An ATP-gated ion channel at the cell nucleus.
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Adenosine Triphosphate↗
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Cyclic nucleotide- and inositol phosphate-gated ion channels in lobster olfactory receptor neurons.
The idea of having two second messenger pathways in olfaction, one mediated by cAMP and the other by inositol 1,4,5-trisphosphate, is supported by evidence that both second messengers directly activate distinct ion channels in the outer dendrite of lobster olfactory receptor neurons. Evidence that both types of second messenger-gated channels can occur in the same patch of membrane suggests that channels of both types can be expressed in one neuron. Evidence of more than one type of inositol phosphate-gated channel in this highly specialized region of the neuron furthers the idea that the output of individual olfactory receptor cells is regulated through multiple effectors and allows that effector diversity may contribute to functional diversity among olfactory receptor cells.
Animals↗
Evidence that zinc inhibits N-methyl-D-aspartate receptor-gated ion channel activation by noncompetitive antagonism of glycine binding.
Zinc noncompetitively antagonizes N-methyl-D-aspartate (NMDA) receptor-mediated responses in cultured neurons. We investigated the mechanism of this inhibition by examining the effect of zinc on ligand binding to three distinct sites on the NMDA receptor in rat hippocampal membranes. Zinc dose-dependently inhibited both the association and dissociation of the NMDA channel blocker [3H]N-(1-[thienyl]cyclohexyl)piperidine ([3H]TCP) but had no effect on steady state levels of [3H]TCP binding. This suggests that zinc inhibits the receptor-gated access of [3H]TCP to its site in the ion channel but has no effect on the binding site itself. Zinc inhibition of [3H]TCP association was not mediated by an action at the NMDA recognition site, because zinc had no effect on NMDA-displaceable L-[3H]glutamate binding. On the other hand, zinc dose-dependently inhibited [3H]glycine binding by a noncompetitive interaction. Stoichiometric analysis of equilibrium binding data indicated the presence of two [3H]glycine binding sites/[3H]TCP binding site. Comparison of the potencies of zinc in inhibiting glycine-dependent [3H]TCP association and [3H]glycine binding suggests that blockade of only one of the two glycine sites is sufficient to prevent [3H]TCP association. We hypothesize that synaptically released zinc inhibits NMDA receptor-mediated responses by binding to a site on the receptor/channel complex, reducing glycine binding, and thereby decreasing what would otherwise be a tonically present action of endogenous extracellular glycine.
Animals↗
Molecular characterization and in situ localization of a full-length cyclic nucleotide-gated channel in rat brain.
Ion channels gated directly by cyclic nucleotides are required for the transduction of sensory signals in photoreceptor cells and olfactory cells. Cyclic nucleotide-gated (CNG) channels may also be expressed in the central nervous system because partial transcripts that share homology with CNG channels have been found therein. We have now isolated and cloned a full-length CNG channel cDNA from adult rat brain. The sequence is identical to that of the alpha-subunit originally found in the olfactory epithelium (CNCalpha3). In situ hybridization, using probes specific for the CNCalpha3 mRNA, suggest that this channel is expressed widely in the rat brain, albeit mostly at relatively low levels. Certain neuronal populations, however, such as deep cerebellar nuclei, olfactory bulb mitral cells and cerebellar Purkinje neurons, appeared specially enriched. The study demonstrates for the first time that a full-length CNG channel mRNA is expressed in the brain, supporting the possibility that CNG channels are involved in central neural communication and plasticity. The sequence reported in this paper has been deposited in the GenBank data base (accession no. AF126808).
Animals↗
Dopamine modulates the kinetics of ion channels gated by excitatory amino acids in retinal horizontal cells.
Upon exposure to dopamine, cultured teleost retinal horizontal cells become more responsive to the putative photoreceptor neurotransmitter L-glutamate and to its analog kainate. We have recorded unitary and whole-cell currents to determine the mechanism by which dopamine enhances ion channels activated by these agents. In single-channel recordings from cell-attached patches with agonist in the patch pipette, the frequency of 5- to 10-pS unitary events, but not their amplitude, increased by as much as 150% after application of dopamine to the rest of the cell. The duration of channel openings also increased somewhat, by 20-30%. In whole-cell experiments, agonists with and without dopamine were applied to voltage-clamped horizontal cells by slow superfusion. Analysis of whole-cell current variance as a function of mean current indicated that dopamine increased the probability of channel opening for a give agonist concentration without changing the amount of current passed by an individual channel. For kainate, noise analysis additionally demonstrated that dopamine did not alter the number of functional channels. Dopamine also increased a slow spectral component of whole-cell currents elicited by kainate or glutamate, suggesting a change in the open-time kinetics of the channels. This effect was more pronounced for currents induced by glutamate than for those induced by kainate. We conclude that dopamine potentiates the activity of horizontal cell glutamate receptors by altering the kinetics of the ion channel to favor the open state.
Analysis of Variance↗
Direct ion channel gating: a new function for intracellular messengers.
1. There is widespread belief that intracellular messengers [e.g., Ca2+, cyclic AMP, cyclic GMP, inositol-1,4,5-triphosphate (IP3)] assert their actions primarily through activation of protein kinases. 2. In studies of excitable cells protein kinase activation has been shown to alter membrane ionic conductance, presumably through phosphorylation of ion channels (see Levitan, 1985). However, recent reports from several laboratories indicate that intracellular messengers can also affect membrane ionic conductances directly without invoking protein kinase activation. 3. In this article we examine those examples of direct activation of ionic conductances by intracellular messengers which are supported by single-channel studies of isolated membrane patches. The list of cell types displaying this kind of response is growing and includes cells of neuronal as well as nonneuronal origin.
Animals↗
Recordings of glutamate-gated ion channels in outside-out patches from Drosophila larval muscle.
Outside-out patches of membrane were excised from muscle fibers 6 and 7 of third-instar wild-type Drosophila larvae. Channels were observed to open in response to short pulses of L-glutamate. At a holding potential of -60 mV, the channels opened to one main conductance level of about 120 pS. The current-voltage plot for the channels was linear and reversed around 0 mV holding potential. The channels were also activated by quisqualate but not by aspartate, N-methyl-D-aspartate (NMDA), kainate, glycine, gamma-aminobutyric acid (GABA) and acetylcholine. At high glutamate concentrations (3 or 10 mM), channel activation reached a peak within 0.3 ms. The channels opened in 'bursts' flickering between open and closed states. The channels opened only for a few milliseconds after switching on the glutamate and channel activity declined after the initial surge to zero with time constants between 5 and 20 ms. During applications of low glutamate concentrations (0.2-0.5 mM) to the same patch the channels opened much less frequently and during most applications no openings were observed. The openings observed were short and 'bursts' of openings were rare. Two exponential components were identified in the open-time distribution obtained with pulsed applications of glutamate (0.5-10 mM) with time constants of about 0.1 and 2.0 ms. The kinetics of the channels seem to be similar to the kinetics of certain glutamate gated channels found on muscle of crayfish and locust.
Animals↗
Visual ecology and voltage-gated ion channels in insect photoreceptors.
That particular membrane conductances are selected for expression to enable the efficient coding of biologically relevant signals is illustrated by recent work on insect photoreceptors. These studies exploit the richness of insect vision and the accessibility of insect photoreceptors to cellular analysis in both intact animal and isolated cell preparations. The distribution of voltage-gated conductances among photoreceptors of different species correlates with visual ecology. Delayed-rectifier K+ channels are found in the rapidly responding photoreceptors of fast-flying flies. The conductance's activation range and dynamics match light-induced signals, and enable a rapid response by reducing the membrane time constant. Slow-moving flies have slowly responding photoreceptors that lack the delayed rectifier, but express an inactivating K+ conductance that is metabolically less demanding. Complementing these findings, locust photoreceptor membranes are modulated diurnally. The delayed rectifier is exhibited during the day and the inactivating K+ current is exhibited at night. Insect photoreceptors also demonstrate the amplification of signals by voltage-gated Na+ channels. In drone-bee photoreceptors, voltage-gated Na+ channels combine with K+ channels to enhance the small transient signals produced by the image of a queen bee passing over the retina. This subthreshold amplifier operates most effectively over the range of light intensities at which drones pursue queens.
Animals↗
Haemonchus contortus: HcGluCla expressed in Xenopus oocytes forms a glutamate-gated ion channel that is activated by ibotenate and the antiparasitic drug ivermectin.
Ion channels are targets for many drugs including insecticides and anthelminthic agents such as ivermectin (IVM) and moxidectin (MOX). IVM has been shown to activate glutamate-gated chloride channels (GluCls) from the free-living nematode, Caenorhabditis elegans. Haemonchus contortus is a parasitic nematode that is also extremely sensitive to IVM. The high sensitivity of H. contortus to IVM is probably the result of the fact that, like C. elegans, H. contortus also express GluCls. To investigate the potential physiological response to IVM in H. contortus we have expressed a GluCl from this parasite (H. contortus glutamate-gated chloride channel, HcGluCla) in Xenopus oocytes. HcGluCla expressed in oocytes formed a homomeric channel that responded to glutamate and ibotenate as well as the anthelmintics IVM and MOX. The response to glutamate and ibotenate was fast acting and reversible whereas the response to IVM and MOX was a slower activating channel that was essentially irreversible. These results suggest that IVM toxicity in H. contortus is the result of its irreversible activation of GluCls.
Animals↗
The Croonian Lecture, 1983. Voltage-gated ion channels in the nerve membrane.
In the Croonian Lecture for 1957, Sir Alan Hodgkin described the role of the channels selective for sodium and potassium ions in the conduction of the nervous impulse. An essential feature of these channels is the manner in which the complex kinetics of their opening and closing is controlled by the electric field across the membrane, and the purpose of the present lecture is to consider the advances that have been made in the past 25 years towards an understanding of the underlying molecular mechanisms. One such advance has been the successful recording, independently of the ionic currents, of the small asymmetry current known as the gating current, that accompanies the conformational changes that take place in the sodium channels. A quantitative analysis of the characteristics of the gating current suggests that activation is brought about by two more or less independent processes operating in parallel, to one of which the slower mechanism of inactivation is coupled sequentially. However, it is clear that a complete picture of the gating system will only be arrived at by combining evidence of this kind with that provided by other new lines of approach such as studies of single ion channels in various tissues by means of fluctuation analysis and the patch-clamping technique, and a reinvestigation of the kinetics of activation of the potassium channels.
Anesthetics, Local↗
Paraoxon: cholinesterase-independent stimulation of transmitter release and selective block of ligand-gated ion channels in cultured hippocampal neurons.
Paraoxon (O,O-diethyl O-p-nitrophenyl phosphate) is the neurotoxic metabolite of the insecticide parathion (O,O-diethyl O-p-nitrophenyl phosphorothioate). The effects of organophosphorus compounds on peripheral synapses have been attributed to inhibition of cholinesterase and to direct actions on muscarinic and nicotinic receptors, but less is known about the actions of organophosphorus compounds, including paraoxon, in the central nervous system. We investigated initially the effects of paraoxon on spontaneous transmitter release by recording miniature postsynaptic currents (MPSCs) from cultured rat hippocampal neurons using the whole-cell mode of the patch-clamp technique. Paraoxon (0.3 microM) in the presence of tetrodotoxin (0.3 microM) and atropine (1 microM) caused a significant increase in the frequency of gamma-aminobutyric acid- and glutamate-mediated MPSCs, but did not change the peak amplitudes or decay-time constants of these MPSCs. In contrast, application of nicotinic agonists or antagonists did not change the MPSC frequency. The presynaptic effect of paraoxon shown here was not mediated by actions on muscarinic or nicotinic receptors, or by elevated acetylcholine levels secondary to inhibition of cholinesterase. In addition, agonists were applied to assess the postsynaptic effects of paraoxon on excitatory and inhibitory amino acid receptors. Paraoxon (30 microM-1 mM) blocked the ion channels of glycine, gamma-aminobutyric acidA, N-methyl-D-aspartic acid and nicotinic acetylcholine receptors, but not the ion channels of kalnate- and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. The combined effects of paraoxon on spontaneous transmitter release and on the functions of several ligand-gated receptors may constitute mechanisms relevant to the neurotoxicity of paraoxon.
Animals↗
HLM1, an essential signaling component in the hypersensitive response, is a member of the cyclic nucleotide-gated channel ion channel family.
The hypersensitive response (HR) in plants is a programmed cell death that is commonly associated with disease resistance. A novel mutation in Arabidopsis, hlm1, which causes aberrant regulation of cell death, manifested by a lesion-mimic phenotype and an altered HR, segregated as a single recessive allele. Broad-spectrum defense mechanisms remained functional or were constitutive in the mutant plants, which also exhibited increased resistance to a virulent strain of Pseudomonas syringae pv tomato. In response to avirulent strains of the same pathogen, the hlm1 mutant showed differential abilities to restrict bacterial growth, depending on the avirulence gene expressed by the pathogen. The HLM1 gene encodes a cyclic nucleotide-gated channel, CNGC4. Preliminary study of the HLM1/CNGC4 gene pro-duct in Xenopus oocytes (inside-out patch-clamp technique) showed that CNGC4 is permeable to both K(+) and Na(+) and is activated by both cGMP and cAMP. HLM1 gene expression is induced in response to pathogen infection and some pathogen-related signals. Thus, HLM1 might constitute a common downstream component of the signaling pathways leading to HR/resistance.
Alleles↗
Three-dimensional solution structure of conotoxin psi-PIIIE, an acetylcholine gated ion channel antagonist.
The three-dimensional structure of conotoxin psi-PIIIE, a 24-amino acid peptide from Conus purpurascens, has been solved using two-dimensional (2D) 1H NMR spectroscopy. Conotoxin psi-PIIIE contains the same disulfide bonding pattern as the mu-conotoxins, which target skeletal muscle sodium channels, but has been shown to antagonize the acetylcholine gated cation channel through a noncompetitive mechanism. Structural information was obtained by the analysis of a series of 2D NOESY spectra as well as measurement of coupling constants from 1D 1H and PE-COSY NMR experiments. Molecular modeling calculations included the use of the distance geometry (DG) algorithm, simulated annealing techniques, and the restrained molecular dynamics method. The resulting structures are considerably similar to the previously published structures for the mu-conotoxins GIIIA and GIIIB, despite the lack of sequence conservation between conotoxin psi-PIIIE and the mu-conotoxins. The structure consists of a series of tight turns, each turn occurring in the position analogous to those of turns described in mu-GIIIA and mu-GIIIB. This suggests the disulfide bonding pattern is able to largely direct the structure of the peptides, creating a stable structural motif which allows extensive sequence substitution of non-cystine residues.
Amino Acid Sequence↗
The use of dwell time cross-correlation functions to study single-ion channel gating kinetics.
The derivation of cross-correlation functions from single-channel dwell (open and closed) times is described. Simulation of single-channel data for simple gating models, alongside theoretical treatment, is used to demonstrate the relationship of cross-correlation functions to underlying gating mechanisms. It is shown that time irreversibility of gating kinetics may be revealed in cross-correlation functions. Application of cross-correlation function analysis to data derived from the locust muscle glutamate receptor-channel provides evidence for multiple gateway states and time reversibility of gating. A model for the gating of this channel is used to show the effect of omission of brief channel events on cross-correlation functions.
Ion Channels↗
Noise and stochastic resonance in voltage-gated ion channels.
Using Monte Carlo techniques, I calculate the effects of internally generated noise on information transfer through the passage of action potential spikes along unmyelinated axons in a simple nervous system. I take the Hodgkin-Huxley (HH) description of Na and K channels in squid giant axons as the basis of the calculations and find that most signal transmission noise is generated by fluctuations in the channel open and closed populations. To bring the model closer to conventional descriptions in terms of thermal noise energy, kT, and to determine gating currents, I express the HH equations in the form of simple relations from statistical mechanics where the states are separated by a Gibbs energy that is modified by the action of the transmembrane potential on dipole moments held by the domains. Using the HH equations, I find that the output response (in the probability of action potential spikes) from small input potential pulses across the cell membrane is increased by added noise but falls off when the input noise becomes large, as in stochastic resonance models. That output noise response is sharply reduced by a small increase in the membrane polarization potential or a moderate increase in the channel densities. Because any reduction of noise incurs metabolic and developmental costs to an animal, the natural noise level is probably optimal and any increase in noise is likely to be harmful. Although these results are specific to signal transmission in unmyelinated axons, I suggest that the conclusions are likely to be general.
Action Potentials↗
Inhibition of NMDA-gated ion channels by the P2 purinoceptor antagonists suramin and reactive blue 2 in mouse hippocampal neurones.
1. The action of suramin and reactive blue 2 on N-methyl-D-aspartate (NMDA)-activated ion current was studied in mouse hippocampal neurones in culture by use of whole-cell patch-clamp recording. 2. Suramin and reactive blue 2 inhibited steady-state current activated by 25 microM NMDA with IC50 values of 68 and 11 microM, respectively. 3. Reactive blue 2 produced a gradual decline of NMDA-activated current to a steady-state, but this slow onset was not an indication of use-dependence, as it could be eliminated by exposure to reactive blue 2 before NMDA application. In addition, NMDA-activated current recovered completely from inhibition by reactive blue 2 in the absence of agonist. 4. The slow onset of inhibition by reactive blue 2 was not apparently due to an action at an intracellular site, as inclusion of 250 microM reactive blue 2 in the recording pipette did not alter inhibition by 25 microM reactive blue 2 applied externally. 5. Reactive blue 2 and suramin inhibited NMDA-gated channels in a voltage-independent manner. 6. Reactive blue 2, 25 microM, decreased the maximal response to NMDA from 1441 to 598 pA without changing its EC50. In contrast, 75 microM suramin increased the EC50 for NMDA from 13 to 35 microM, and decreased the maximal response to NMDA from 1822 to 1498 pA. Schild analysis of suramin inhibition of NMDA-activated current yielded a nonlinear plot. 7. Both agents decreased the maximal response to glycine without altering its EC50. 8. Suramin and reactive blue 2 appear to inhibit NMDA receptor-channels in a manner that is noncompetitive with respect to both NMDA and glycine. However, inhibition by suramin differed from that by reactive blue 2, in that suramin significantly increased the EC50 of NMDA.
Animals↗
Mechanoelectrical and voltage-gated ion channels in mammalian vestibular hair cells.
Mammalian vestibular afferents respond robustly to head movements at low frequencies and provide input to reflexes that control eye, head and body position. Vestibular organs have distinctive regions and hair cells: Type II cells receive bouton afferent endings and type I cells receive large calyx afferent endings. In the rodent utricle, type II cells are broadly tuned to frequencies between 10 and 30 Hz. Other recent data suggest that otolith organs function in this frequency range, which is higher than previously imagined. Some of the tuning derives from adaptation of the transducer current, which is best fitted with a double exponential decay with time constants of approximately 4 and 40 ms. Further tuning is provided by basolateral conductances, principally outwardly rectifying, voltage-gated K+ conductances. The kinetics of the K+ currents tend to vary with location in the sensory epithelium and therefore may contribute to regional variation in afferent physiology. Type I hair cells have a large, negatively activating K+ conductance, g(K,L), that confers a very low input resistance and therefore attenuates the receptor potential. This may reduce nonlinearity in the receptor potential, a possibly useful feature for the motor reflexes served by the vestibular system. On the other hand, the small receptor potentials together with unusually negative resting potentials are hard to reconcile with calcium-mediated quantal transmission. This problem may be overcome by factors that inhibit g(K,L)'s activation at resting potential. Also, the calyx may support nonquantal transmission.
Animals↗
Rate-amplitude correlation from single-channel records. A hidden structure in ion channel gating kinetics?
Lifetime probability density functions from single-channel recording are usually assumed to follow a multiexponential form. The amplitudes and rate constants for each exponential component are presumed to be independent. We have explored this assumption and have found a correlation between the amplitudes and the rate constants in certain cases. We examine this correlation and the possibility that other functional forms may also properly describe these distribution functions.
Electric Conductivity↗