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PubMed2000

The Arabidopsis dnd1 "defense, no death" gene encodes a mutated cyclic nucleotide-gated ion channel.

Gene-for-gene disease resistance typically includes a programmed cell death response known as the hypersensitive response (HR). The Arabidopsis thaliana dnd1 mutant was previously isolated as a line that failed to produce the HR in response to avirulent Pseudomonas syringae pathogens; plants homozygous for the recessive dnd1-1 mutation still carry out effective gene-for-gene resistance. The dnd1-1 mutation also causes constitutive systemic resistance and elevated levels of salicylic acid. In the present study, a positional cloning approach was used to isolate DND1. DND1 encodes the same protein as AtCNGC2, a cyclic nucleotide-gated ion channel of previously unknown organismal function that can allow passage of Ca(2+), K(+) and other cations [Leng, Q., Mercier, R. W., Yao, W. & Berkowitz, G. A. (1999) Plant Physiol. 121, 753-761]. By using a nahG transgene, we found that salicylic acid is required for the elevated resistance caused by the dnd1 mutation but that removal of salicylic acid did not completely eliminate the dwarf and loss-of-HR phenotypes of mutant dnd1 plants. A stop codon that would severely truncate the DND1 gene product was identified in the dnd1-1 allele. This demonstrates that broad-spectrum disease resistance and inhibition of the HR can be activated in plants by disruption of a cyclic nucleotide-gated ion channel.

Arabidopsis↗
PubMed2006

Distance measurements reveal a common topology of prokaryotic voltage-gated ion channels in the lipid bilayer.

Voltage-dependent ion channels are fundamental to the physiology of excitable cells because they underlie the generation and propagation of the action potential and excitation-contraction coupling. To understand how ion channels work, it is important to determine their structures in different conformations in a membrane environment. The validity of the crystal structure for the prokaryotic K(+) channel, K(V)AP, has been questioned based on discrepancies with biophysical data from functional eukaryotic channels, underlining the need for independent structural data under native conditions. We investigated the structural organization of two prokaryotic voltage-gated channels, NaChBac and K(V)AP, in liposomes by using luminescence resonance energy transfer. We describe here a transmembrane packing representation of the voltage sensor and pore domains of the prokaryotic Na channel, NaChBac. We find that NaChBac and K(V)AP share a common arrangement in which the structures of the Na and K selective pores and voltage-sensor domains are conserved. The packing arrangement of the voltage-sensing region as determined by luminescence resonance energy transfer differs significantly from that of the K(V)AP crystal structure, but resembles that of the eukaryotic K(V)1.2 crystal structure. However, the voltage-sensor domain in prokaryotic channels is closer to the pore domain than in the K(V)1.2 structure. Our results indicate that prokaryotic and eukaryotic channels that share similar functional properties have similar helix arrangements, with differences arising likely from the later introduction of additional structural elements.

Bacterial Proteins↗
PubMed2005

Effects of toluene on seizures induced by convulsants acting at distinct ligand-gated ion channels.

Toluene is one of the most widely used solvents. Electrophysiological studies indicated that this solvent directly affects various ligand gated ion channels including NMDA, GABA(A), nicotinic and glycine receptors. The effect of toluene on seizures induced by chemoconvulsants acting on these receptors was compared. Mice were pretreated with toluene (100-1000 mg/kg, i.p.) or corn oil followed by a timed intravenous infusion of NMDA, bicuculline, picrotoxin, nicotine or strychnine to induce seizures. Toluene increased seizure thresholds and lethal doses induced by nicotine, NMDA, picrotoxin and bicuculline, but not strychnine in the used doses. The relative susceptibility to anticonvulsant effect of toluene was in the order: nicotine > NMDA > bicuculline > picrotoxin > strychnine. These findings support a unique anticonvulsant profile of toluene and suggest that nicotinic and NMDA receptors may be more sensitive than GABA(A) and glycine receptors to toluene exposure in seizure-related neural circuits.

Animals↗
PubMed1997

Expression of the P2X2 receptor subunit of the ATP-gated ion channel in the retina.

The site of extracellular ATP signalling in the retina was investigated by examining expression of the P2X2 receptor (P2X2R) subunit which assembles to form ATP-gated ion channels. Indirect in situ RT-PCR in situ hybridization localized the presence of mRNA for the P2X2R subunit within the soma of photoreceptors, inner nuclear layer neurones and the retina ganglion cells. Use of an antiserum specific for the P2X2R subunit confirmed the expression of the protein by these cells and demonstrated a particularly dense immunolabelling within the inner plexiform layer containing the dendritic processes of the retina ganglion cells. The outer segment of the photoreceptors also exhibited P2X2R-like immunoreactivity. The extensive expression of ATP-gated ion channel protein within the retina suggests that extracellular ATP plays diverse neurohumoral roles in regulation of visual processing and cellular homeostasis.

Adenosine Triphosphate↗
PubMed2000

Investigations into the mechanism of action of the new anticonvulsant retigabine. Interaction with GABAergic and glutamatergic neurotransmission and with voltage gated ion channels.

Retigabine (N-(2-amino-4-(4-fluorobenzylamino)phenyl) carbamic acid ethyl ester, CAS 150812-12-7, D-23129) is a novel anticonvulsant currently undergoing phase II clinical trials. The compound was shown to possess broad spectrum and potent anticonvulsant properties both in vitro and in vivo. The mechanism of action of this drug is currently not fully understood. In previous studies a potent opening effect on K+ channels and an increased release of newly synthesized gamma-aminobutyric acid (GABA) were reported. The aim of this study was to investigate the interaction of retigabine with GABA, kainate and N-methyl-D-aspartate (NMDA) induced currents as well as with voltage gated Na+ and Ca++ channels. Retigabine concentration dependently potentiated GABA induced currents in rat cortical neurones. Significant effects were only seen with concentrations of 10 mumol/l and above. The action of retigabine was not antagonised by flumazenil indicating interaction with other than benzodiazepine binding sites. In comparison with the K+ channel opening effect which can be seen at concentrations as low as 0.1 mumol/l the contribution of this mechanism to the anticonvulsant activity of retigabine may be minor. Inhibitory effects observed on voltage activated Na+ and Ca++ channels as well as on kainate induced currents were only observed at the highest concentration tested (100 mumol/l) and can be considered non specific. No significant interaction with NMDA induced currents was observed.

Animals↗
PubMed2004

Localization of voltage-gated ion channels in mammalian brain.

The intrinsic electrical properties of neurons are shaped in large part by the action of voltage-gated ion channels. Molecular cloning studies have revealed a large family of ion channel genes, many of which are expressed in mammalian brain. Much recent effort has focused on determining the contribution of the protein products of these genes to neuronal function. This requires knowledge of the abundance and distribution of the constituent subunits of the channels in specific mammalian central neurons. Here we review progress made in recent studies aimed at localizing specific ion channel subunits using in situ hybridization and immunohistochemistry. We then discuss the implications of these results in terms of neuronal physiology and neuronal mechanisms underlying the observed patterns of expression.

Animals↗
PubMed2006

Inhibition of calpain and caspase-3 prevented apoptosis and preserved electrophysiological properties of voltage-gated and ligand-gated ion channels in rat primary cortical neurons exposed to glutamate.

Glutamate toxicity in traumatic brain injury, ischemia, and Huntington's disease causes cortical neuron death and dysfunction. We tested the efficacy of calpain and caspase-3 inhibitors alone and in combination to prevent neuronal death and preserve electrophysiological functions in rat primary cortical neurons following glutamate exposure. Cortical neurons exposed to 0.5 microM glutamate for 24 h committed mostly apoptotic death as determined by Wright staining and ApopTag assay. Levels of expression, formation of active forms, and activities of calpain and caspase-3 were increased following glutamate exposure. Also, in situ double labeling identified conformationally active caspase-3-p20 fragment and chromatin condensation in apoptotic neurons. Pretreatment of cortical neurons with 0.2 microM N-benzyloxylcarbonyl-Leu-Nle-aldehyde (calpain-specific inhibitor) and 100 microM N-benzyloxylcarbonyl-Asp(OCH3)-Glu(OCH3)-Val-Asp(OCH3)-fluoromethyl ketone (caspase-3-specific inhibitor) provided strong neuroprotection. Standard patch-clamp techniques were used to measure the whole-cell currents associated with Na+ channels, N-methyl-D-aspartate receptors, and kainate receptors. The lack of a change in capacitance indicated that neurons treated with inhibitor(s) plus glutamate did not undergo apoptotic shrinkage and maintained the same size as the control neurons. Whole-cell currents associated with Na+ channels, N-methyl-D-aspartate receptors, and kainate receptors were similar in amplitude and activation/inactivation kinetics for cells untreated and treated with inhibitor(s) and glutamate. Spontaneous synaptic activity as observed by miniature end-plate currents was also similar. Prevention of glutamate-induced apoptosis by calpain and caspase-3 inhibitors preserved normal activities of crucial ion channels such as Na+ channels, N-methyl-D-aspartate receptors, and kainate receptors in neurons. Our studies strongly imply that calpain and caspase-3 inhibitors may also provide functional neuroprotection in the animal models of traumatic brain injury and neurodegenerative diseases.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Differential modulatory actions of the volatile convulsant flurothyl and its anesthetic isomer at inhibitory ligand-gated ion channels.

A challenge for theories of general anesthesia is the existence of compounds predicted to be anesthetics but which, instead, do not produce anesthesia and often elicit other behavioral effects such as convulsions. This study focused on flurothyl (bis[2,2, 2-trifluoroethyl] ether), a potent volatile convulsant, and its anesthetic isomer, 'iso-flurothyl' (1,1,1,3,3, 3-hexafluoro-2-methoxypropane). The effects of flurothyl and iso-flurothyl were studied using the whole-cell patch-clamp technique on agonist-activated chloride currents in human GABA(A), glycine, and GABA(C) rho(1) receptors expressed in HEK 293 cells. GABA(A) and glycine receptors are promising molecular targets for the actions of inhaled ether general anesthetics. Flurothyl acted as a non-competitive antagonist at GABA(A) alpha(2)beta(1) and alpha(2)beta(1)gamma(2s) receptors, but had no effect at glycine alpha(1) receptors. Flurothyl had biphasic actions on GABA responses at GABA(C) rho(1) receptors. In contrast, iso-flurothyl enhanced ('potentiated') submaximal agonist responses at GABA(A) and glycine receptors, but had no effect on GABA responses at GABA(C) rho(1) receptors. Point mutations in GABA(A) and glycine receptor subunits, which have been previously shown to abolish potentiation of agonist responses by the ether anesthetics enflurane and isoflurane, also ablated potentiation of agonist responses by iso-flurothyl. These same mutations in the GABA(A) receptor had only modest effects on the inhibitory actions of flurothyl. GABA(A) receptors with mutations conferring insensitivity to antagonism by picrotoxin were still inhibited by flurothyl, suggesting that picrotoxin and flurothyl antagonize GABA responses by distinct sites or mechanisms of action. In summary, antagonism of GABA(A) receptors is likely to account for the convulsant effects of flurothyl, while the general anesthetic actions of iso-flurothyl, like those of other ether anesthetics, may be related to positive modulation of GABA(A) and/or glycine receptors.

Amino Acid Sequence↗
PubMed1998

The development of voltage-gated ion channels and its relation to activity-dependent development events.

Spontaneous activity is an essential feature in the development of the nervous system. The patterns of activity and the waveform and ionic dependence of the action potentials that occur during such activity are fine-tuned to carry out certain developmental functions, and are therefore generally not compatible with the mature physiological function of the cell. For this reason, the patterns of ion channel development that create spontaneous activity early in the development of a given cell type are complex and not easily predicted from the mature properties of that same cell. Ion channels are often found that are specific to early stages of development, and that either are not retained in the mature cell or whose properties are greatly changed during later differentiation. The exact significance of such patterns of channel development is just now becoming clear, as we understand more about the mechanisms linking spontaneous activity to later developmental events.

Animals↗
PubMed1996

Modulation of amino acid-gated ion channels by protein phosphorylation.

The major excitatory and inhibitory amino acid receptors in the mammalian central nervous system are considered to be glutamate, gamma-aminobutyric acid type A (GABAA), and glycine receptors. These receptors are widely acknowledged to participated in fast synaptic neurotransmission, which ultimately is responsible for the control of neuronal excitability. In addition to these receptors being regulated by endogenous factors, including the natural neurotransmitters, they also form target substrates for phosphorylation by a number of protein kinases, including serine/threonine and tyrosine kinases. The process of phosphorylation involves the transfer of a phosphate group(s) from adenosine triphosphate to one or more serine, threonine, or tyrosine residues, which are invariably found in an intracellular location within the receptor Phosphorylation is an important means of receptor regulation since it represents a covalent modification of the receptor structure, which can have important implications for ion channel function. This chapter reviews the current molecular and biochemical evidence regarding the sites of phosphorylation for both native neuronal and recombinant glutamate, GABAA and glycine receptors, and also reviews the functional electrophysiological implications of phosphorylation for receptor function.

Amino Acid Sequence↗
PubMed1998

Voltage- and ligand-gated ion channels in floor plate neuroepithelia of the rat.

Whole-cell patch-clamp recordings were used to characterize the membrane properties and ion channel complement of floor plate neuroepithelia in embryonic and neonatal rats. The average resting potential was close to -60 mV, the capacitance was approximately 7 pS and the membrane time constant averaged 31 ms, in both neonates and embryos. Two types of K+ current were identified (i) a slowly activating, slowly inactivating current that was present in all cells, and (ii) a rapidly inactivating current that was present in 39% of cells from neonates and 64% of cells from embryos. K+ currents were significantly larger in neonates than embryos. Na+ currents were absent from all neuroepithelial cells examined. In contrast, the majority of floor plate cells exhibited a significant Ca2+ current. Biophysically this current activated at potentials positive to 60 mV and exhibited fast, voltage-dependent, inactivation. The Ca2+ current was equipermeant to Ca2+ and Ba2+, sensitive to 40-120 microM Ni2+ and only slightly inhibited by 100 microM Cd2+. These and other observations indicated this current is mediated by low-voltage-activated (i.e. T-type) Ca2+ channels. The majority of floor plate cells tested also exhibited responses to the neurotransmitter GABA which produced robust inward currents at negative membrane potentials, in chloride-loaded cells. Both the pharmacology and voltage-dependence of the GABA-activated currents indicated they arose from activation of GABA(A) receptors.

Animals↗