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Yousra El Ghaleb, Marta Campiglio, Bernhard E Flucher
The voltage-gated calcium channel CaV 1.1a primarily functions as voltage-sensor in skeletal muscle excitation-contraction (EC) coupling. In embryonic muscle the splice variant CaV 1.1e, which lacks exon 29, additionally function as a genuine L-type calcium channel. Because previous work in most laboratories used a CaV 1.1 expression plasmid containing a single amino acid substitution (R165K) of a critical gating charge in the first voltage-sensing domain (VSD), we corrected this substitution and analyzed its effects on the gating properties of the L-type calcium currents in dysgenic myotubes...
January 14, 2019: Channels
Xiying Guo, Haowen Liu, Zhigang Huang, Yanting Wang, Yan Zhang, Lu-Yang Wang, Chunyang Cao, Sheng Wang, Jiuping Ding
Large-conductance Ca2+ -activated K+ (BK) channels are composed of a pore-forming α and a variable number of auxiliary β subunits and play important roles in regulating excitability, action potential waveforms and firing patterns, particularly in neurons and endocrine and cardiovascular cells. The β2 subunits increase the diversity of gating and pharmacological properties. Its extracellular loop contains eight cysteine residues, which can pair to form a high-order structure, underlying the stability of the extracellular loop of β2 subunits and the functional effects on BK channels...
November 26, 2018: Channels
Jaime S Horton, Takuya Shiraishi, Naghum Alfulaij, Andrea L Small-Howard, Helen C Turner, Tatsuki Kurokawa, Yasuo Mori, Alexander J Stokes
Background Activation of the atrial natriuretic signaling pathway is intrinsic to the pathological responses associated with a range of cardiovascular diseases that stress the heart, especially those involved in sustained cardiac pressure overload which induces hypertrophy and the pathological remodeling that frequently leads to heart failure. We identify transient receptor potential cation channel, subfamily V, member 1, as a regulated component, and therapeutic target of this signaling system. Methods We undertook biochemical, calcium imaging and electrophysiological experiments to analyze interactions and regulation of TRPV1...
November 13, 2018: Channels
Bohumila Jurkovicova Tarabova, Katarina Mackova, Lucia Moravcikova, Maria Karmazinova, Lubica Lacinova
Contributions of voltage sensing S4 segments in domains I - IV of CaV 3.1 channel to channel activation were analyzed. Neutralization of the uppermost charge in individual S4 segments by exchange of arginine for cysteine was employed. Mutant channels with single exchange in domains I -IV, in two adjacent domains, and in all four domains were constructed and expressed in HEK 293 cells. Changes in maximal gating charge Qmax and the relation between Qmax and maximal conductance Gmax were evaluated. Qmax was the most affected by single mutation in domain I and by double mutations in domains I + II and I + IV...
November 7, 2018: Channels
Mohammad-Reza Ghovanloo, Colin H Peters, Peter C Ruben
Voltage-gated sodium channels are key contributors to membrane excitability. These channels are expressed in a tissue-specific manner. Mutations and modulation of these channels underlie various physiological and pathophysiological manifestations. The effects of changes in extracellular pH on channel gating have been studied on several sodium channel subtypes. Among these, Nav1.5 is the most pH-sensitive channel, with Nav1.2 and Nav1.4 being mostly pH-resistant channels. However, pH effects have not been characterized on other sodium channel subtypes...
October 26, 2018: Channels
Dongyi Zhao, Jianing Li, Corey Seehus, Xuan Huang, Meimi Zhao, Shiqi Zhang, Wuyang Wang, Hong-Long Ji, Feng Guo
No abstract text is available yet for this article.
August 23, 2018: Channels
Alexandra Pinggera, Giulia Negro, Petronel Tuluc, Morris J Brown, Andreas Lieb, Jörg Striessnig
Recently, we and others identified somatic and germline de novo gain-of-function mutations in CACNA1D, the gene encoding the α1-subunit of voltage-gated Cav 1.3 Ca2+ -channels. While somatic mutations identified in aldosterone producing adenomas (APAs) underlie treatment-resistant hypertension, germline CACNA1D mutations are associated with a neurodevelopmental disorder characterized by a wide symptomatic spectrum, including autism spectrum disorder. The number of newly identified CACNA1D missense mutations is constantly growing, but their pathogenic potential is difficult to predict in silico, making functional studies indispensable to assess their contribution to disease risk...
2018: Channels
Qadeer Aziz, Yiwen Li, Andrew Tinker
Potassium currents determine the resting membrane potential and govern repolarisation in cardiac myocytes. Here, we review the various currents in the sinoatrial node focussing on their molecular and cellular properties and their role in pacemaking and heart rate control. We also describe how our recent finding of a novel ATP-sensitive potassium channel population in these cells fits into this picture.
2018: Channels
Hila Wardak, Omar A Z Tutakhel, Jenny Van Der Wijst
The renal thiazide-sensitive sodium-chloride cotransporter (NCC), located in the distal convoluted tubule (DCT) of the kidney, plays an important role in blood pressure regulation by fine-tuning sodium excretion. The human SLC12A3 gene, encoding NCC, gives rise to three isoforms, of which only the third isoform (NCC3 ) has been extensively investigated so far. However, recent studies unraveled the importance of the isoforms 1 and 2, collectively referred to as NCC splice variant (NCCSV ), in several (patho)physiological conditions...
2018: Channels
T Schneider, S Alpdogan, J Hescheler, F Neumaier
During the recording of whole cell currents from stably transfected HEK-293 cells, the decline of currents carried by the recombinant human Cav2.3+β3 channel subunits is related to adenosine triphosphate (ATP) depletion after rupture of the cells. It reduces the number of functional channels and leads to a progressive shift of voltage-dependent gating to more negative potentials (Neumaier F., et al., 2018). Both effects can be counteracted by hydrolysable ATP, whose protective action is almost completely prevented by inhibition of serine/threonine but not tyrosine or lipid kinases...
2018: Channels
Man Liu, Samuel C Dudley
Human heart failure is characterized by arrhythmogenic electrical remodeling consisting mostly of ion channel downregulations. Reversing these downregulations is a logical approach to antiarrhythmic therapy, but understanding the pathophysiological mechanisms of the reduced currents is crucial for finding the proper treatments. The unfolded protein response (UPR) is activated by endoplasmic reticulum (ER) stress and has been found to play pivotal roles in different diseases including neurodegenerative diseases, diabetes mellitus, and heart disease...
2018: Channels
Paul Linsdell
Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a member of the ATP-binding cassette (ABC) family of membrane transport proteins, most members of which function as ATP-dependent pumps. CFTR is unique among human ABC proteins in functioning not as a pump, but as an ion channel. Recent structural data has indicated that CFTR shares broadly similar overall architecture and ATP-dependent conformational changes as other ABC proteins. Functional investigations suggest that CFTR has a unique open portal connecting the cytoplasm to the transmembrane channel pore, that allows for a continuous pathway for Cl- ions to cross the membrane in one conformation...
2018: Channels
Marlen Dierich, Michael G Leitner
Kv 12.1 K+ channels are expressed in several brain areas, but no physiological function could be attributed to these subunits so far. As genetically-modified animal models are not available, identification of native Kv 12.1 currents must rely on characterization of distinct channel properties. Recently, it was shown in Xenopus laevis oocytes that Kv 12.1 channels were modulated by membrane PI(4,5)P2 . However, it is not known whether these channels are also sensitive to physiologically-relevant PI(4,5)P2 dynamics...
2018: Channels
Alessandro Alaimo, Ainhoa Etxeberria, Juan Camilo Gómez-Posada, Carolina Gomis-Perez, Juncal Fernández-Orth, Covadonga Malo, Alvaro Villarroel
Heteromers of Kv7.2/Kv7.3 subunits constitute the main substrate of the neuronal M-current that limits neuronal hyper-excitability and firing frequency. Calmodulin (CaM) binding is essential for surface expression of Kv7 channels, and disruption of this interaction leads to diseases ranging from mild epilepsy to early onset encephalopathy. In this study, we addressed the impact of a charge neutralizing mutation located at the periphery of helix B (K526N). We found that, CaM binding and surface expression was impaired, although current amplitude was not altered...
2018: Channels
Sylvia Y M Yao, James D Young
The human SLC28 family of concentrative (Na+ -dependent) nucleoside transporters has three members, hCNT1, hCNT2 and hCNT3. Previously, we have used heterologous expression in Xenopus laevis oocytes in combination with an engineered cysteine-less hCNT3 protein hCNT3(C-) to undertake systematic substituted cysteine accessibility method (SCAM) analysis of the transporter using the membrane-impermeant thiol reactive reagent p-chloromercuribenzene sulfonate (PCMBS). A continuous sequence of more than 300 individual amino acid residue positions were investigated, including the entire transport domain of the protein, as well as important elements of the corresponding hCNT3 structural domain...
2018: Channels
Liberty François-Moutal, David Donald Scott, Samantha Perez-Miller, Vijay Gokhale, May Khanna, Rajesh Khanna
Drug discovery campaigns directly targeting the voltage-gated sodium channel NaV1.7, a highly prized target in chronic pain, have not yet been clinically successful. In a differentiated approach, we demonstrated allosteric control of trafficking and activity of NaV1.7 by prevention of SUMOylation of collapsin response mediator protein 2 (CRMP2). Spinal administration of a SUMOylation incompetent CRMP2 (CRMP2 K374A) significantly attenuated pain behavior in the spared nerve injury (SNI) model of neuropathic pain, underscoring the importance of SUMOylation of CRMP2 as a pathologic event in chronic pain...
2018: Channels
Robert Bähring
Kv channel-interacting proteins (KChIPs) belong to the neuronal calcium sensor (NCS) family of Ca2+ -binding EF-hand proteins. KChIPs constitute a group of specific auxiliary β-subunits for Kv4 channels, the molecular substrate of transient potassium currents in both neuronal and non-neuronal tissues. Moreover, KChIPs can interact with presenilins to control ER calcium signaling and apoptosis, and with DNA to control gene transcription. Ca2+ binding via their EF-hands, with the consequence of conformationl changes, is well documented for KChIPs...
2018: Channels
Qing Zhang, Junjie Chen, Yao Qin, Juejin Wang, Lei Zhou
The voltage-gated L-type calcium channel (LTCC) is essential for multiple cellular processes. In the heart, calcium influx through LTCC plays an important role in cardiac electrical excitation. Mutations in LTCC genes, including CACNA1C, CACNA1D, CACNB2 and CACNA2D, will induce the dysfunctions of calcium channels, which result in the abnormal excitations of cardiomyocytes, and finally lead to cardiac arrhythmias. Nevertheless, the newly found mutations in LTCC and their functions are continuously being elucidated...
2018: Channels
Emely Thompson, Jodene Eldstrom, David Fedida
The IKs current is important in the heart's response to sympathetic stimulation. β-adrenergic stimulation increases the amount of IKs and creates a repolarization reserve that shortens the cardiac action potential duration. We have recently shown that 8-CPT-cAMP, a membrane-permeable cAMP analog, changes the channel kinetics and causes it to open more quickly and more often, as well as to higher subconductance levels, which produces an increase in the IKs current. The mechanism proposed to underlie these kinetic changes is increased activation of the voltage sensors...
2018: Channels
Alexis S Hill, Yehuda Ben-Shahar
Degenerin/Epithelial Sodium Channels (DEG/ENaCs) are a large family of animal-specific non-voltage gated ion channels, with enriched expression in neuronal and epithelial tissues. While neuronal DEG/ENaCs were originally characterized as sensory receptor channels, recent studies indicate that several DEG/ENaC family members are also expressed throughout the central nervous system. Human genome-wide association studies have linked DEG/ENaC-coding genes with several neurologic and psychiatric disorders, including epilepsy and panic disorder...
2018: Channels
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