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Potassium Channels

Shu Li, Bohua Wu, Wei Han
Helical hinges are common in transmembrane (TM) proteins. Hinging motions of TM helices are associated with the functional dynamics of many important membrane proteins such as various G-protein coupled receptors (GPCR) and potassium channels. Although coarse-grained (CG) simulations are useful for studying membrane proteins, they are limited in describing accurately the hinge-related protein dynamics. In this study, we have overcome this limitation through a further development of the MARTINI CG model. The key improvement lay in implementation of additional local structural types and parameterization of the model against a structural library of TM helices obtained from the Protein Data Bank...
February 14, 2019: Journal of Physical Chemistry. B
Fan Zhang, Yani Liu, Dandan Zhang, Xizhenzi Fan, Decheng Shao, Han Li
Osteoarthritic pain has a strong impact on patients' quality of life. Understanding the pathogenic mechanisms underlying osteoarthritic pain will likely lead to the development of more effective treatments. In the present study of osteoarthritic model rats, we observed a reduction of M-current density and a remarkable decrease in the levels of KCNQ2 and KCNQ3 proteins and mRNAs in dorsal root ganglia (DRG) neurons, which were associated with hyperalgesic behaviors. The activation of KCNQ/M channels with flupirtine significantly increased the mechanical threshold and prolonged the withdrawal latency of osteoarthritic model rats at 3-14 days after model induction, and all effects of flupirtine were blocked by KCNQ/M-channel antagonist, XE-991...
February 13, 2019: Pharmacology
Xueting Gao, Siyun Gao, Yi Guan, Lin Huang, Jiale Huang, Li Lin, Yuan Liu, Hong Zhao, Bijun Huang, Tianyou Yuan, Yi Liu, Dandan Liang, Yangyang Zhang, Xiue Ma, Li Li, Jun Li, Daizhan Zhou, Dan Shi, Liang Xu, Yi-Han Chen
TLRs have been proven to be essential mediators for the early innate immune response. Overactivation of TLR-mediated immune signaling promotes deterioration of cardiovascular diseases; however, the role of TLRs in the heart under physiologic conditions remains neglected. Here, we show that Tlr3 deficiency induced the endoplasmic reticulum (ER) retention of Kv4.2/4.3 proteins and consequent degradation via the ubiquitin-proteasome pathway. Knockout of Tlr3 resulted in a prolonged QT interval (the space between the start of the Q wave and the end of the T wave) in mice with no significant signs of inflammation and tissue abnormality in cardiac muscles...
February 13, 2019: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Zhaoyang Hu, Thomas Jepps, Leng Zhou, Jin Liu, Mufeng Li, Geoffrey W Abbott
Activation of anti-apoptotic signaling cascades such as the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways is protective in a variety of tissues in the context of ischemia reperfusion (IR) injury. Hepatic IR injury causes clinically significant hepatocellular damage in surgical procedures including liver transplantation and hepatic resection, increasing associated morbidity and mortality. We previously found that the cardiovascular-expressed potassium channel ancillary subunit, KCNE4, sex-specifically influences the cardiac RISK/SAFE pathway response to IR, and that Kcne4 deletion testosterone-dependently exacerbates cardiac IR injury...
February 13, 2019: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Hiroko Kotajima-Murakami, Ayumi Takano, Yasukazu Ogai, Shotaro Tsukamoto, Maki Murakami, Daisuke Funada, Yuko Tanibuchi, Hisateru Tachimori, Kazushi Maruo, Tsuyoshi Sasaki, Toshihiko Matsumoto, Kazutaka Ikeda
AIMS: Pharmacotherapy for methamphetamine dependence has not yet been developed in Japan or elsewhere in the world. Ifenprodil is a blocker of G protein-activated inwardly rectifying potassium channels that play a key role in the mechanism of action of addictive substances. Our aim is to examine the safety, efficacy, and outcomes of ifenprodil for the treatment of methamphetamine dependence in a randomized, double-blind, placebo-controlled trial. METHODS: The recruitment of outpatients with methamphetamine dependence began in January 2018...
February 12, 2019: Neuropsychopharmacology reports
Brandon M Brown, Hai M Nguyen, Heike Wulff
As their name implies, cation channels allow the regulated flow of cations such as sodium, potassium, calcium, and magnesium across cellular and intracellular membranes. Cation channels have long been known for their fundamental roles in controlling membrane potential and excitability in neurons and muscle. In this review, we provide an update on the recent advances in our understanding of the structure-function relationship and the physiological and pathophysiological role of cation channels. The most exciting developments in the last two years, in our opinion, have been the insights that cryoelectron microscopy has provided into the inner life and the gating of not only voltage-gated channels but also mechanosensitive and calcium- or sodium-activated channels...
2019: F1000Research
Dora Matzakos-Karvouniari, Lionel Gil, Elaine Orendorff, Olivier Marre, Serge Picaud, Bruno Cessac
During early development, waves of activity propagate across the retina and play a key role in the proper wiring of the early visual system. During a particular phase of the retina development (stage II) these waves are triggered by a transient network of neurons, called Starburst Amacrine Cells (SACs), showing a bursting activity which disappears upon further maturation. The underlying mechanisms of the spontaneous bursting and the transient excitability of immature SACs are not completely clear yet. While several models have attempted to reproduce retinal waves, none of them is able to mimic the rhythmic autonomous bursting of individual SACs and reveal how these cells change their intrinsic properties during development...
February 12, 2019: Scientific Reports
A P Luiz, D I MacDonald, S Santana-Varela, Q Millet, S Sikandar, J N Wood, E C Emery
The ability to detect environmental cold serves as an important survival tool. The sodium channels NaV 1.8 and NaV 1.9, as well as the TRP channel Trpm8, have been shown to contribute to cold sensation in mice. Surprisingly, transcriptional profiling shows that NaV 1.8/NaV 1.9 and Trpm8 are expressed in nonoverlapping neuronal populations. Here we have used in vivo GCaMP3 imaging to identify cold-sensing populations of sensory neurons in live mice. We find that ∼80% of neurons responsive to cold down to 1 °C do not express NaV 1...
February 12, 2019: Proceedings of the National Academy of Sciences of the United States of America
Graciela Kearney, Javier Zorrilla de San Martín, Lucas G Vattino, Ana Belén Elgoyhen, Carolina Wedemeyer, Eleonora Katz
In the mature mammalian cochlea, inner hair cells (IHCs) are mainly innervated by afferent fibers that convey sound information to the central nervous system. During postnatal development, however, medial olivocochlear (MOC) efferent fibers transiently innervate the IHCs. The MOC-IHC synapse, functional from postnatal day (P)0 to hearing onset (P12), undergoes dramatic changes in the sensitivity to acetylcholine (ACh) and in the expression of key postsynaptic proteins. To evaluate whether there are associated changes in the properties of ACh release during this period, we used a cochlear preparation from mice of either sex at P4, P6-7 and P9-11 and monitored transmitter release from MOC terminals in voltage-clamped IHCs in the whole-cell configuration...
February 12, 2019: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Dibyadeep Datta, Sheng-Tao Yang, Veronica Galvin, John Solder, Fei Luo, Yury M Morozov, Jon Arellano, Alvaro Duque, Pasko Rakic, Amy Arnsten, Min Wang
Noradrenergic (NE) α1-adrenoceptors (α1-AR) contribute to arousal mechanisms, and play an important role in therapeutic medications, e.g. for treating Post-Traumatic Stress Disorder (PTSD). However, little is known about how α1-AR stimulation influences neuronal firing in the dorsolateral prefrontal cortex (dlPFC), a newly evolved region that is dysfunctional in PTSD and other mental illnesses. The current study examined the effects of α1-AR manipulation on neuronal firing in dlPFC of rhesus monkeys performing a visuospatial working memory task, focusing on the "Delay cells" that maintain spatially-tuned information across the delay period...
February 12, 2019: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Albert Snowball, Elodie Chabrol, Robert C Wykes, Tawfeeq Shekh-Ahmad, Jonathan H Cornford, Andreas Lieb, Michael P Hughes, Giulia Massaro, Ahad A Rahim, Kevan S Hashemi, Dimitri M Kullmann, Matthew C Walker, Stephanie Schorge
Refractory focal epilepsy is a devastating disease for which there is frequently no effective treatment. Gene therapy represents a promising alternative, but treating epilepsy in this way involves irreversible changes to brain tissue, so vector design must be carefully optimized to guarantee safety without compromising efficacy. We set out to develop an epilepsy gene therapy vector optimized for clinical translation. The gene encoding the voltage-gated potassium channel Kv1.1, KCNA1 , was codon-optimized for human expression and mutated to accelerate the channels' recovery from inactivation...
February 12, 2019: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Salman Sadullah Usmani, Piyush Agrawal, Manika Sehgal, Pradeep Kumar Patel, Gajendra P S Raghava
Immunosuppression proved as a captivating therapy in several autoimmune disorders, asthma as well as in organ transplantation. Immunosuppressive peptides are specific for reducing efficacy of immune system with wide range of therapeutic implementations. `ImmunoSPdb' is a comprehensive, manually curated database of around 500 experimentally verified immunosuppressive peptides compiled from 79 research article and 32 patents. The current version comprises of 553 entries providing extensive information including peptide name, sequence, chirality, chemical modification, origin, nature of peptide, its target as well as mechanism of action, amino acid frequency and composition, etc...
January 1, 2019: Database: the Journal of Biological Databases and Curation
Ingrid M Quintana, Johannes Gibhardt, Asan Turdiev, Elke Hammer, Fabian M Commichau, Vincent T Lee, Christian Magni, Jörg Stülke
Cyclic di-adenosine monophosphate (c-di-AMP) is a second messenger involved in diverse metabolic processes including osmolyte uptake, cell wall homeostasis, as well as antibiotic and heat resistance. In Lactococcus lactis , a lactic acid bacterium which is used in the dairy industry and as a cell factory in biotechnological processes, the only reported interaction partners of c-di-AMP are the pyruvate carboxylase and BusR, the transcription regulator of the busAB operon for glycine betaine uptake. However, recent studies uncovered a major role of c-di-AMP in the control of potassium homeostasis, and potassium as the signal that triggers c-di-AMP synthesis...
February 11, 2019: Journal of Bacteriology
Jesusa Capera, Clara Serrano-Novillo, María Navarro-Pérez, Silvia Cassinelli, Antonio Felipe
Ion channels are transmembrane proteins that conduct specific ions across biological membranes. Ion channels are present at the onset of many cellular processes, and their malfunction triggers severe pathologies. Potassium channels (KChs) share a highly conserved signature that is necessary to conduct K⁺ through the pore region. To be functional, KChs require an exquisite regulation of their subcellular location and abundance. A wide repertoire of signatures facilitates the proper targeting of the channel, fine-tuning the balance that determines traffic and location...
February 9, 2019: International Journal of Molecular Sciences
Marsha L Pierce, Suneet Mehrotra, Aaryn C Mustoe, Jeffrey A French, Thomas F Murray
The neurohypophyseal hormone oxytocin (OT) regulates biological functions in both peripheral tissues and the central nervous system (CNS). In the CNS, OT influences social processes including peer relationships, maternal-infant bonding and affiliative social relationships. In mammals, the nonapeptide OT structure is highly conserved with leucine in the 8th position (Leu8 -OT). In marmosets ( Callithrix ) a nonsynonymous nucleotide substitution in the OXT gene codes for proline in the 8th residue position (Pro8 -OT)...
February 9, 2019: Molecular Pharmacology
Chris X Dupont, Kirsten S Denman, Ahmed A Hawash, Andrew A Voss, Mark M Rich
Patients with myotonia congenita suffer from muscle stiffness caused by muscle hyperexcitability. Although loss-of-function mutations in the ClC-1 muscle chloride channel have been known for 25 years to cause myotonia congenita, this discovery has led to little progress on development of therapy. Currently, treatment is primarily focused on reducing hyperexcitability by blocking Na+ current. However, other approaches such as increasing K+ currents might also be effective. For example, the K+ channel activator retigabine, which opens KCNQ channels, is effective in treating epilepsy because it causes hyperpolarization of the resting membrane potential in neurons...
February 7, 2019: Experimental Neurology
Asmae Assaidi, Ikram Dib, Monique Tits, Luc Angenot, Said Bellahcen, Nourelhouda Bouanani, Abdelkhaleq Legssyer, Mohammed Aziz, Hassane Mekhfi, Mohammed Bnouham, Michel Frederich, Abderrahim Ziyyat
OBJECTIVE: This study aims to evaluate the vasodilatory effect of Chenopodium ambrosioides on the isolated rat aorta, and to explore its mechanism of action. METHODS: The vasorelaxant effect and the mode of action of various extracts from the leaves of C. ambrosioides were evaluated on thoracic aortic rings isolated from Wistar rats. In addition, ethyl acetate and methanol fractions were analyzed, using thin-layer chromatography and high-performance liquid chromatography techniques, for their polyphenolic content...
January 28, 2019: Journal of Integrative Medicine
Zhaoyang Hu, Jin Liu, Leng Zhou, Xin Tian, Geoffrey W Abbott
Sudden cardiac death (SCD) is the leading global cause of mortality. SCD often arises from cardiac ischemia reperfusion (IR) injury, pathologic sequence variants within ion channel genes, or a combination of the two. Alternative approaches are needed to prevent or ameliorate ventricular arrhythmias linked to SCD. Here, we investigated the efficacy of remote ischemic preconditioning (RIPC) of the limb versus the liver in reducing ventricular arrhythmias in a mouse model of SCD. Mice lacking the Kcne2 gene, which encodes a potassium channel β subunit associated with acquired Long QT syndrome were exposed to IR injury via coronary ligation...
February 2019: Physiological Reports
Wen-Hua Zhang, Wei-Zhu Liu, Ye He, Wen-Jie You, Jun-Yu Zhang, Hong Xu, Xiao-Li Tian, Bao-Ming Li, Lin Mei, Andrew Holmes, Bing-Xing Pan
BACKGROUND: The role of the amygdala in mediating stress coping has been long appreciated. However, basolateral amygdala (BLA) projection neurons (PNs) are organized into discrete output circuits, and it remains unclear whether stress differentially impacts these circuits. METHODS: Mice were exposed to acute restraint stress or chronic restraint stress (CRS), and c-fos expression was measured as a proxy for neuronal activation in Retrobead retrogradely labeled dorsomedial prefrontal cortex-targeting PNs (BLA→dmPFC) and non-dmPFC-targeting PNs (BLA↛dmPFC)...
December 20, 2018: Biological Psychiatry
Simon Wheeler, Ralf Schmid, Dan J Sillence
The accumulation of lipids in the late endosomes and lysosomes of Niemann⁻Pick type C disease (NPCD) cells is a consequence of the dysfunction of one protein (usually NPC1) but induces dysfunction in many proteins. We used molecular docking to propose (a) that NPC1 exports not just cholesterol, but also sphingosine, (b) that the cholesterol sensitivity of big potassium channel (BK) can be traced to a previously unappreciated site on the channel's voltage sensor, (c) that transient receptor potential mucolipin 1 (TRPML1) inhibition by sphingomyelin is likely an indirect effect, and (d) that phosphoinositides are responsible for both the mislocalization of annexin A2 (AnxA2) and a soluble NSF (N-ethylmaleimide Sensitive Fusion) protein attachment receptor (SNARE) recycling defect...
February 7, 2019: International Journal of Molecular Sciences
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