Amplification of small signals by voltage-gated sodium channels in drone photoreceptors

Summary Photoreceptor cells of the drone,Apismellifera , have a voltage-gated Na⁺ membrane conductance that can be blocked by tetrodotoxin (TTX) and generates an action potential on abrupt depolarization: an action potential is triggered by the rising phase of a receptor potential evoked by an intense light flash (Autrum and von Zwehl 1964; Baumann 1968). We measured the intracellular voltage response to a small (9%), brief (30 ms) decrease in light intensity from a background, and found that its amplitude was decreased by 1M TTX. The response amplitude was maximal when the background intensity depolarized the cell to –38 mV. With intensities depolarizing the cell membrane to –45 to –33 mV the average response amplitude was decreased by TTX from 1.2mV to 0.5mV. TTX is also known to decrease the voltage noise during steady illumination (Ferraro et al. 1983) but, despite this, the ratio of peak-to-peak signal to noise was, on average, decreased by TTX. The results suggest that drone photoreceptors use voltage-gated Na⁺ channels for graded amplification of responses to small, rapid changes in light intensity.Abbreviations TTX tetrodotoxin - V _i intracellular potential with respect to the bath - V _o extracellular potential - V _m,V _i-V _o approximate transmembrane potential - S amplitude of the voltage response to an 8.9% decrease in light intensity - N voltage noise, usually measured as root mean square voltage deviation as described in Methods     

Regulation of ion channels by integrins

Ion channels are regulated by protein phosphorylation and dephosphorylation of serine, threonine, and tyrosine residues. Evidence for regulation of channels by tyrosine phosphorylation comes primarily from investigations of the effects of growth factors, which act through receptor tyrosine kinases. The purpose of the present work is to summarize evidence for the regulation of ion channels by integrins, through their downstream, nonreceptor tyrosine kinases. We review both direct and indirect evidence for this regulation, with particular emphasis on Ca2+-activated K+ and voltage-gated Ca2+ channels. We then discuss the critical roles that cytoskeletal, focal-adhesion, and channel-associated scaffolding proteins may play in localizing nonreceptor tyrosine kinases to the vicinity of ion channels. We conclude by speculating on the physiological significance of these regulatory pathways.     

Can electromagnetic radiations induce changes in the kinetics of voltage-dependent ion channels?

Ion channels are protein molecules, which can assume distinct open and closed conformational states, a phenomenon termed ion channel kinetics. The transitions from one state to another depend on the potential energy barrier that separates those two states. Therefore, it is rational to suppose that electromagnetic waves could interact with this barrier and induce changes in the rate transitions of this kinetic process. Our aim is to answer the question: can electromagnetic radiations induce changes in the kinetics of voltage-dependent ion channels? We simulated the effects of the low and high frequency electromagnetic waves on the sodium and potassium channels of the giant axon of Loligo. The key parameter measured was the fractional open time (fv), because it reflects the voltage dependence of the kinetics of channels. The electromagnetic radiations induced the following changes in the kinetics of the potassium and sodium channels: i/ low frequency waves kept the potassium channel 50% of the time open independent on the mean voltage applied through the membrane; ii/ a gradual inhibition of the inactivation on the sodium channel, when the amplitudes of the low frequency waves were increased; iii/ high frequency waves on the potassium channel, decreased both Vo (voltage in which the channel stays 50% open) and the steepness of fv (d fv/dV) as the amplitudes of the waves increased, and iv/ high frequency and low amplitude radiations on the sodium channel decreased the maximum value of fv (in relation to control), while high amplitudes increased this value. In conclusion, high and low frequency electromagnetic radiations were able to change the kinetics of the potassium and sodium channels in a squid giant axon model.     

Functional modifications of acid-sensing ion channels by ligand-gated chloride channels

Together, acid-sensing ion channels (ASICs) and epithelial sodium channels (ENaC) constitute the majority of voltage-independent sodium channels in mammals. ENaC is regulated by a chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Here we show that ASICs were reversibly inhibited by activation of GABA(A) receptors in murine hippocampal neurons. This inhibition of ASICs required opening of the chloride channels but occurred with both outward and inward GABA(A) receptor-mediated currents. Moreover, activation of the GABA(A) receptors modified the pharmacological features and kinetic properties of the ASIC currents, including the time course of activation, desensitization and deactivation. Modification of ASICs by open GABA(A) receptors was also observed in both nucleated patches and outside-out patches excised from hippocampal neurons. Interestingly, ASICs and GABA(A) receptors interacted to regulate synaptic plasticity in CA1 hippocampal slices. The activation of glycine receptors, which are similar to GABA(A) receptors, also modified ASICs in spinal neurons. We conclude that GABA(A) receptors and glycine receptors modify ASICs in neurons through mechanisms that require the opening of chloride channels.     

The ion channels coded by viruses

Pathogenicity and virulence are multifactorial traits, depending on interaction of viruses with susceptible cells and organisms. The ion channels coded by viruses, viroporins, represent only one factor taking part in the cascade of interactions between virus and cell, leading to the entry of virus, replication and to profound changes in membrane permeability. The M2 protein from influenza A virus forms proton-selective, pH-regulated channel involved in regulating vesicular pH, a function important for the correct maturation of HA glycoprotein. The NB glycoprotein of influenza B viruses is an integral membrane protein with an ion channel activity. The CM2 protein of influenza C virus is an integral membrane glycoprotein structurally analogous to influenza A virus M2 and influenza B virus NB proteins. The picornavirus 3A protein is involved in cell lysis and shows homology with other lytic proteins. Vpu is an oligomeric integral membrane protein encoded by HIV-1, which forms ion channels. The togavirus 6K protein shows structural similarities with other viroporins.     

Diseases caused by voltage-gated ion channels

Ion channels regulate the transfer of ions between the outer and the inner surface of the cell membrane. The opening of ion channels may be triggered by the binding of a ligand or variations in the membrane potential. Voltage-gated ion channels are an important class of such channels, that are involved in the generation and propagation of action potentials and play a key role in cell to cell communication. As a consequence of cloning and sequencing of ion channel genes, their role in diseases affecting excitable tissues such as the nervous system, heart and skeletal muscle has been examined, and a new class of diseases has emerged. We will review disorders caused by mutations in voltage-gated ion channels affecting these excitable tissues as well as non-excitable tissues such as the kidney. The clinician should be aware of this new class of diseases because pharmacological agents modulating channel functions are available. Characterization of these gene defects should lead to better treatment of these disorders.     

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.     

Mechanosensitive ion channels

The article concentrates on the concepts of mechanosensitive ion channels that are present in practically all cells of an organism. Considered are kinetic scheme and activation principles of mechanic-sensitive ion channels. The forces affecting those channels are discussed in detail. The qualities of the channels in lipid monolayer, bilayer and real cell membrane are under consideration. Discussed are various models that analyze possibilities of channel opening depending on the membrane tension. Under discussion are the data received from studying single channels, currents in whole-cell configuration and cloned channels built into bilayer, liposomes and membrane blebs. Problems of transmitting mechanic energy to the channel through the bilayer and through the cytoskeleton are investigated. Inhibitors and activators of mechanosensitive ion channels are mentioned and their effects are considered. The functional classification of mechanosensitive ion channels is given. Described are cation SACs, potassium SACs, Ca(2+)-sensitive and Ca(2+)-insensitive SACs, anion SACs, nonselective SACs and SICs. It is proved that mechanosensitive ion channels can produce considerable currents enough to change the cell electrogenesis.     

Regulation of epithelial ion channels by Rab GTPases

Epithelial ion channels are crucial to many of life's processes and disruption of their functions can lead to several disorders. Cystic fibrosis, an autosomal recessive disorder, is caused by defects in the biosynthesis or function of the CFTR chloride channel. Similarly, mutations in certain ENaC genes leading to increased or reduced channel activity cause diseases such as Liddle's syndrome or PHA. In order for ion channel proteins to be functional they need to be expressed on the plasma membrane. Thus, molecules that modulate the trafficking of ion channels to and from the membrane are of utmost significance. Among the numerous factors that regulate their functioning is a family of small GTPases known as Rab proteins. While Rabs have always played a pivotal role in membrane trafficking, their diversity of functions and plethora of interacting partners have lately been brought to light. Recent studies reveal that multiple Rab isoforms physically interact with and/or modulate the activity of several ion channels. Rab proteins have the ability to serve as molecular switches and many of the ion channels are regulated differentially by the GTP- or GDP-bound Rab isoforms. This review examines the role of Rab GTPases in the trafficking of ion channels, including CFTR, ENaC, TRPV5/6, and aquaporins, based on recent evidence.     

The properties of ion channels formed by zervamicins

The zervamicins (Zrv) are a family of 16 residue peptaibol channel formers, related to the 20 residue peptaibol alamethicin (Alm), but containing a higher proportion of polar sidechains. Zrv-1113 forms multi-level channels in planar lipid (diphytanoyl phosphatidylcholine) bilayers in response to cis positive voltages. Analysis of the voltage and concentration dependence of macroscopic conductances induced by Zrv-IIB suggests that, on average, channels contain ca. 13 peptide monomers. Analysis of single channel conductance levels suggests a similar value. The pattern of successive conductance levels is consistent with a modified helix bundle model in which the higher order bundle are distorted within the plane of the bilayer towards a torpedo shaped cross-section. The kinetics of intro-burst switching between adjacent conductance levels are shown to be approximately an order of magnitude faster for Zrv-IIB than for Alm. The channel forming properties of the related naturally occurring peptaibols, Zrv-Leu and Zrv-IC, have also been demonstrated, as have those of the synthetic apolar analogue Zrv-Al-16. The experimental studies on channel formation are combined with the known crystallographic structures of Zrv-Al-16 and Zrv-Leu to develop a molecular model of Zrv-II3 channels.Abbreviations Alm Alamethicin - Zrv Zervamicin - CFP Channel forming peptide - Aib -aminoisobutyric acid Correspondence to: M. S. P. Sansom     

Regulation of ion channels by phosphatidylinositol 4,5-bisphosphate

Phosphatidylinositol 4,5-bisphosphate is a signaling phospholipid of the plasma membrane that has a dynamically changing concentration. In addition to being the precursor of inositol trisphosphate and diacylglycerol, it complexes with and regulates many cytoplasmic and membrane proteins. Recent work has characterized the regulation of a wide range of ion channels by phosphatidylinositol 4,5-bisphosphate, helping to redefine the role of this lipid in cells and in neurobiology. In most cases, phosphatidylinositol 4,5-bisphosphate increases channel activity, and its hydrolysis by phospholipase C reduces channel activity.