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Two-Pore Domain Potassium Channels in Pain and Depression
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
With the analysis of crystal structures, and the continuous exploration of mechanism of action and functions, we have gained a deeper understanding of the K2P family. The K2P family is widely distributed in the body, and its expression level is even more abundant in the nervous system. Moreover, this family has a unique biophysical property that mediates the background K+ currents of various types of cells. Therefore, K2P channels play an irreplaceable role in regulating cell excitability and affecting nerve signal transduction. With the maturity of gene knockout technology, in recent years, the functional characteristics of the K2P family have been continuously identified: both TREK-1 and TRAAK KO mice show increased sensitivity to pain. TREK-1 and TASK-3 KO mice also show an antidepressant phenotype. Therefore, researchers found that the K2P family is not only a good analgesic target but also an attractive antidepressant target. There are many endogenous factors regulating the activity of the K2P family members in vivo, suggesting that it is a good candidate for regulation. Therefore, drugs designed for this family may achieve better analgesic or antidepressant effects than what is currently available. Significantly, each member of this family has a unique distribution pattern in the body. Although they are structurally similarities between the family members, their sequence similarity is low. Hence, there is an opportunity for rational drug design for K2P channels.
Intestinal Muscle Effects of Clostridium Difficile Toxins
Published in William J. Snape, Stephen M. Collins, Effects of Immune Cells and Inflammation on Smooth Muscle and Enteric Nerves, 2020
The electrophysiologic basis by which toxin A may regulate muscle cell excitability was studied in rabbit ileal muscle strips in which simultaneous measurements of intracellular membrane potential and contractility were made following exposure.8 In experiments in which toxin A was injected into an isolated ileal loop in vivo and incubated for a period of 2 hours, the excised tissue demonstrated several specific electromechanical changes, namely membrane depolarization, increased frequency of slow waves and action potentials, and increased amplitude of spontaneous phasic contractions (Figure 1). There was no net effect on action potential peak voltage inasmuch as there was a concurrent decrease of of action potential amplitude in association with membrane depolarization. The administration of toxin A into the intestinal loop also caused a significant increase of the amplitude and temporal regularity of the phasic contractile response to muscarinic activation with carbachol (Figure 2). In contrast to the profound effects of in vivo toxin exposure, normal ileal muscle strips administered toxin directly in vitro showed no significant change of any resting or carbachol-activated electrophysiological property or contractile response. Morphological and ultrastructural studies of the muscularis demonstrated the presence of marked cellular infiltrate in the lamina propria, but no effect of the toxin on any membranes, nuclear structures, cytoskeletal components, or organelles.
Sedative and Hypnotic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Arup Kumar Misra, Pramod Kumar Sharma
Barbiturates acts by increasing the efficacy of GABA on the receptor and thus increases the total time of opening of the chloride channel by allowing greater influx of chloride ions. This act of barbiturate causes hyperpolarization and depresses the cell excitability. The barbiturates enhance GABA action more as compared with benzodiazepines. It also directly activates GABAA receptors and thus enhance GABA actions. Overdose of barbiturates may cause excessive potentiation of the receptor which may increase its toxicity and lead to sedation, hypnosis, respiratory depression, coma, and death (Saunders and Ho, 1990).
Microglia and HPA axis in depression: An overview of participation and relationship
Published in The World Journal of Biological Psychiatry, 2022
Gabriele Cheiran Pereira, Elisa Piton, Brenda Moreira dos Santos, Luis Guilherme Ramanzini, Luis Fernando Muniz Camargo, Rossano Menezes da Silva, Guilherme Vargas Bochi
Different factors can activate the HPA axis, from immune responses to emotional stress, increasing GC release (Timmermans et al. 2019). Following exposure to a stressor, the HPA axis is stimulated, and GCs are released in the brain to restore physiological and behavioural homeostasis (Yiallouris et al. 2019). In addition to this adaptive response, involvement of these hormones in neuronal activities such as nerve cell excitability, neuronal survival, neuroplasticity, and neurogenesis has been suggested (Oakley and Cidlowski 2011). Under normal conditions, lower cortisol levels interact with cortical and limbic structures, such as the prefrontal cortex and hippocampus, to promote cognitive and emotional processing (Qin et al. 2016). However, at chronically elevated levels, GCs can exert negative structural and functional effects in these brain structures (Sorrells and Sapolsky 2007; McEwen and Morrison 2013).
Mechano-gated channels in C. elegans
Published in Journal of Neurogenetics, 2020
Evolutionary genetics revealed that potassium channels are widely expressed archaic ion channels across species. Potassium channels control the influx and efflux of K+ ions through cell membranes (Douguet & Honore, 2019). The opposing polarization and depolarization of potassium versus calcium and sodium channels promote membrane potential/cell excitability for numerous vital cellular mechanics as well as survival. To date, four main classes of potassium channels are known—Calcium-activated (Kca), Inward rectifying (Kir), Tandem/two pore domain (K2P) and voltage-gated potassium channels (KV). Previously known as K+ background (leak) channels, K2P channel subunits are encoded by 15 KCNK mammalian genes, 11 Drosophila genes and 50 putative C. elegans genes. Out of the four potassium ion channels, only two K2P subfamilies—Tandem pore domain in weak rectifying K+ channel (TWIK) and TWIK-related K+ channel (TREK) have been divulged as mechano-gated channels. Thus far, TREK1 (KCNK2), TREK2 (KCNK10) and TRAAK (TWIK-related arachidonic acid-stimulated K+) channels have been found to be mechano-gated channels in mammals (Chalfie, 2009) but there is yet no mechanically activated K2P channel exposed in C. elegans.
Effect of whole body vibration on spasticity in hemiplegic legs of patients with stroke
Published in Topics in Stroke Rehabilitation, 2018
Kodai Miyara, Shuji Matsumoto, Tomohiro Uema, Tomokazu Noma, Keiko Ikeda, Akihiko Ohwatashi, Ryoji Kiyama, Megumi Shimodozono
Another study showed that after an 8-week WBV intervention, knee spasticity was reduced, but ankle spasticity was unchanged.9 Although MAS is a common measure of spasticity, it may not detect minute changes because of its qualitative analysis.12 The H-reflex indirectly measures the excitability levels of alpha motor neurons, but this increase is not always detected through the H-reflex in patients with spasticity.13 However, F-wave parameters (i.e. F-wave amplitude and F/M ratio) are more sensitive to changes of lower motor neuron excitability associated with spasticity than T and H-reflexes.14 The F-wave represents spinal cord anterior horn cell excitability.15 The F-wave amplitude and the F/M ratio are correlated with motor neuron excitability, and are increased in spastic patients.16–18 To our knowledge, the effect of WBV on motor neuron excitability has not been investigated. The purpose of this study was to identify the effect of WBV on spasticity in the hemiplegic legs of patients with stroke using F-wave parameters.