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The Cell Membrane in the Steady State
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
An ion channel consists of a receptor-type protein, referred to as a channel protein, or aquaporin, which surrounds an aqueous pore that forms a direct connection between the external and internal aqueous media. The pore allows passage of ions between these two media, subject to certain restrictions. The channel protein may have some carbohydrate groups attached to it on the extracellular side (Figure 2.2). Since ion channels and their aqueous pores are central to the electrical properties and behavior of the cell membrane, they will be considered here in a little more detail.
Ischemic Inhibition of Calcium Slow Current in the Heart
Published in Samuel Sideman, Rafael Beyar, Analysis and Simulation of the Cardiac System — Ischemia, 2020
In summary, the Ca2+ slow channels of the heart are regulated by cAMP in a stimulatory fashion. Elevation of cAMP produces a very rapid increase in number of slow channels available for voltage activation during excitation. The probability of a slow channel opening at a given voltage is increased and the mean open time of a given channel is increased. The mechanism whereby cAMP stimulates the slow channels is by means of the cAMP-dependent protein kinase and phosphorylation of one or more proteins. Presumably a protein that is phosphorylated is the slow channel protein itself or an associated regulatory-type (stimulatory) protein. Therefore, any agent that increases the cAMP level of the myocardial cell will tend to potentiate Isi, Ca2+ influx, and contraction.
Overview of Ion Channels, Antiepileptic Drugs, and Seizures
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
The application of the techniques of molecular biology to the study of ion channels has led to attempts at identifying the portions of the channel protein that are vital to specific K+ channel function.25 The function of K+ channels in neurons is basically inhibitory in that they provide the outward current which inward Na+ and Ca2+ must counteract to produce the depolarization that subserves excitability.22 Three classes of K+ channels have been categorized. Two types of voltage-dependent channels, delayed rectifiers and A (and A-like) channels have been described. A second class of K+ channels is called inward rectifiers, and a third class of Ca+-dependent K+ channels also has been described.22 The neurotrans-mitter and second messenger-regulated channels (M channels and S channels) also are known,26 but will not be discussed here.
The force-from-lipid principle and its origin, a ‘what is true for E. coli is true for the elephant’ refrain
Published in Journal of Neurogenetics, 2022
Besides MscL, MscS, and Piezo1, described above, the two-pore-domain K+ channels, and TREK (Berrier et al., 2013; Brohawn, Su, & MacKinnon, 2014) as well as OSCA/TMEM63 (Murthy et al., 2018) have also been purified and shown to be mechanosensitive in lipid bilayers. Less rigorously tested are also MS currents observed in various membrane blebs, largely devoid of cytoskeleton. In addition, there are MS channels functionally expressed heterologously, where the channels are alien to the host cytoskeletons and do not likely interact. For example, TRPV4 from rat can be functionally expressed in Xenopus oocyte as well as in yeast cells and remains mechanosensitive (Loukin, Su, & Kung, 2009). That MS channels of very different structures, coming from bacteria to human, all draw their gating force from the lipid bilayer indicates that FFL is a general evolutionary conserved principle. In simplest terms, the bilayer is an amphipathic structure with set internal forces. (See below). An embedded channel protein in its closed state has its own amphipathic structure fitting this force environment. Stretching the bilayer generates a mismatch, which drives the protein to a new (open) structure.
What’s new in chronic pain pathophysiology
Published in Canadian Journal of Pain, 2020
To summarize, there are strong implications regarding a patient’s pain experience and analgesic outcomes as directed by his or her genetic code. Enzymatic activity can significantly alter sensation, addictive behaviors, and medication metabolism, complicating a clinical picture. SNPs and other mutations in ion channel genes may lead to channelopathies that may fundamentally alter how a patient experiences and responds to a nociceptive stimulus. Moreover, some patients may suffer from painful conditions entirely caused by a genetic mutation resulting in a defective channel protein. Understanding of opioid metabolism variability has influenced prescription practices, most notably codeine use in pediatric populations. There is little use of genetic testing in practice today; looking to the future, genetic mapping and screening may help provide direction for pharmaceutical management and abuse risk. Gene therapies may represent a means to affect and interact with these complex systems to prevent or treat acute and chronic pain.
Improving genetic diagnostics of skeletal muscle channelopathies
Published in Expert Review of Molecular Diagnostics, 2020
Vinojini Vivekanandam, Roope Männikkö, Emma Matthews, Michael G. Hanna
Myotonia Congenita (MC) is the most common skeletal muscle channelopathy. It is caused by mutations in the CLCN1 gene, which encodes the voltage-gated chloride channel ClC-1. The functional channel protein is comprised of two gene products [5]. The symptoms of myotonia generally present in the first or second decade of life [6]. Symptoms of myotonia are prominent at the initiation of movement and often improve with repeated activity – a phenomenon known as ‘warm up.’ Patients with recessively inherited myotonia congenita tend to have more severe symptoms compared to patients with dominant mutations [5] and additionally, some patients with recessive MC have transient weakness at the initiation of movement. Hundreds of pathogenic mutations have been identified in CLCN1, the majority of CLCN1 mutations are missense, with Gly230Glu the most common [2,7].