point mutations in the human skeletal chloride channel CIC-1 give rise to myotonia congenita. Point mutations in the inwardly rectifying K+ channel Kir2.1 give rise to a syndrome characterized by periodic paralysis, severe cardiac arrhythmias and skeletal alterations (Andersen's syndrome). Involvement of the same ion channel can thus give rise to different phenotypes. In addition, the same mutation can lead to different phenotypes or similar phenotypes can be caused by different mutations on the same or on different channel subtypes. Bearing in mind, the complexity of this field, the growing number of potential channelopathies (such as the myotonic dystrophies), and the time and cost of the genetic procedures, before a biomolecular approach is addressed, it is mandatory to apply strict diagnostic protocols to screen the patients. In this study we propose a protocol to be applied in the diagnosis of the hereditary muscle channelopathies and we demonstrate that muscle biopsy studies and muscle cell cultures may significantly contribute towards the correct diagnosis of the channel involved. DNA-based diagnosis is now a reality for many of the channelopathies. This has obvious genetic counselling, prognostic and therapeutic implications.

Adult↗