scholarly journals Ion channel regulation by protein S-acylation

2014 ◽  
Vol 143 (6) ◽  
pp. 659-678 ◽  
Author(s):  
Michael J. Shipston
Keyword(s):  
Life Cycle ◽  
Ion Channels ◽  
Ion Channel ◽  
Physiological Function ◽  
Protein S ◽  
Cysteine Residues ◽  
Acid Modification ◽  
Ion Channel Regulation ◽  
Channel Function ◽  
Voltage Gated Ion Channels

Protein S-acylation, the reversible covalent fatty-acid modification of cysteine residues, has emerged as a dynamic posttranslational modification (PTM) that controls the diversity, life cycle, and physiological function of numerous ligand- and voltage-gated ion channels. S-acylation is enzymatically mediated by a diverse family of acyltransferases (zDHHCs) and is reversed by acylthioesterases. However, for most ion channels, the dynamics and subcellular localization at which S-acylation and deacylation cycles occur are not known. S-acylation can control the two fundamental determinants of ion channel function: (1) the number of channels resident in a membrane and (2) the activity of the channel at the membrane. It controls the former by regulating channel trafficking and the latter by controlling channel kinetics and modulation by other PTMs. Ion channel function may be modulated by S-acylation of both pore-forming and regulatory subunits as well as through control of adapter, signaling, and scaffolding proteins in ion channel complexes. Importantly, cross-talk of S-acylation with other PTMs of both cysteine residues by themselves and neighboring sites of phosphorylation is an emerging concept in the control of ion channel physiology. In this review, I discuss the fundamentals of protein S-acylation and the tools available to investigate ion channel S-acylation. The mechanisms and role of S-acylation in controlling diverse stages of the ion channel life cycle and its effect on ion channel function are highlighted. Finally, I discuss future goals and challenges for the field to understand both the mechanistic basis for S-acylation control of ion channels and the functional consequence and implications for understanding the physiological function of ion channel S-acylation in health and disease.

Ion channel regulation by G proteins

1995 ◽  
Vol 75 (4) ◽  
pp. 865-885 ◽  
Author(s):  
K. Wickman ◽  
D. E. Clapham
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
G Protein ◽  
G Proteins ◽  
Second Messengers ◽  
Channel Activity ◽  
Ion Channel Regulation ◽  
Protein Subunits ◽  
Channel Regulation ◽  
Intracellular Cascades

Ion channels are poised uniquely to initiate, mediate, or regulate such distinct cellular activities as action potential propagation, secretion, and gene transcription. In retrospect, it is not surprising that studies of ion channels have revealed considerable diversities in their primary structures, regulation, and expression. From a functional standpoint, the various mechanisms coopted by cells to regulate channel activity are particularly fascinating. Extracellular ligands, membrane potential, phosphorylation, ions themselves, and diffusible second messengers are all well-established regulators of ion channel activity. Heterotrimeric GTP-binding proteins (G proteins) mediate many of these types of ion channel regulation by stimulating or inhibiting phosphorylation pathways, initiating intracellular cascades leading to elevation of cytosolic Ca2+ or adenosine 3',5'-cyclic monophosphate levels, or by generating various lipid-derived compounds. In some cases, it seems that activated G protein subunits can interact directly with ion channels to elicit regulation. Although there is currently little direct biochemical evidence to support such a mechanism, it is the working hypothesis for the most-studied G protein-regulated ion channels.

scholarly journals Supramolecular Assemblies and Localized Regulation of Voltage-Gated Ion Channels

2009 ◽  
Vol 89 (2) ◽  
pp. 411-452 ◽  
Author(s):  
Shuiping Dai ◽  
Duane D. Hall ◽  
Johannes W. Hell
Keyword(s):  
Ion Channels ◽  
Glutamate Receptors ◽  
Ryanodine Receptor ◽  
Ion Channel Regulation ◽  
Voltage Gated ◽  
Signaling Complex ◽  
Channel Regulation ◽  
Fight Or Flight Response ◽  
Voltage Gated Ion Channels ◽  
Gated Ion Channels

This review addresses the localized regulation of voltage-gated ion channels by phosphorylation. Comprehensive data on channel regulation by associated protein kinases, phosphatases, and related regulatory proteins are mainly available for voltage-gated Ca2+ channels, which form the main focus of this review. Other voltage-gated ion channels and especially Kv7.1-3 (KCNQ1-3), the large- and small-conductance Ca2+-activated K+ channels BK and SK2, and the inward-rectifying K+ channels Kir3 have also been studied to quite some extent and will be included. Regulation of the L-type Ca2+ channel Cav1.2 by PKA has been studied most thoroughly as it underlies the cardiac fight-or-flight response. A prototypical Cav1.2 signaling complex containing the β2 adrenergic receptor, the heterotrimeric G protein Gs, adenylyl cyclase, and PKA has been identified that supports highly localized via cAMP. The type 2 ryanodine receptor as well as AMPA- and NMDA-type glutamate receptors are in close proximity to Cav1.2 in cardiomyocytes and neurons, respectively, yet independently anchor PKA, CaMKII, and the serine/threonine phosphatases PP1, PP2A, and PP2B, as is discussed in detail. Descriptions of the structural and functional aspects of the interactions of PKA, PKC, CaMKII, Src, and various phosphatases with Cav1.2 will include comparisons with analogous interactions with other channels such as the ryanodine receptor or ionotropic glutamate receptors. Regulation of Na+ and K+ channel phosphorylation complexes will be discussed in separate papers. This review is thus intended for readers interested in ion channel regulation or in localization of kinases, phosphatases, and their upstream regulators.

Regulation of ion transport by oxidants

2013 ◽  
Vol 305 (9) ◽  
pp. L595-L603 ◽  
Author(s):  
Charles A. Downs ◽  
My N. Helms
Keyword(s):  
Oxidative Stress ◽  
Ion Channels ◽  
Ion Channel ◽  
Redox Regulation ◽  
Experimental Biology ◽  
Cellular Functions ◽  
Ion Channel Regulation ◽  
Channel Regulation ◽  
Made In

Ion channels perform a variety of cellular functions in lung epithelia. Oxidant- and antioxidant-mediated mechanisms (that is, redox regulation) of ion channels are areas of intense research. Significant progress has been made in our understanding of redox regulation of ion channels since the last Experimental Biology report in 2003. Advancements include: 1) identification of nonphagocytic NADPH oxidases as sources of regulated reactive species (RS) production in epithelia, 2) an understanding that excessive treatment with antioxidants can result in greater oxidative stress, and 3) characterization of novel RS signaling pathways that converge upon ion channel regulation. These advancements, as discussed at the 2013 Experimental Biology Meeting in Boston, MA, impact our understanding of oxidative stress in the lung, and, in particular, illustrate that the redox state has profound effects on ion channel and cellular function.

Voltage-Gated Ion Channels and Hereditary Disease

1999 ◽  
Vol 79 (4) ◽  
pp. 1317-1372 ◽  
Author(s):  
Frank Lehmann-Horn ◽  
Karin Jurkat-Rott
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Recombinant Dna ◽  
Hereditary Disease ◽  
Hereditary Diseases ◽  
Technological Advancement ◽  
Myotonia Congenita ◽  
Voltage Gated ◽  
Voltage Gated Ion Channels ◽  
Gated Ion Channels

By the introduction of technological advancement in methods of structural analysis, electronics, and recombinant DNA techniques, research in physiology has become molecular. Additionally, focus of interest has been moving away from classical physiology to become increasingly centered on mechanisms of disease. A wonderful example for this development, as evident by this review, is the field of ion channel research which would not be nearly as advanced had it not been for human diseases to clarify. It is for this reason that structure-function relationships and ion channel electrophysiology cannot be separated from the genetic and clinical description of ion channelopathies. Unique among reviews of this topic is that all known human hereditary diseases of voltage-gated ion channels are described covering various fields of medicine such as neurology (nocturnal frontal lobe epilepsy, benign neonatal convulsions, episodic ataxia, hemiplegic migraine, deafness, stationary night blindness), nephrology (X-linked recessive nephrolithiasis, Bartter), myology (hypokalemic and hyperkalemic periodic paralysis, myotonia congenita, paramyotonia, malignant hyperthermia), cardiology (LQT syndrome), and interesting parallels in mechanisms of disease emphasized. Likewise, all types of voltage-gated ion channels for cations (sodium, calcium, and potassium channels) and anions (chloride channels) are described together with all knowledge about pharmacology, structure, expression, isoforms, and encoding genes.

scholarly journals PIP2: A critical regulator of vascular ion channels hiding in plain sight

2020 ◽  
Vol 117 (34) ◽  
pp. 20378-20389 ◽  
Author(s):  
Osama F. Harraz ◽  
David Hill-Eubanks ◽  
Mark T. Nelson
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Intracellular Signaling ◽  
Vascular Function ◽  
Current Knowledge ◽  
Ion Channel Regulation ◽  
Channel Regulation ◽  
Scant Attention ◽  
Blood Flow Control ◽  
Hydrolysis Of

The phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP2), has long been established as a major contributor to intracellular signaling, primarily by virtue of its role as a substrate for phospholipase C (PLC). Signaling by Gq-protein–coupled receptors triggers PLC-mediated hydrolysis of PIP2into inositol 1,4,5-trisphosphate and diacylglycerol, which are well known to modulate vascular ion channel activity. Often overlooked, however, is the role PIP2itself plays in this regulation. Although numerous reports have demonstrated that PIP2is critical for ion channel regulation, how it impacts vascular function has received scant attention. In this review, we focus on PIP2as a regulator of ion channels in smooth muscle cells and endothelial cells—the two major classes of vascular cells. We further address the concerted effects of such regulation on vascular function and blood flow control. We close with a consideration of current knowledge regarding disruption of PIP2regulation of vascular ion channels in disease.

scholarly journals Role of lysophosphatidic acid in ion channel function and disease

2018 ◽  
Vol 120 (3) ◽  
pp. 1198-1211 ◽  
Author(s):  
Ileana Hernández-Araiza ◽  
Sara L. Morales-Lázaro ◽  
Jesús Aldair Canul-Sánchez ◽  
León D. Islas ◽  
Tamara Rosenbaum
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Lysophosphatidic Acid ◽  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Channel Function ◽  
Transient Receptor ◽  
Lipid Protein Interactions

Lysophosphatidic acid (LPA) is a bioactive phospholipid that exhibits a wide array of functions that include regulation of protein synthesis and adequate development of organisms. LPA is present in the membranes of cells and in the serum of several mammals and has also been shown to participate importantly in pathophysiological conditions. For several decades it was known that LPA produces some of its effects in cells through its interaction with specific G protein-coupled receptors, which in turn are responsible for signaling pathways that regulate cellular function. Among the target proteins for LPA receptors are ion channels that modulate diverse aspects of the physiology of cells and organs where they are expressed. However, recent studies have begun to unveil direct effects of LPA on ion channels, highlighting this phospholipid as a direct agonist and adding to the knowledge of the field of lipid-protein interactions. Moreover, the roles of LPA in pathophysiological conditions associated with the function of some ion channels have also begun to be clarified, and molecular mechanisms have been identified. This review focuses on the effects of LPA on ion channel function under normal and pathological conditions and highlights our present knowledge of the mechanisms by which it regulates the function and expression of N- and T-type Ca++ channels; M-type K+ channel and inward rectifier K+ channel subunit 2.1; transient receptor potential (TRP) melastatin 2, TRP vanilloid 1, and TRP ankyrin 1 channels; and TWIK-related K+ channel 1 (TREK-1), TREK-2, TWIK-related spinal cord K+ channel (TRESK), and TWIK-related arachidonic acid-stimulated K+ channel (TRAAK).

scholarly journals Approaches for unveiling the kinetic mechanisms of voltage gated ion channels in neurons

2019 ◽  
Author(s):  
◽  
Marco Antonio Navarro
Keyword(s):  
Experimental Data ◽  
Ion Channels ◽  
Ion Channel ◽  
Rate Constants ◽  
Markov Models ◽  
Neuronal Firing ◽  
Voltage Gated ◽  
Voltage Gated Ion Channels ◽  
Parameter Constraints ◽  
Gated Ion Channels

Ionic currents drive cellular function within all living cells to perform highly specific tasks. For excitable cells, such as muscle and neurons, voltage-gated ion channels have finely tuned kinetics that allow the transduction of Action potentials to other cells. Voltage-gated ion channels are molecular machines that open and close depending on electrical potential. Neuronal firing rates are largely determined by the overall availability of voltage-gated Na+ and K+ currents.This work describes new approaches for collecting and analyzing experimental data that can be used to streamline experiments. Ion channels are composed of multimeric complexes regulated by intracellular factors producing complex kinetics. The stochastic behavior of thousands of individual ion hannels coordinates to produce cellular activity. To describe their activity and test hypotheses about the channel, experimenters often fit Markov models to a set of experimental data. Markov models are defined by a set of states, whose transitions described by rate constants. To improve the modeling process, we have developed computational approaches to introduce kinetic constraints that reduces the parameter search space. This work describes the implementation and mathematical transformations required to describe linear and non-linear parameter constraints that govern rate constants. Not all ion channel behaviors can easily be described by rate constants. Therefore, we developed and implemented a penalty-based mechanism that can be used to guide the optimization engine to produce a model with a desired behavior, such as single-channel open probability and use dependent effects. To streamline data collection for experiments in brain slice preparations, we developed a 3D virtual software environment that incorporates data from micro-positioning motors and scientific cameras in real-time. This environment provides positional feedback to the investigator and allows for the creation of data maps including both images and electrical recordings. We have also produced semi-automatic targeting procedures that simplifies the overall experimental experience. Experimentally, this work also examines how the kinetic mechanism of voltage gated Na channels regulates the neuronal firing of brainstem respiratory neurons. These raphe neurons are intrinsic pacemakers that do not rely on synaptic connections to elicit activity. I explored how intracellular calcium regulates the kinetics of TTX-sensitive Na+ currents using whole-cell patch clamp electrophysiology. Established with intracellular Ca2+ buffers, high [Ca2+] levels greater than ~7 [micro]M did not change the voltage dependence of steady-state activation and inactivation, but slightly slowed inactivation time course. However, the recovery from inactivation and use dependence inactivation is slowed by high intracellular [Ca2+]. Overall, these approaches described in this work have improved data acquisition and data analysis to create better ion channel models and enhance the electrophysiology experience.

Ion channels and disease

2020 ◽  
pp. 246-255
Author(s):  
Frances Ashcroft ◽  
Paolo Tammaro
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Single Channel ◽  
Cell Types ◽  
Channel Structure ◽  
Channel Proteins ◽  
Channel Function ◽  
Ion Channel Proteins ◽  
Single Channel Currents ◽  
Channel Currents

Ion channels are membrane proteins that act as gated pathways for the movement of ions across cell membranes. They are found in both surface and intracellular membranes and play essential roles in the physiology of all cell types. An ever-increasing number of human diseases are now known to be caused by defects in ion channel function. To understand how ion channel defects give rise to disease, it is helpful to understand how the ion channel proteins work. This chapter therefore considers what is known of ion channel structure, explains the properties of the single ion channel, and shows how single-channel currents give rise to action potentials and synaptic potentials.

scholarly journals Fluorescence Imaging of Electrically Stimulated Cells

2003 ◽  
Vol 8 (6) ◽  
pp. 660-667 ◽  
Author(s):  
Paul Burnett ◽  
Janet K. Robertson ◽  
Jeffrey M. Palmer ◽  
Richard R. Ryan ◽  
Adrienne E. Dubin ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Ion Channels ◽  
Ion Channel ◽  
High Throughput ◽  
Pharmacological Intervention ◽  
Voltage Gradient ◽  
Channel Activity ◽  
Voltage Gated ◽  
Voltage Gated Ion Channels ◽  
Gated Ion Channels

Designing high-throughput screens for voltage-gated ion channels has been a tremendous challenge for the pharmaceutical industry because channel activity is dependent on the transmembrane voltage gradient, a stimulus unlike ligand binding to G-protein-coupled receptors or ligand-gated ion channels. To achieve an acceptable throughput, assays to screen for voltage-gated ion channel modulators that are employed today rely on pharmacological intervention to activate these channels. These interventions can introduce artifacts. Ideally, a high-throughput screen should not compromise physiological relevance. Hence, a more appropriate method would activate voltage-gated ion channels by altering plasma membrane potential directly, via electrical stimulation, while simultaneously recordingthe operation of the channel in populations of cells. The authors present preliminary results obtained from a device that is designed to supply precise and reproducible electrical stimuli to populations of cells. Changes in voltage-gated ion channel activity were monitored using a digital fluorescent microscope. The prototype electric field stimulation (EFS) device provided real-time analysis of cellular responsiveness to physiological and pharmacological stimuli. Voltage stimuli applied to SK-N-SH neuroblastoma cells cultured on the EFS device evoked membrane potential changes that were dependent on activation of voltage-gated sodium channels. Data obtained using digital fluorescence microscopy suggests suitability of this system for HTS.

Channelopathies: Their Contribution to Our Knowledge About Voltage-Gated Ion Channels

Physiology ◽  
1997 ◽  
Vol 12 (3) ◽  
pp. 105-112
Author(s):  
F Lehmann-Horn ◽  
R Rudel
Keyword(s):  
Skeletal Muscle ◽  
Ion Channels ◽  
Ion Channel ◽  
Chloride Channels ◽  
Gene Products ◽  
Sodium Potassium ◽  
Voltage Gated ◽  
Voltage Dependent ◽  
Genes Encoding ◽  
Voltage Gated Ion Channels

Since 1990, many mutations in genes encoding voltage-dependent sodium, potassium, calcium, and chloride channels have been discovered to cause disorders of heart, skeletal muscle, brain, or kidney. Study of the defective gene products has furthered our knowledge not only of pathology but also of ion-channel function.

Sign in / Sign up

Export Citation Format

Share Document