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The Cell Membrane in the Steady State
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
Ion channels are of various types. Some channels are in a dynamic state of spontaneous and random opening and closing and may be open for less than 1 ms at a time. Other channels are gated, that is, they are opened or closed by a variety of influences, such as the binding of some small molecules (referred to as ligands) to (i) the external side of the channel protein, as in the case of neurotransmitters (Section 6.1.2), or (ii) to the internal side of the protein, as in the case of second messenger systems (Section 6.3). The gating could also be due to (i) phosphorylation, (ii) the voltage across the membrane, as in the initiation and propagation of the action potential (Chapters 3 and 4), (iii) mechanical deformation, as in the case of muscle receptors (Section 9.4), or (iv) other physical stimuli such as light, as in the case of photoreceptors, or heat, as in the case of temperature receptors.
Cell Components and Function
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Ion channels are membrane-spanning proteins that form pores that allow ion transport. These channels are selective and conduct ions across electrochemical gradients at a high rate. External signals cause ion channels to undergo conformational changes. Depending on the signal, the ion channels may ‘open’ or ‘close’, a process called gating. The gate is a region of the protein channel that prevents ion flow in the closed state. Ion channels may be (i) ligand-gated (gating mediated by a neurotransmitter or chemical binding to sensor region of the channel), (ii) voltage-gated (membrane potential changes near channel) or (iii) mechanosensitive (activation by pressure, stretch or temperature).
Ion Channels and The Control of Uterine Contractility
Published in Robert E. Garfield, Thomas N. Tabb, Control of Uterine Contractility, 2019
In the myometrium, an increase in the concentration of free calcium in the cytoplasm is essential for the initiation of contraction. Calcium can enter the cell through plasma membrane channels of two different classes. Voltage-sensitive ion channels mediate rapid, voltage-gated changes in ion conductance during the action potential. The calcium entering during action potentials serves as the primary intracellular second messenger for initiating excitation-contraction coupling and multiple calcium-activated biochemical processes. In addition, these channels can be regulated by receptor-dependent processes, including protein phosphorylation and interaction with GTP-binding proteins. In contrast, ligand-gated ion channels are opened in response to activation of an associated receptor. Typical channels of this class include the nonspecific channels that are opened by activation of membrane receptors. Generally, activation of ligand-gated ion channels mediates local increases in ion conductance, producing depolarization or hyperpolarization of the membrane.
Automated patch clamp in drug discovery: major breakthroughs and innovation in the last decade
Published in Expert Opinion on Drug Discovery, 2021
Alison Obergrussberger, Søren Friis, Andrea Brüggemann, Niels Fertig
Patch-clamp electrophysiology remains an important technique in studying ion channels; indeed, it is still considered the gold standard since it was first described by Neher and Sakmann in the 1970s [1]. Ion channels are integral membrane proteins which allow ion current flow across the cell membrane. They are involved in almost all physiological processes, and their malfunction underlies many disease states, making them important pharmacological targets. Conventional patch clamp is a very information-rich technique, but it requires skilled personnel to perform experiments, and typically, only one experiment can be performed at a time. In the late 1990s and early 2000s, the field of ion-channel research was revolutionized by the development of the automated patch-clamp (APC) technique. The most successful approach involved replacing the patch-clamp pipette with a planar substrate (for review, see [2]), making the experiments easier to perform and offering the option for recording multiple cells in parallel. In the last two decades, much has changed in the field of ion-channel drug discovery and APC, with increased throughput and enhanced simplicity. We summarize the main changes in the last decade and attempt to look into the future of what’s to come.
Prevention of sudden unexpected death in epilepsy: current status and future perspectives
Published in Expert Review of Neurotherapeutics, 2020
Max Christian Pensel, Robert Daniel Nass, Erik Taubøll, Dag Aurlien, Rainer Surges
It has been well known for decades that AEDs can work differently when used in generalized epilepsy compared to focal epilepsy [114]. Therefore, scientific trials examining the efficacy and safety of AEDs have commonly been carried out either in patients with focal epilepsy or in patients with generalized epilepsy, avoiding a mixture of generalized and focal epilepsies in the same study [115–117]. In studies on possible associations between the use of specific AEDs and SUDEP, however, this knowledge has largely been neglected [8,10,118–120]. Furthermore, an increased vulnerability to drug-induced cardiac arrhythmia may be present in an unknown proportion of individuals with generalized genetic epilepsy (formerly called idiopathic) as there is an overlap between cardiac and neuronal channelopathies [121,122]. Increasing evidence suggest that the congenital long QT syndrome can be associated with not only malignant arrhythmias but also genuine epilepsy [122–128] and individuals with congenital long QT syndrome can be put at risk if treated with ion channel blockers increasing the risk of cardiac arrhythmia [129]. Alterations of cardiac repolarization are not uncommon in TCSs [63], and if a patient in addition to having a GTCS has a cardiac channelopathy and is being treated with an ion channel blocker, the risk of a fatal arrhythmia may be particularly increased.
Using Xenopus oocytes in neurological disease drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Steven L. Zeng, Leland C. Sudlow, Mikhail Y. Berezin
Ion channels act as entryways for ions to penetrate the otherwise impermeable cell membrane. Along with supporting regulatory and other proteins, ion channels establish a connection between the environment and the neurons. The opening and closing of these channels are highly regulated. Ion channels respond only to specific signals, such as binding of a neurotransmitter, alteration in electrical membrane potential, phosphorylation of one or more subunits, and so on. Malfunctioning ion channels are the major common causes of a large number of neurological disorders [6,7]. Aberrant K+ and other ion channels are responsible for neuromyotonia [8], episodic ataxia type-1 [9] and benign familial neonatal convulsions [10] among many other genetic and acquired neurological disorders [11]. Defects in voltage-gated Na+ channels lead to pain [12] and epilepsy [13]. Calcium channels are accountable for several psychiatric disorders [14]. Advancement in the study of ion channels has made it possible to evaluate channel dysfunctions at the various levels from the single channel to the complex neuronal systems, and the whole organism.