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The stimulus
Published in Alan Weiss, The Electroconvulsive Therapy Workbook, 2018
Familiarity with some of the basic principles of neuronal physiology is important in understanding the electrical stimulus applied in ECT. The action potential, illustrated in Figure 5.4.2, is the basic mechanism by which electrical energy travels along a neuronal axon. Action potentials are generated by specific voltage-gated ion channels embedded within the cell membrane that are shut when the membrane potential is near the resting potential. Following a stimulus they rapidly open, allowing sodium ions to rush into the neuron, which has a relative negative charge compared to the outside, changing the electrochemical gradient increasing the membrane potential causing more channels to open. The process continues rapidly until all of the ion channels have opened causing a large increase in membrane potential. The sodium ion channels close and they are actively transported out of the membrane. Potassium channels are then activated and there is an outward flow of potassium ions returning the electrochemical gradient back to the resting state after a transient negative shift during which the plasma membrane is incapable of firing. The sodium and potassium gated ion channels open and close as the membrane reaches the threshold potential in response to a signal from another neuron (Guyton and Hall, 2016).
Overview of Mechanisms for Coupling of Receptor-Agonist Interactions With Physiological Effects
Published in John C. Matthews, Fundamentals of Receptor, Enzyme, and Transport Kinetics, 2017
All living cells maintain an unequal distribution of ions across their plasma membranes. Na+ and Ca+ + are high in concentration outside the cell while K+ and Mg++ are high in concentration inside the cell. These ionic gradients are maintained at the expense of metabolic energy by ion pumping enzymes in the membranes. Cells use these ionic gradients for various signaling purposes. They do so by employing receptor-modulated ion channels to control (or gate) the flow of ions down their electrochemical gradients from one side of the membrane to the other. Two results of ions flowing across membranes are useful for signaling purposes. One is that changes in transmembrane ion flow result in alterations in transmembrane voltages (or polarities). There are many membrane-incorporated effector systems, particularly voltage-gated ion channels, which can sense changes in transmembrane voltage and initiate their action in response.
The principal targets for drug action
Published in Hugh McGavock, How Drugs Work, 2017
Many ion channels react to electrical rather than chemical signals. Such voltage-gated ion channels open and close in response to changes in the voltage across the cell membrane. Calcium channels in cardiac muscle are important examples (seeChapter 10), and the ability to block them has greatly improved the treatment of angina, hypertension and some cardiac arrhythmias.
Antinociceptive peptides from venomous arthropods
Published in Toxin Reviews, 2023
Jessica A. I. Muller, Lai Y. Chan, Monica C. Toffoli-Kadri, Marcia R. Mortari, David J. Craik, Johannes Koehbach
The μ-TRTX-Df1a inhibits Nav1.1–1.7 channels, with a higher affinity to Nav1.2–1.3 and 1.7 and blocks Cav3 channels, with a higher affinity to Cav3.1 and 3.3 (Cardoso et al.2017). The authors evaluated the μ-TRTX-Df1a in an OD1 murine model (OD1 is a peptide from scorpion added in this model to induce pain activation specifically via inhibition of Nav1.7 channel inactivation) and the i.pl. injection reduced nociception. Composed of 34 amino acids and six cysteines, μ-TRTX-Df1a also has an amidated C-terminus. Structural analysis revealed the peptides to have a hydrophobic and a hydrophilic surface patch. The hydrophobic patch is dominated by aromatic residues, including the central Trp4, Phe5, Trp27 and Trp30 residues and the peripheral Trp32 and Phe34 residues. A conserved large hydrophobic patch surrounded by positively charged residues which is potentially involved in the interactions with the hydrophobic core of the cell membrane and the S3–S4 linker regions of the voltage‐gated ion channels. Also, the authors observed that the C-terminal amidation is important to the activity, because when this was removed, the peptide lost its inhibitory activity against Nav channels (Cardoso et al.2017).
Concurrent sodium channelopathies and amyotrophic lateral sclerosis supports shared pathogenesis
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2020
John P. Franklin, Johnathan Cooper-Knock, Aravindhan Baheerathan, Tobias Moll, Roope Männikkö, Mark Heverin, Orla Hardiman, Pamela J. Shaw, Michael G. Hanna
We hypothesized that ALS may be linked to genetic mutations in other voltage-gated ion channels. Rare-variant burden testing using whole genome sequencing data from 4495 ALS patients and 1925 controls (databrowser.projectmine.com/) within the superfamily of voltage-gated ion channels (Accession:ssf81324) identified one gene, SCN7A, which passed multiple testing correction (p = 0.00029, beta = 0.41, Firth logistic regression; rare-variants defined as missense and MAF < 0.01, Supplementary Table) consistent with an enrichment of ALS-associated mutations. SCN7A encodes a type II sodium channel, NaX, and is expressed in glial cells. NaX is not voltage-gated, and channel permeability is proportional to extracellular [Na+] so as to mediate [Na+] homeostasis (11). We identified 67 rare predicted pathogenic (12) ALS-associated variants within SCN7A of which 3 are premature stop codon variants which undoubtedly lead to haploinsufficiency (Supplementary Table). We propose that SCN7A loss of function may disrupt extracellular [Na+] homeostasis and lead to neuronal hyperexcitability.
Genomic sequencing in severe epilepsy: a step closer to precision medicine
Published in Expert Review of Precision Medicine and Drug Development, 2020
Mariagrazia Esposito, Ilaria Lagorio, Diego Peroni, Alice Bonuccelli, Alessandro Orsini, Pasquale Striano
Currently available ASDs target receptor-gated or voltage-gated ion channels are useful for a large number of epilepsy patients. Despite this advancement, one third of patients are still pharmacoresistant, and have to relate to long-term effects and an unmet medical need exits for pharmacoresistant patients and epilepsy-comorbidities [95]. Despite these interesting examples of ‘precise’ treatment in patients with epilepsy (Table 1), disease-specific treatments are currently available for only a minority of genetic epilepsies. Future efforts surely have to focus also on understanding the molecular mechanisms of synaptic and network activity. On the other hand, the genetic bases of many epileptic syndromes are well studied with the goal of identifying new drugs targets and tailored therapies. As the basic mechanisms of the epilepsies are understood, especially with respect to the genetic epilepsies, novel molecular targets will be identified and provide unique opportunities to address the problems of refractory epilepsy and epileptogenesis. Future studies should also investigate the interactions of new tailored drugs and currently available AEDs, in fact, their effect can possibly be synergic.