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PubMed2003

Basic concepts of ion channel physiology and anaesthetic drug effects.

Ion channels regulate a diversity of physiological functions such as neuronal signalling, cardiac excitability and immune cell response. All of these systems may be affected during the conduct of general as well as local anaesthesia. Thus, the investigation of anaesthetic action on ion channels has become the focus of an increasing number of laboratory studies. Consequently, the concepts of ion channel physiology are becoming important for understanding the scientific and pharmacological basis of clinical anaesthesia. This brief guide is intended to help in understanding the increasing number of studies concerned with the effects of anaesthetic agents on ionic currents. The generation of ionic currents requires a complex molecular interplay of ions, ion channel proteins and lipid membranes. Anaesthetic agents frequently exhibit more than a single effect on ion channel function. Their effects can be described by quantifying the pharmacological alteration of ion channel activation, conductance and inactivation. Many physiological functions are directly influenced by ion channels. Pharmacological action on ion channels is thus fundamental to effects as well as side-effects of anaesthetic agents. The alteration of ion channel function by anaesthetic agents consequently determines their clinical effects.

Anesthetics↗
PubMed2001

Ion-channel regulation by G proteins.

Ion channels are end-targets (effectors) in a large number of regulatory pathways that are initiated by G-protein-coupled neurotransmitters and hormones. Modulation of ion channels by G proteins can be indirect (via second messengers and protein kinases) or direct, via physical interactions between G-protein subunits and the channel protein. These direct physical interactions are the focus of this review. A direct regulation has been firmly established for several voltage-dependent Ca(2+) channels and the G-protein-activated K(+) channels. In these ion-channel families, the G-protein beta gamma subunits (G beta gamma) are the active regulators, whereas the role of the alpha subunits (G alpha) remains poorly understood. Accumulating evidence suggests that intricate relationships between the receptor, G alpha, G beta gamma and the ion channel play a major role in determining the specificity and magnitude of the overall regulation.

Animals↗
PubMed1991

Molecular aspects of voltage-dependent ion channels.

Voltage-dependent ion channels appear to form a large family whose individual structures suggest a lineage to a common ancestral channel protein. These channels share the feature of having a number (usually four or five) of homologous subunits or homologous internal repeat domains. Each contains a positively charged amphipathic helix at a conserved location within each of these subunits or repeat domains; voltage-dependent gating may be a property of this conserved S4 helix. In each channel, the ion pore itself is thought to be formed by contributions from helices of each of the subunits or domains which are themselves disposed in a pseudosymmetrical fashion around the aqueous pore. In spite of these similarities, each channel type, as well as subtypes within each type, exhibit unique kinetic and pharmacological properties, and varying patterns of tissue and cellular expression. Presumably these unique aspects of channel function are contributed by the variable regions of the protein structure and in this regard the cytoplasmic loops connecting the repeat domains or the amino- and carboxy-termini of the individual subunits may play a particular role. An appreciation of both the common aspects of channel structure and the unique characteristics of the specific channel of interest will be useful in determining its contribution to the pathobiology of hypertension and in planning therapeutic approaches in which the channel may play a role.

Amino Acid Sequence↗
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↗
PubMed2003

High throughput electrophysiology: new perspectives for ion channel drug discovery.

Proper function of ion channels is crucial for all living cells. Ion channel dysfunction may lead to a number of diseases, so-called channelopathies, and a number of common diseases, including epilepsy, arrhythmia, and type II diabetes, are primarily treated by drugs that modulate ion channels. A cornerstone in current drug discovery is high throughput screening assays which allow examination of the activity of specific ion channels though only to a limited extent. Conventional patch clamp remains the sole technique with sufficiently high time resolution and sensitivity required for precise and direct characterization of ion channel properties. However, patch clamp is a slow, labor-intensive, and thus expensive, technique. New techniques combining the reliability and high information content of patch clamping with the virtues of high throughput philosophy are emerging and predicted to make a number of ion channel targets accessible for drug screening. Specifically, genuine HTS parallel processing techniques based on arrays of planar silicon chips are being developed, but also lower throughput sequential techniques may be of value in compound screening, lead optimization, and safety screening. The introduction of new powerful HTS electrophysiological techniques is predicted to cause a revolution in ion channel drug discovery.

Animals↗
PubMed2004

Mechanisms of channel gating of the ligand-gated ion channel superfamily inferred from protein structure.

The nicotinic-like ligand-gated ion channel superfamily consists of a group of structurally related receptors that activate an ion channel after the binding of extracellular ligand. The recent publications of the crystal structure of an acetylcholine binding protein and a refined electron micrograph structure of the membrane-bound segment of an acetylcholine receptor have led to insights into the molecular determinants of receptor function. Although the structures confirmed much biochemical and electrophysiological data obtained about the receptors, they also provide opportunities to study further the mechanisms that allow channel activation stimulated by ligand-binding. Here we review the mechanisms of channel gating that have been elucidated by information gained from the structures of the acetylcholine binding protein and membrane-bound segment of the acetylcholine receptor.

Acetylcholine↗
PubMed1992

The roles of serine and threonine sidechains in ion channels: a modelling study.

The ion channel of the nicotinic acetylcholine receptor (nAChR) is believed to be lined by transmembrane M2 helices. A "4-8-12" sequence motif, comprising serine (S) or threonine (T) residues at positions 4, 8 and 12 of M2, is conserved between different members, anion and cation selective, of the nAChR superfamily. Parallel bundles of 4-8-12 motif-containing helices are considered as simplified models of ion channels. The relationship between S and T sidechain conformations and channel-ion interactions is explored via evaluation of interaction energies of K+ and of Cl- ions with channel models. Energy calculations are used to determine optimal chi 2 (C alpha-C beta-O gamma-H gamma) values in the presence of K+ or Cl- ions. 4-8-12 motif-containing bundles may form favourable interactions with either cations or anions, dependent upon the chi 2 values adopted. Parallel-helix and tilted-helix bundles are considered, as are heteromeric models designed to mimic the Torpedo nAChR. The main conclusion of the study is that conformational flexibility at chi 2 enables both S and T residues to form favourable interactions with anions or cations. Consequently, there is apparently no difference between S and T residues in their interactions with permeant ions, which suggests that the presence of T vs. S residues within the 4-8-12 motif is not a major mechanism whereby anion/cation selectivity may be generated. The implications of these studies with respect to more elaborate models of nAChR and related receptors are considered.

Amino Acid Sequence↗
PubMed2006

Peptides inhibitors of acid-sensing ion channels.

Acid-sensing ion channels (ASICs) channels are proton-gated cationic channels mainly expressed in central and peripheric nervous system and related to the epithelial amiloride-sensitive Na(+) channels and to the degenerin family of ion channels. ASICs comprise four proteins forming functional channel subunits (ASIC1a, ASIC1b, ASIC2a, and ASIC3) and two proteins (ASIC2b and ASIC4) without yet known activators. Functional channels are activated by external pH variations ranging from pH(0.5) 6.8 to 4.0 and currents are characterized by either rapid kinetics of inactivation (ASIC1a, ASIC1b, ASIC3) or slow kinetics of inactivation (ASIC2a) and sometimes the presence of a plateau phase (ASIC3). ASIC1a and ASIC3, which are expressed in nociceptive neurons, have been implicated in inflammation and knockout mice studies support the role of ASIC3 in various pain processes. ASIC1a seems more related to synaptic plasticity, memory, learning and fear conditioning in the CNS. ASIC2a contributes to hearing in the cochlea, sour taste sensation, and visual transduction in the retina. The pharmacology of ASICs is limited to rather nonselective drugs such as amiloride, nonsteroid anti-inflammatory drugs, and neuropeptides. Recently, two peptides, PcTx1 and APETx2, isolated from a spider and a sea anemone, have been characterized as selective and high-affinity inhibitors for ASIC1a and ASIC3 channels, respectively. PcTx1 inhibits ASIC1a homomers with an affinity of 0.7 nM (IC(50)) without any effect on ASIC1a containing heteromers and thus helped to characterize ASIC1a homomeric channels in peripheric and central neurons. PcTx1 acts as a gating modifier since it shifts the channel from the resting to an inactivated state by increasing its affinity for H(+). APETx2 is less selective since it inhibits several ASIC3-containing channels (IC(50) from 63 nM to 2 microM) and to date its mode of action is unknown. Nevertheless, APETx2 structure is related to other sea anemone peptides, which act as gating modifiers on Nav and Kv channels.

Acid Sensing Ion Channels↗
PubMed1996

Ion channels in the sarcoplasmic reticulum of striated muscle.

This review provides a summary of current concepts about the structure and single-channel properties of ryanodine receptor calcium release channels and counter ion channels that facilitate Ca2+ release and reuptake by the sarcoplasmic reticulum. Some recent results, obtained with single ryanodine receptor ion channels incorporated into lipid bilayers from terminal cisternae vesicles of rabbit skeletal muscle and sheep ventricular myocardium, are described. The ryanodine receptor is the major Ca2+ release channel in skeletal and cardiac muscle and has been studied in far greater detail than other sarcoplasmic reticulum ion channel proteins. Several ryanodine receptor genes have been cloned and sequenced, and isoforms of the protein have been detected in muscle and in endoplasmic reticulum of brain and many other tissues from mammals, lower vertebrates, nematodes and drosophila. The proteins from all species are tetramers of a peptide with a molecular mass of approximately equal to 560 kDa, containing approximately equal to 5000 amino acids, with a similar maximum single-channel conductance of 500-800 row S for monovalent cations at 250mM. Results presented here include: Ca2+ activation and adaptation of activity in skeletal ryanodine receptors with rapid changes in [Ca2+] controlled by perfusion; activation by FK506 and regulation of cooperative gating of skeletal ryanodine receptor channel activity by FK506-binding proteins; activation and block of cardiac ryanodine receptors by addition of reactive disulphides and by bilayer voltage. Effects of phosphorylation, calmodulin, triadin, calsequestrin and interactions with the alpha 1 subunit of the dihydropyridine receptor on ryanodine receptor activity are summarized. Potassium and chloride channels in skeletal muscle sarcoplasmic reticulum, are described.

Animals↗
PubMed2004

Artificial ion channel formed by cucurbit[n]uril derivatives with a carbonyl group fringed portal reminiscent of the selectivity filter of K+ channels.

Novel artificial ion channels (1 and 2) based on CB[n] (n = 6 and 5, respectively) synthetic receptors with carbonyl-fringed portals (diameter 3.9 and 2.4 A, respectively) can transport proton and alkali metal ions across a lipid membrane with ion selectivity. Fluorometric experiments using large unilamellar vesicles showed that 1 mediates proton transport across the membranes, which can be blocked by a neurotransmitter, acetylcholine, reminiscent of the blocking of the K+ channels by polyamines. The alkali metal ion transport activity of 1 follows the order of Li+ > Cs+ approximately Rb+ > K+ > Na+, which is opposite to the binding affinity of CB[6] toward alkali metal ions. On the other hand, the transport activity of 2 follows the order of Li+ > Na+, which is also opposite to the binding affinity of 2 toward these metal ions, but virtually no transport was observed for K+, Rb+, and Cs+. It is presumably because the carbonyl-fringed portal size of 2 (diameter 2.4 A) is smaller than the diameters of these alkali metal ions. To determine the transport mechanism, voltage-clamp experiments on planar bilayer lipid membranes were carried out. The experiments showed that a single-channel current of 1 for Cs+ transport is approximately 5 pA, which corresponds to an ion flux of approximately 3 x 107 ions/s. These results are consistent with an ion channel mechanism. Not only the structural resemblance to the selectivity filter of K+ channels but also the remarkable ion selectivity makes this model system unique.

Biomimetic Materials↗
PubMedDate not supplied

Ion channels: structure and function.

Ion channels are ubiquitous membrane proteins in mammalian cells. Their critical physiological roles include control of the electrical potential across the membrane, facilitation of neuromuscular and neuronal transmission, signal transduction, and regulation of secretion and contractility. The alliance of techniques in biochemistry, electrophysiology, pharmacology, and molecular biology has provided insights into the three-dimensional structure of channel proteins and has allowed specific aspects of functional correlates to be better understood. Promises for the future include molecular genetic approaches to the treatment of disorders such as long QT syndrome and more rational design of drugs targeted to ion channels, including antiarrhythmic agents.

Action Potentials↗
PubMed1996

[Molecular structure and expression of ion channels in the heart].

Ion channels are essential for the generation and maintenance of the cardiac action potential. The successful cloning of ion channels has shed considerable light into their structure and function. The combination of molecular biological and electrophysiological studies has paved the ground to develop general concepts for understanding properties of these channels, such as gating mechanism, kinetics of activation and inactivation, ion selectivity and pharmacological properties. Recently, several cDNAs encoding cardiac inwardly rectifying K+ channels, including classical inwardly rectifying, G-protein-gated, and ATP-sensitive K+ channels, have been isolated. Identification of these molecular mechanisms may point to novel approaches to the treatment of cardiac arrhythmias. This review focuses on the molecular properties and functional roles of cardiac ion channels.

Adenosine Triphosphate↗
PubMed1996

Ion channel associated proteins.

Neuronal ion channels are directly associated in vivo with a wide variety of proteins. New classes of channel-associated proteins have been identified recently, including the PSD-95/SAP90 family of channel-clustering molecules and components of the synaptic vesicle release machinery. Recent findings suggest that non-pore-forming subunits of ion channels may also have cell biological functions independent of their effects on channel electrophysiological properties.

Animals↗
PubMed1992

Photodynamic inactivation of an ion channel: gramicidin A.

The ion channel formed by the peptide gramicidin A in planar lipid membranes is inactivated by visible light in the presence of the photosensitizer Rose Bengal. This is concluded from the strong decrease of the membrane conductance by more than two orders of magnitude. Experiments performed at different oxygen concentrations, in the presence of the singlet oxygen quenchers beta-carotene or alpha-tocopherol indicate, that presumably a type I process between the dye Rose Bengal and the tryptophan residues of the gramicidin channel with a subsequent oxidation of the tryptophans is responsible for the loss of the conductance properties of the channel.

Amino Acid Sequence↗
PubMed2004

Ion channels and lymphocyte activation.

The ion channels expressed by T lymphocytes play key roles in the control of the membrane potential and calcium signaling, thereby affecting signal transduction pathways that lead to the activation of these cells following antigenic stimulation. Disruption of these pathways can attenuate or prevent the response of T-cells to antigenic challenge resulting in immune suppression. Studies using ion channel blockers of high affinity and specificity have shown that this interference can be achieved at the level of ion channels. Suppression of immune functions by channel blockers has been demonstrated in vitro and in vivo. New information about the molecular structure of ion channels facilitates the design of more potent and more specific inhibitors. Thus, T-cell ion channels are likely to serve as targets for immunomodulatory drugs in the near future. Here, the biophysical properties, tissue distribution, regulation of expression, molecular pharmacology and role in T-cell activation of the voltage-gated Kv1.3 and the Ca(2+)-activated IKCa1 potassium channels and those of the Ca(+) release-activated Ca(2+) (CRAC) channel are reviewed.

Animals↗
PubMed2003

TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions.

Trace metal ions such as Zn(2+), Fe(2+), Cu(2+), Mn(2+), and Co(2+) are required cofactors for many essential cellular enzymes, yet little is known about the mechanisms through which they enter into cells. We have shown previously that the widely expressed ion channel TRPM7 (LTRPC7, ChaK1, TRP-PLIK) functions as a Ca(2+)- and Mg(2+)-permeable cation channel, whose activity is regulated by intracellular Mg(2+) and Mg(2+).ATP and have designated native TRPM7-mediated currents as magnesium-nucleotide-regulated metal ion currents (MagNuM). Here we report that heterologously overexpressed TRPM7 in HEK-293 cells conducts a range of essential and toxic divalent metal ions with strong preference for Zn(2+) and Ni(2+), which both permeate TRPM7 up to four times better than Ca(2+). Similarly, native MagNuM currents are also able to support Zn(2+) entry. Furthermore, TRPM7 allows other essential metals such as Mn(2+) and Co(2+) to permeate, and permits significant entry of nonphysiologic or toxic metals such as Cd(2+), Ba(2+), and Sr(2+). Equimolar replacement studies substituting 10 mM Ca(2+) with the respective divalent ions reveal a unique permeation profile for TRPM7 with a permeability sequence of Zn(2+) approximately Ni(2+) >> Ba(2+) > Co(2+) > Mg(2+) >/= Mn(2+) >/= Sr(2+) >/= Cd(2+) >/= Ca(2+), while trivalent ions such as La(3+) and Gd(3+) are not measurably permeable. With the exception of Mg(2+), which exerts strong negative feedback from the intracellular side of the pore, this sequence is faithfully maintained when isotonic solutions of these divalent cations are used. Fura-2 quenching experiments with Mn(2+), Co(2+), or Ni(2+) suggest that these can be transported by TRPM7 in the presence of physiological levels of Ca(2+) and Mg(2+), suggesting that TRPM7 represents a novel ion-channel mechanism for cellular metal ion entry into vertebrate cells.

Animals↗
PubMed1989

Block of stretch-activated ion channels in Xenopus oocytes by gadolinium and calcium ions.

Gadolinium ions produce three distinct kinds of block of the stretch-activated (SA) ion channels in Xenopus oocytes: a concentration-dependent reduction in channel open time, a concentration-dependent reduction in open channel current, and a unique, steeply concentration-dependent, reversible inhibition of channel opening. This last effect reduces the probability of a channel being open from about 10(-1) at 5 microM to less than 10(-5) at 10 microM gadolinium. Calcium has effects on open time and current similar to that of gadolinium, but this channel is permeable to calcium and calcium does not completely inhibit channel activity. The availability of a blocker for SA ion channels may help to define their physiological function, and will simplify the use of oocytes as an expression system for ion channels.

Animals↗
PubMed1987

Effects of ionizing radiation on artificial (planar) lipid membranes. I. Radiation inactivation of the ion channel gramicidin A.

The ion channel formed by the pentadecapeptide gramicidin A in planar lipid membranes is extremely sensitive to ionizing radiation. The membrane conductance may drop by several orders of magnitude under appropriate experimental conditions (low pH and presence of oxygen). The radiation sensitivity is strongly reduced for gramicidin M-. This analogue has the four tryptophan residues replaced by phenylalanines. Experiments performed in the presence of various radical scavengers suggest that the inactivation of the channel is due to a combined action of OH and of HO2 radicals at the tryptophan residues. The shape of the inactivation curves following continuous radiolysis or pulse radiolysis were found to be in fair agreement with a simple model which assumes that the damage of a single tryptophan residue is sufficient for channel inactivation. The conductance of inactivated channels could not be resolved within the experimental accuracy. This is contrary to photolysis of gramicidin channels found by Busath and Waldbilling (1983), where a broad distribution of low conductance states was observed. The inactivation by radiolysis seems to represent an 'all-or-none-process' of the channel conductance.

Dose-Response Relationship, Radiation↗