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.     

Advancing proteomics with ion/ion chemistry

Mass spectrometers, instruments that use electric and/or magnetic fields to measure a gas-phase ion's mass-to-charge ratio (m/z), are used in a wide variety of applications--with the field having a reputation for providing good sensitivity and high-informing power. Protein analysis (proteomics) is a relatively recent affair for the field and was enabled in the late 1980s with the advent of biomolecule ionization methods such as electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI). Today, the area of protein analysis garners considerable attention from many in the mass spectrometry (MS) field; given the myriad of possible protein forms and their broad dynamic range (abundance) in the cell, the analytical challenge is paramount. Here we discuss a developing technology--ion/ion chemical reactions--that promises to transform how we think about and conduct protein sequence analysis via MS.     

Ligand-gated ion channels: mechanisms underlying ion selectivity

Anion/cation selectivity is a critical property of ion channels and underpins their physiological function. Recently, there have been numerous mutagenesis studies, which have mapped sites within the ion channel-forming segments of ligand-gated ion channels that are determinants of the ion selectivity. Site-directed mutations to specific amino acids within or flanking the M2 transmembrane segments of the anion-selective glycine, GABA(A) and GABA(C) receptors and the cation-selective nicotinic acetylcholine and serotonin (type 3) receptors have revealed discrete, equivalent regions within the ion channel that form the principal selectivity filter, leading to plausible molecular mechanisms and mathematical models to describe how ions preferentially permeate these channels. In particular, the dominant factor determining anion/cation selectivity seems to be the sign and exposure of charged amino acids lining the selectivity filter region of the open channel. In addition, the minimum pore diameter, which can be influenced by the presence of a local proline residue, also makes a contribution to such ion selectivity in LGICs with smaller diameters increasing anion/cation selectivity and larger ones decreasing it.     

Monovalent ion and calcium ion fluxes in sarcoplasmic reticulum

Summary The ion permeability of sarcoplasmic reticulum vesicles from skeletal and heart muscle has been characterized by radioisotope flux, osmotic and membrane potential measurements, and by incorporating vesicles into planar phospholipid bilayers. The sarcoplasmic reticulum membrane is uniquely permeable to various biologically relevant monovalent ions. At least two and possibly three separate passive permeation systems for monovalent ions have been identified: 1) a K⁺, Na⁺ channel, 2) an anion channel, and 3) a H⁺ (OH^–) permeable pathway which may or may not be synonymous with the anion channel. A possible physiological function of these monovalent ion permeation systems is to permit rapid movement of K⁺, Na⁺, H⁺ and Cl across the membrane to counter electrogenic Ca²⁺ fluxes during Ca²⁺ release and uptake by sacroplasmic reticulum.     

Microvillar ion channels: cytoskeletal modulation of ion fluxes

The recently presented theory of microvillar Ca(2+)signaling [Lange, K. (1999) J. Cell. Physiol.180, 19-35], combined with Manning's theory of "condensed counterions" in linear polyelectrolytes [Manning, G. S. (1969). J. Chem. Phys.51, 924-931] and the finding of cable-like ion conductance in actin filaments [Lin, E. C. & Cantiello, H. F. (1993). Biophys. J.65, 1371-1378], allows a systematic interpretation of the role of the actin cytoskeleton in ion channel regulation.Ion conduction through actin filament bundles of microvilli exhibits unique nonlinear transmission properties some of which closely resemble that of electronic semiconductors: (1) bundles of microfilaments display significant resistance to cation conduction and (2) this resistance is decreased by supply of additional energy either as thermal, mechanical or electromagnetic field energy. Other transmission properties, however, are unique for ionic conduction in polyelectrolytes. (1) Current pulses injected into the filaments were transformed into oscillating currents or even into several discrete charge pulses closely resembling that of single-channel recordings. Discontinuous transmission is due to the existence of counterion clouds along the fixed anionic charge centers of the polymer, each acting as an "ionic capacitor". (2) The conductivity of linear polyelectrolytes strongly decreases with the charge number of the counterions; thus, Ca(2+)and Mg(2+)are effective modulator of charge transfer through linear polyelectrolytes. Field-dependent formation of divalent cation plugs on either side of the microvillar conduction line may generate the characteristic gating behavior of cation channels. (3) Mechanical movement of actin filament bundles, e.g. bending of hair cell microvilli, generates charge translocations along the filament structure (mechano-electrical coupling). (4) Energy of external fields, by inducing molecular dipoles within the polyelectrolyte matrix, can be transformed into mechanical movement of the system (electro-mechanical coupling). Because ionic transmission through linear polyelectrolytes is very slow compared with electronic conduction, only low-frequency electromagnetic fields can interact with the condensed counterion systems of linear polyelectrolytes.The delineated characteristics of microvillar ion conduction are strongly supported by the phenomenon of electro-mechanical coupling (reverse transduction) in microvilli of the audioreceptor (hair) cells and the recently reported dynamics of Ca(2+)signaling in microvilli of audio- and photoreceptor cells. Due to the cell-specific expression of different types and combinations of ion channels and transporters in the microvillar tip membrane of differentiated cells, the functional properties of this cell surface organelle are highly variable serving a multitude of different cellular functions including receptor-mediated effects such as Ca(2+)signaling, regulation of glucose and amino acid transport, as well as modulation of membrane potential. Even mechanical channel activation involved in cell volume regulation can be deduced from the systematic properties of the microvillar channel concept. In addition, the specific ion conduction properties of microfilaments combined with their proposed role in Ca(2+)signaling make microvilli the most likely cellular site for the interaction with external electric and magnetic fields.     

Interaction of intracellular ion buffering with transmembrane-coupled ion transport

The role of the Na/Ca exchanger in the control of cellular excitability and tension development is a subject of current interest in cardiac physiology. It has been suggested that this coupled transporter is responsible for rapid changes in intracellular calcium activity during single beats, generation of plateau currents, which control action potential duration, and control of intracellular sodium during Na/K pump suppression, which may occur during terminal states of ischemia. The actual behavior of this exchanger is likely to be complex for several reasons. First, the exchanger transports two ionic species and thus its instantaneous flux rate depends on both intracellular sodium and calcium activity. Secondly, the alteration in intracellular calcium activity, which is caused by a given transmembrane calcium flux, and which controls the subsequent exchanger rate, is a complex function of available intracellular calcium buffering. The buffers convert the ongoing transmembrane calcium fluxes into changes in activity that are a small and variable fraction of the change in total calcium concentration. Using a number of simple assumptions, we model changes in intracellular calcium and sodium concentration under the influence of Na/Ca exchange, Na/K ATPase and Ca-ATPase pumps, and passive sodium and calcium currents during periods of suppression and reactivation of the Na/K ATPase pump. The goal is to see whether and to what extent general notions of the role of the Na/Ca exchanger used in planning and interpreting experimental studies are consistent with its function as derived from current mechanistic assumptions about the exchanger. We find, for example, that based on even very high estimates of intracellular calcium buffering, it is unlikely that Na/Ca exchange alone can control intracellular sodium during prolonged Na/K pump blockade. It is also shown that Na/Ca exchange can contaminate measurements of Na/K pump currents under a variety of experimental conditions. The way in which these and other functions are affected by the dissociation constants and total capacity of the intracellular calcium buffers are also explored in detail.     

Some physiological effects of air ion treatment without ion inhalation

A companion paper describes experiments in which only the nostrils of rats were exposed to ionized air. This paper gives results obtained from experiments similar, except that the bridge of the animal's nose was exposed to ions but inhalation of the ionized atmosphere was prevented. The heart rate was unaffected by negative air ion exposure, positive air ions caused depressed heartrate.Respiration rate was generally unaffected by ions although there was a possible final difference under negative air ion treatment.

---

Zusammenfassung In einer vorausgegangenen Arbeit wurde über Experimente berichtet, in denen nur die Nasenlöcher von Ratten ionisierter Luft ausgesetzt waren.Hier wurden die Ergebnisse von Ähnlichen Experimenten zusammengestellt,in denen nur die Umgebung der Nase von Ratten (enthaart) der ionisierten Luft ausgesetzt war und nicht die Atmung. Die Herzfrequenz blieb bei Einwirkung neg. Luftionen unverÄndert,bei Einwirkung pos. Luftionen war sie verlangsamt. Die Atemfrequenz blieb unbeeinflusst, es bestand jedoch die Möglichkeit einer Differenz am Ende der Behandlung mit neg. Ionen.

---

Resume Dans un mémoire précédent, on a rapporté sur des expériences faites en n'exposant que les narines de rats à de l'air ionisé.On donne ici le résultat d'essais semblables effectués en n'exposant que les alentours (rasés) des narines de rats à de l'air ionisé, mais à l'exclusion de l'air respiré. Les pulsations du coeur restèrent inchangées dans le cas d'ions négatifs, elles furent ralenties par des ions positifs. La respiration est restée la mÊme bien qu'une petite différence soit possible à la fin du traitement par ions négatifs.

     

IRBIT: A regulator of ion channels and ion transporters

IRBIT (also called AHCYL1) was originally identified as a binding protein of the intracellular Ca^2 + channel inositol 1,4,5-trisphosphate (IP₃) receptor and functions as an inhibitory regulator of this receptor. Unexpectedly, many functions have subsequently been identified for IRBIT including the activation of multiple ion channels and ion transporters, such as the Na⁺/HCO₃⁻ co-transporter NBCe1-B, the Na⁺/H⁺ exchanger NHE3, the Cl⁻ channel cystic fibrosis transmembrane conductance regulator (CFTR), and the Cl⁻/HCO₃⁻ exchanger Slc26a6. The characteristic serine-rich region in IRBIT plays a critical role in the functions of this protein. In this review, we describe the evolution, domain structure, expression pattern, and physiological roles of IRBIT and discuss the potential molecular mechanisms underlying the coordinated regulation of these diverse ion channels/transporters through IRBIT. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.     

Activation of potassium ion transport in mitochondria by cadmium ion

Low levels of Cd2+ (1-5 microM) produce rapid swelling of mitochondria, which is respiration-dependent and uncoupler-sensitive. No cation requirement is apparent, since the swelling occurs in a medium containing only sucrose and the respiratory substrate. The swelling is inhibited by ruthenium red, suggesting that this effect of Cd2+ requires its entry into mitochondria. In medium containing 9 mM K+, addition of Cd2+ along with ruthenium red increases the rate of K+ influx threefold. In the presence of K+, Rb+ or Li+, but not of Na+, addition of Cd2+ produces first efflux of H+ into the medium followed by discharge of the pH gradient or uncoupling. Only the latter effect is inhibited by ruthenium red, showing that the efflux and influx of H+ are independent reactions. The H+ efflux appears to be an antiport response to the induced K+ entry. Its activation by Cd2+ is similar to the known effect of p-chloromercuriphenyl sulfonate. The H+ influx or uncoupling appears to result from binding of Cd2+ to some matrix-facing membrane site, perhaps the dithiol group on coupling factor B, and may relate to apparent permeability changes associated Cd2+-induced swelling.     

Extracellular ion transport

It is a misconception to think that extracellular electric currents of biologic origin are carried by all of the ions in the extracellular medium. It is established that, for certain reasonable boundary conditions, only those ion species that are transported across the plasma membranes of the biological system, or that chemically derive from or contribute to these species, can contribute to the extracellular electric current at steady state. In the absence of convection, the extracellular current will be carried largely by diffusion of the transported ion species, at steady state. Extracellular electric potential gradients are shown to arise in a secondary manner, as a result of the electroneutrality condition. The effect of non-turbulent convection is included in the derivations and discussion.     

Mitochondrial ion channels

Ion channels are proteins, which facilitate the ions flow throught biological membranes. In recent years the structure as well as the function of the plasma membrane ion channels have been well investigated. The knowledge of intracellular ion channels however is still poor. Up till now, the calcium channel described in endoplasmatic reticulum and mitochondrial porine are the examples of intracellular ion channels, which have been well characterized. The mitochondrial potassium channels: regulated by ATP (mitoK(ATP)) and of big conductance activated by Ca2+ (mitoBK(Ca)), which were described in inner mitochondrial membrane, play a key role in the protection of heart muscle against ischemia. In this review the last date concerning the mitochondrial ion channels as well as they function in cell metabolism have been presented.