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At least 19 recordsLinked to original sources
PubMed2004

Structural changes during ion channel gating.

Ion channels are generally multi-subunit complexes, with the ion conduction pathway formed at the subunit interface. In moving between the closed and open states, three structurally distinct channels, represented by the recently determined structures of a mechanosensitive, ligand-gated and K(+) selective channel, all move transmembrane helices away from the central ion conduction pathway. In all three cases, this results in the displacement of a hydrophobic gate from the ion conduction pathway, freeing ion movement. The channels achieve this by moving the transmembrane helices as rigid bodies using three major types of motion: MscL tilts its helices, the nicotinic ACh receptor rotates its helices, and KirBac1.1 bends its helices. In all cases, the gating motions are likely to take place rapidly. These large and fast movements provide a possible explanation for why the conduction pathways of a wide range of different ion channels are formed at the interface between subunits.

Amino Acid Sequence↗
PubMed2004

A new approach to define dynamics of the ion channel gates.

Voltage-gated ion channels are of great importance in the generation and propagation of electrical signals in the excitable cell membranes. How these channels respond to changes in the potential across the membrane has been a challenging problem, and different approaches have been proposed to address the mechanism of voltage sensing and gating in these channels. In this study, we attempt a new approach by considering a simple two-state gate system and applying the path probability method to construct a nonequilibrium statistical mechanical model of the system. The model which is based on the principles of statistical physics provides a firm physical basis for ion channel gating.

Cell Membrane↗
PubMed2002

Voltage-sensing mechanism is conserved among ion channels gated by opposite voltages.

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) ion channels are found in rhythmically firing cells in the brain and in the heart, where the cation current through HCN channels (called I(h) or I(f)) causes these cells to fire repeatedly. These channels are also found in non-pacing cells, where they control resting membrane properties, modulate synaptic transmission, mediate long-term potentiation, and limit extreme hyperpolarizations. HCN channels share sequence motifs with depolarization-activated potassium (Kv) channels, such as the fourth transmembrane segment S4. S4 is the main voltage sensor of Kv channels, in which transmembrane movement of S4 charges triggers the opening of the activation gate. Here, using cysteine accessibility methods, we investigate whether S4 moves in an HCN channel. We show that S4 movement is conserved between Kv and HCN channels, which indicates that S4 is also the voltage sensor in HCN channels. Our results suggest that a conserved voltage-sensing mechanism operates in the oppositely voltage-gated Kv and HCN channels, but that there are different coupling mechanisms between the voltage sensor and activation gate in the two different channels.

Amino Acid Motifs↗
PubMed2003

Metal ion effects on ion channel gating.

Metal ions affect ion channels either by blocking the current or by modifying the gating. In the present review we analyse the effects on the gating of voltage-gated channels. We show that the effects can be understood in terms of three main mechanisms. Mechanism A assumes screening of fixed surface charges. Mechanism B assumes binding to fixed charges and an associated electrostatic modification of the voltage sensor. Mechanism C assumes binding and an associated non electrostatic modification of the gating. To quantify the non-electrostatic effect we introduced a slowing factor, A. A fourth mechanism (D) is binding to the pore with a consequent pore block, and could be a special case of Mechanisms B or C. A further classification considers whether the metal ion affects a single site or multiple sites. Analysing the properties of these mechanisms and the vast number of studies of metal ion effects on different voltage-gated on channels we conclude that group 2 ions mainly affect channels by classical screening (a version of Mechanism A). The transition metals and the Zn group ions mainly bind to the channel and electrostatically modify the gating (Mechanism B), causing larger shifts of the steady-state parameters than the group 2 ions, but also different shifts of activation and deactivation curves. The lanthanides mainly bind to the channel and both electrostatically and non-electrostatically modify the gating (Mechanisms B and C). With the exception of the ether-à-go-go-like channels, most channel types show remarkably similar ion-specific sensitivities.

Animals↗
PubMed2001

A voltage-gated ion channel expressed specifically in spermatozoa.

Calcium ions play a primary role in the regulation of sperm cell behavior. We report finding a voltage-gated ion channel (CatSper2) that is expressed in male germ cells but not in other cells. The putative channel contains 6 transmembrane segments, making it more similar to the voltage-gated potassium channels, but the ion selectivity pore domain sequence resembles that of a Ca(v) channel. The mRNA is expressed during the meiotic or postmeiotic stages of spermatogenesis, and the protein is localized to the sperm flagellum, suggesting a role in the regulation of sperm motility. The mRNA for the channel is present in mouse, rat, and human sperm cells, and the gene is found on chromosome 2 E5-F1 in the mouse and 15q13 in the human. Recently, another voltage-gated channel (CatSper) that has features similar to the one reported here was discovered. It also is expressed within the flagellum and is required for normal fertility of mice. However, expression of CatSper2 alone or coexpression with CatSper in cultured cells, or attempts to coimmunoprecipitate the two proteins from germ cells failed to demonstrate that these two unique but similar alpha-like subunits form either a homo- or heterotetramer. It is possible, therefore, that two independent alpha subunits, different from other known voltage-gated channels, regulate sperm motility.

Amino Acid Sequence↗
PubMed2000

Single-cell mRNA expression of HCN1 correlates with a fast gating phenotype of hyperpolarization-activated cyclic nucleotide-gated ion channels (Ih) in central neurons.

Hyperpolarization-activated currents (Ih) are key players in shaping rhythmic neuronal activity. Although candidate genes for Ih channels have been cloned (HCN1-HCN4), the subunit composition of different native Ih channels is unknown. We used a combined patch-clamp and qualitative single-cell reverse transcription multiplex polymerase chain reaction (RT-mPCR) approach to analyse HCN1-4 coexpression profiles in four neuronal populations in mouse CNS. Coexpression of HCN2, HCN3 and HCN4 mRNA was detected in single neurons of all four neuronal cell types analysed. In contrast, HCN1 mRNA was detected in neocortical and hippocampal pyramidal neurons but not in dopaminergic midbrain and thalamocortical neurons. HCN1 expression was correlated with significantly faster activation kinetics on the level of individual neurons. Semiquantitative single-cell RT-mPCR analysis demonstrated that HCN1 mRNA expression is at least eightfold higher in cortical neurons than subcortical neurons. We show that single neurons possess complex coexpression patterns of Ih candidate genes. Alternative expression of HCN1 is likely to be an important molecular determinant to generate the different neuronal Ih channel species adapted to tune either subcortical or cortical network activity.

Animals↗
PubMed1998

Structure and function of voltage-gated ion channels.

Voltage-gated ion channels are key molecules for the generation of electrical signals in cells. They are integral membrane proteins which are activated by a depolarized membrane potential resulting in a conformational change, allowing ions to permeate. Voltage-gated ion channels can either be inactivated from this open state by an additional conformational change which leads to a nonconducting state of the channel, or they may be deactivated by a repolarized membrane potential. Following the first successful cloning of voltage-gated ion channels in 1984 the combination of molecular biological and electrophysiological techniques has been very fruitful in the investigation of the structure and function of these membrane proteins. From these studies a molecular picture of the structural elements important for the activity of voltage-gated ion channels has been established. This has assisted in clarifying the molecular basis of the electrical excitability of cells.

Amino Acid Sequence↗
PubMed2002

New structural perspectives on K(+) channel gating.

Ion channel gating is a two-stage process. It involves an initial energy transduction step, sensitive to a variety of physical stimuli (voltage, ligand binding, and tension), followed by the structural rearrangements that allow ion permeation. New structural data provides fresh information on both steps and offers unprecedented insight into how ion channels open and close at the molecular level.

Archaeal Proteins↗
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↗
PubMed2005

Allosteric modulation of ligand-gated ion channels.

Ligand-gated ion channels (LGICs) are cell surface proteins that play an important role in fast synaptic transmission and in the modulation of cellular activity. Due to their intrinsic properties, LGICs respond to neurotransmitters and other effectors (e.g. pH) and transduce the binding of a ligand into an electrical current on a microsecond timescale. Following activation, LGICs open allowing an ion flux across the cell membrane. Depending upon the charge and concentration of ions, the flux can cause a depolarization or hyperpolarization, thus modulating excitability of the cell. While our understanding of LGICs has significantly progressed during the past decade, many properties of these proteins are still poorly understood, in particular their modulation by allosteric effectors. LGICs are often thought as a simple on-off switches. However, a closer look at these receptors reveals a complex behavior and a wide repertoire of subtle modulation by intrinsic and extrinsic factors. From a physiological point of view, this modulation can be seen as an additional level of complexity in the cell signaling process. Here we review the allosteric modulation of LGICs in light of the latest findings and discuss the suitability of this approach to the design of new therapeutic molecules.

Allosteric Regulation↗
PubMed2000

Specific binding sites for alcohols and anesthetics on ligand-gated ion channels.

Ligand-gated ion channels are a target for inhaled anesthetics and alcohols in the central nervous system. The inhibitory strychnine-sensitive glycine and gamma-aminobutyric acid type A receptors are positively modulated by anesthetics and alcohols, and site-directed mutagenesis techniques have identified amino acid residues important for the action of volatile anesthetics and alcohols in these receptors. A key question is whether these amino acids are part of an alcohol/anesthetic-binding site. In the present study, we used an alkanethiol anesthetic to covalently label its binding site by mutating selected amino acids to cysteine. We demonstrated that the anesthetic propanethiol, or alternatively, propyl methanethiosulfonate, covalently binds to cysteine residues introduced into a specific second transmembrane site in glycine receptor and gamma-aminobutyric acid type A receptor subunits and irreversibly enhances receptor function. Moreover, upon permanent occupation of the site by propyl disulfide, the usual ability of octanol, enflurane, and isoflurane to potentiate the function of the ion channels was lost. This approach provides strong evidence that the actions of anesthetics in these receptors are due to binding at a single site.

Alcohols↗
PubMed2001

Fast kinetic analysis of ligand-gated ion channels.

Ligand-gated ion channels mediate fast synaptic transmission in the central and peripheral nervous system and the neuromuscular junction. Their common principle of function is the conversion of a chemical signal--neurotransmitter binding--into an electrical signal, i.e., an ion influx into the postsynaptic cell. The transient nature of this signal requires experimental setups that provide adequate temporal resolution and the use of transient kinetic analysis rather than equilibrium methods for a correct description of receptor function. Although the highly specialized geometry of a synapse that allows very rapid delivery of neurotransmitter is difficult to mimic in an experimental system, a variety of techniques for rapid kinetic analysis are available, making it possible to determine at least some steps of receptor function with sufficient accuracy. This article provides an overview of strategies and methods of fast ligand application and kinetic analysis using whole-cell and single channel patch clamp.

Animals↗
PubMed1995

Structure and function of voltage-gated ion channels.

Voltage-gated ion channels are responsible for generation of electrical signals in cell membranes. Their principal subunits are members of a gene family and can function as voltage-gated ion channels by themselves. They are expressed in association with one or more auxiliary subunits which increase functional expression and modify the functional properties of the principal subunits. Structural elements that are required for voltage-dependent activation, selective ion conductance, and inactivation have been identified, and their mechanisms of action are being explored through mutagenesis, expression in heterologous cells, and functional analysis. These experiments reveal that this family of channels is built upon a common structural theme with variations appropriate for functional specialization of each channel type.

Animals↗
PubMed2006

The distribution and targeting of neuronal voltage-gated ion channels.

Voltage-gated ion channels have to be at the right place in the right number to endow individual neurons with their specific character. Their biophysical properties together with their spatial distribution define the signalling characteristics of a neuron. Improper channel localization could cause communication defects in a neuronal network. This review covers recent studies of mechanisms for targeting voltage-gated ion channels to axons and dendrites, including trafficking, retention and endocytosis pathways for the preferential localization of particular ion channels. We also discuss how the spatial localization of these channels might contribute to the electrical excitability of neurons, and consider the need for future work in this emerging field.

Action Potentials↗
PubMed1991

Diffusion model in ion channel gating. Extension to agonist-activated ion channels.

Previously, we described a model which treats ion channel gating as a discrete diffusion problem. In the case of agonist-activated channels at high agonist concentration, the model predicts that the closed lifetime probability density function from single channel recording approximates a power law with an exponent of -3/2 (Millhauser, G. L., E. E. Salpeter, and R. E. Oswald. 1988a. Proc. Natl. Acad. Sci. USA. 85: 1503-1507). This prediction is consistent with distributions derived from a number of ligand-gated channels at high agonist concentration (Millhauser, G. L., E. E. Salpeter, and R. E. Oswald. 1988b. Biophys. J. 54: 1165-1168.) but does not describe the behavior of ion channels at low activator concentrations. We examine here an extension of this model to include an agonist binding step. This extended model is consistent with the closed time distributions generated from the BC3H-1 nicotinic acetylcholine receptor for agonist concentrations varying over three orders of magnitude.

Animals↗
PubMed2001

Molecular modeling of ligand-gated ion channels: progress and challenges.

There has been rapid progress in molecular modeling of LGICs in recent years. The convergence of improved software for molecular mechanics/dynamics, techniques of chimeric substitution and site-directed mutations, and the first X-ray structures of transmembrane ion channels will make it possible to build reasonable models of neuronal ion channels well in advance of publication of their crystal structures. These models will not only serve as guides for future site-directed mutagenesis, but they will also be a starting point for understanding the dynamics of ion channel gating.

Amino Acid Sequence↗
PubMed1995

Proteins that interact with the pore-forming subunits of voltage-gated ion channels.

Voltage-gated ion channels are composed of pore-forming subunits, as well as auxiliary subunits that modify the functions of these channels. In addition, the channels interact with other modulatory proteins in a more transient manner, although with significant effects on channel activity. Even though many second-messenger systems influence the voltage-gated ion channels, only in a few cases has clear evidence for direct protein-protein interactions been demonstrated. Recent biochemical and genetic studies have helped to elucidate the scope of the interactions between these ion channels and various modulatory proteins by determining the structures and functions of nonpore-forming subunits.

Animals↗