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https://www.readbyqxmd.com/read/29330545/de-novo-bk-channel-variant-causes-epilepsy-by-affecting-voltage-gating-but-not-ca2-sensitivity
#1
Xia Li, Sibylle Poschmann, Qiuyun Chen, Walid Fazeli, Nelly Jouayed Oundjian, Francesca M Snoeijen-Schouwenaars, Oliver Fricke, Erik-Jan Kamsteeg, Marjolein Willemsen, Qing Kenneth Wang
Epilepsy is one of the most common neurological diseases and it causes profound morbidity and mortality. We identified the first de novo variant in KCNMA1 (c.2984 A > G (p.(N995S)))-encoding the BK channel-that causes epilepsy, but not paroxysmal dyskinesia, in two independent families. The c.2984 A > G (p.(N995S)) variant markedly increased the macroscopic potassium current by increasing both the channel open probability and channel open dwell time. The c.2984 A > G (p.(N995S)) variant did not affect the calcium sensitivity of the channel...
January 12, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29325119/mir-96-is-required-for-normal-development-of-the-auditory-hindbrain
#2
Tina Schlüter, Christina Berger, Elena Rosengauer, Pascal Fieth, Constanze Krohs, Kathy Ushakov, Karen P Steel, Karen B Avraham, Alexander Hartmann, Felix Felmy, Hans Gerd Nothwang
The peripheral deafness gene Mir96 is expressed in both the cochlea and central auditory circuits. To investigate whether it plays a role in the auditory system beyond the cochlea, we characterized homozygous Dmdo/Dmdo mice with a point mutation in miR-96. Anatomical analysis demonstrated a significant decrease in volume of auditory nuclei in Dmdo/Dmdo mice. This decrease resulted from decreased cell size. Non-auditory structures in the brainstem of Dmdo/Dmdo mice or auditory nuclei of the congenital deaf Cldn14-/- mice revealed no such differences...
January 9, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29323236/molecular-determinants-of-ca2-sensitivity-at-the-intersubunit-interface-of-the-bk-channel-gating-ring
#3
Qin Li, Yingxin Li, Hua Wei, Hao-Min Pan, Alexandre G Vouga, Brad S Rothberg, Yunkun Wu, Jiusheng Yan
The large-conductance calcium-activated K+ (BK) channel contains two intracellular tandem Ca2+-sensing RCK domains (RCK1 and RCK2), which tetramerize into a Ca2+ gating ring that regulates channel opening by conformational expansion in response to Ca2+ binding. Interestingly, the gating ring's intersubunit assembly interface harbors the RCK2 Ca2+-binding site, known as the Ca2+ bowl. The gating ring's assembly interface is made in part by intersubunit coordination of a Ca2+ ion between the Ca2+ bowl and an RCK1 Asn residue, N449, and by apparent intersubunit electrostatic interactions between E955 in RCK2 and R786 and R790 in the RCK2 of the adjacent subunit...
January 11, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29319175/bk-channels-blockage-inhibits-hypoxia-induced-migration-and-chemoresistance-to-cisplatin-in-human-glioblastoma-cells
#4
Paolo Rosa, Luigi Catacuzzeno, Luigi Sforna, Giorgio Mangino, Silvia Carlomagno, Gabriella Mincione, Vincenzo Petrozza, Giuseppe Ragona, Fabio Franciolini, Antonella Calogero
Glioblastoma (GBM) cells express large-conductance, calcium-activated potassium (BK) channels, whose activity is important for several critical aspects of the tumor, such as migration/invasion and cell death. GBMs are also characterized by a heavy hypoxic microenvironment that exacerbates tumor aggressiveness. Since hypoxia modulates the activity of BK channels in many tissues, we hypothesized that a hypoxia-induced modulation of these channels may contribute to the hypoxia-induced GBM aggressiveness. In U87-MG cells, hypoxia induced a functional upregulation of BK channel activity, without interfering with their plasma membrane expression...
January 10, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29290926/trafficking-of-bk-channel-subunits-controls-arterial-contractility
#5
EDITORIAL
M Dennis Leo, Jonathan H Jaggar
No abstract text is available yet for this article.
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29259649/chloroform-extract-of-artemisia-annua-l-relaxes-mouse-airway-smooth-muscle
#6
Jun Huang, Li-Qun Ma, Yongle Yang, Nana Wen, Wan Zhou, Congli Cai, Qing-Hua Liu, Jinhua Shen
Artemisia annua L. belongs to the Asteraceae family, which is indigenous to China. It has valuable pharmacological properties, such as antimalarial, anti-inflammatory, and anticancer properties. However, whether it possesses antiasthma properties is unknown. In the current study, chloroform extract of Artemisia annua L. (CEAA) was prepared, and we found that CEAA completely eliminated acetylcholine (ACh) or high K+-elicited (80 mM) contractions of mouse tracheal rings (TRs). Patch-clamp technique and ion channel blockers were employed to explore the underlying mechanisms of the relaxant effect of CEAA...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/29248193/effects-of-mechanical-stretch-on-the-functions-of-bk-and-l-type-ca2-channels-in-vascular-smooth-muscle-cells
#7
Zhiguo Zhang, Yuqiao Wen, Jing Du, Yang Yu, Sisi Liu, Xiaoan Wu, Hucheng Zhao
It is well recognized that pathologically increased mechanical stretch plays a critical role in vascular remodeling during hypertension. However, how the stretch modulates the functions of ion channels of vascular smooth muscle cells (VSMCs) remains to be elucidated. Here, we demonstrated the effects of mechanical stretch on the activity of large conductance calcium, voltage-activated potassium (BK) and L-type Ca2+ channels. In comparison with 5% stretch (physiological), 15% stretch (pathological) upregulated the current density of L-type Ca2+ and BK channels as well as the frequency and amplitude of calcium oscillation in VSMCs...
November 23, 2017: Journal of Biomechanics
https://www.readbyqxmd.com/read/29237755/differential-contribution-of-ca2-sources-to-day-and-night-bk-current-activation-in-the-circadian-clock
#8
Joshua P Whitt, Beth A McNally, Andrea L Meredith
Large conductance K+ (BK) channels are expressed widely in neurons, where their activation is regulated by membrane depolarization and intracellular Ca2+ (Ca2+i). To enable this regulation, BK channels functionally couple to both voltage-gated Ca2+ channels (VGCCs) and channels mediating Ca2+ release from intracellular stores. However, the relationship between BK channels and their specific Ca2+ source for particular patterns of excitability is not well understood. In neurons within the suprachiasmatic nucleus (SCN)-the brain's circadian clock-BK current, VGCC current, and Ca2+i are diurnally regulated, but paradoxically, BK current is greatest at night when VGCC current and Ca2+i are reduced...
December 13, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/29217678/hrpu-2-a-homologue-of-mammalian-hnrnp-u-regulates-synaptic-transmission-by-controlling-the-expression-of-slo-2-potassium-channel-in-c-elegans
#9
Ping Liu, Sijie Jason Wang, Zhao-Wen Wang, Bojun Chen
Slo2 channels are large-conductance potassium channels abundantly expressed in the nervous system. However, it is unclear how their expression level in neurons is regulated. Here we report that HRPU-2, an RNA-binding protein homologous to mammalian hnRNP U, plays an important role in regulating the expression of SLO-2 (a homologue of mammalian Slo2) in C. elegans Loss-of-function (lf) mutants of hrpu-2 were isolated in a genetic screen for suppressors of a sluggish phenotype caused by a hyperactive SLO-2. In hrpu-2(lf) mutants, SLO-2-mediated delayed outward currents in neurons are greatly decreased, and neuromuscular synaptic transmission is enhanced...
December 7, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29211339/%C3%AE-3-adrenoceptor-agonists-inhibit-carbachol-evoked-ca2-oscillations-in-murine-detrusor-myocytes
#10
Caoimhin S Griffin, Eamonn Bradley, Mark A Hollywood, Noel G McHale, Keith D Thornbury, Gerard P Sergeant
OBJECTIVE: To test if carbachol-evoked Ca2+ oscillations in freshly isolated murine detrusor myocytes were affected by β3-adrenoceptor modulators. MATERIAL & METHODS: Isometric tension recordings were made from strips of murine detrusor and intracellular Ca2+ measurements were made from isolated detrusor myocytes using confocal microscopy. Transcriptional expression of β-AR sub-types in detrusor strips and isolated detrusor myocytes was assessed using RT-PCR and real-time quantitative PCR...
December 6, 2017: BJU International
https://www.readbyqxmd.com/read/29204711/voltage-sensitive-potassium-channels-of-the-bk-type-and-their-coding-genes-are-alcohol-targets-in-neurons
#11
Alex M Dopico, Anna N Bukiya, Jill C Bettinger
Among all members of the voltage-gated, TM6 ion channel superfamily, the proteins that constitute calcium- and voltage-gated potassium channels of large conductance (BK) and their coding genes are unique for their involvement in ethanol-induced disruption of normal physiology and behavior. Moreover, in vitro studies document that BK activity is modified by ethanol with an EC50~23 mM, which is near blood alcohol levels considered legal intoxication in most states of the USA (0.08 g/dL = 17.4 mM). Following a succinct introduction to our current understanding of BK structure and function in central neurons, with a focus on neural circuits that contribute to the neurobiology of alcohol use disorders (AUD), we review the modifications in organ physiology by alcohol exposure via BK and the different molecular elements that determine the ethanol response of BK in alcohol-naïve systems, including the role of an ethanol-recognizing site in the BK-forming slo1 protein, modulation of accessory BK subunits, and their coding genes...
December 5, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29188803/activation-of-human-smooth-muscle-bk-channels-by-hydrochlorothiazide-requires-cell-integrity-and-the-presence-of-bk-%C3%AE-1-subunit
#12
Pedro Martín, Melisa Moncada, Guruprasad Kuntamallappanavar, Alex M Dopico, Verónica Milesi
Thiazide-like diuretics are the most commonly used drugs to treat arterial hypertension, with their efficacy being linked to their chronic vasodilatory effect. Previous studies suggest that activation of the large conductance voltage- and Ca2+-dependent K+ (BK) channel (Slo 1, MaxiK channel) is responsible for the thiazide-induced vasodilatory effect. But the direct electrophysiological evidence supporting this claim is lacking. BK channels can be associated with one small accessory β-subunit (β1-β4) that confers specific biophysical and pharmacological characteristics to the current phenotype...
November 30, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29163049/tagging-of-endogenous-bk-channels-with-a-fluorogen-activating-peptide-reveals-%C3%AE-4-mediated-control-of-channel-clustering-in-cerebellum
#13
Christopher P Pratt, Dika A Kuljis, Gregg E Homanics, Jianjun He, Dmytro Kolodieznyi, Srikanth Dudem, Mark A Hollywood, Alison L Barth, Marcel P Bruchez
BK channels are critical regulators of neuronal activity, controlling firing, neurotransmitter release, cerebellar function, and BK channel mutations have been linked to seizure disorders. Modulation of BK channel gating is well characterized, regulated by accessory subunit interactions, intracellular signaling pathways, and membrane potential. In contrast, the role of intracellular trafficking mechanisms in controlling BK channel function, especially in live cells, has been less studied. Fluorogen-activating peptides (FAPs) are well-suited for trafficking and physiological studies due to the binding of malachite green (MG)-based dyes with sub-nanomolar affinity to the FAP, resulting in bright, photostable, far-red fluorescence...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29160573/activation-of-voltage-dependent-k-channels-strongly-limits-hypoxia-induced-elevation-of-ca-2-i-in-rat-carotid-body-glomus-cells
#14
Jiaju Wang, Donghee Kim
Large-conductance KCa (BK) and other voltage-dependent K(+) channels (Kv) are highly expressed in carotid body (CB) glomus cells, but their role in hypoxia-induced excitation is still not well defined and remains controversial. We addressed this issue by studying the effects of inhibitors of BK (IBTX) and BK/Kv (TEA/4-AP) on [Ca(2+) ]i responses to a wide range of hypoxia at different levels of resting cell Em. IBTX and TEA/4-AP did not affect the basal [Ca(2+) ]i in isolated glomus cells bathed in 5 mm KClo , but elicited transient increases in [Ca(2+) ]i in cells that were moderately depolarized (11-20 mV) by elevation of [KCl]o (12-20 mm)...
November 21, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29152668/the-role-of-astrocytic-calcium-and-trpv4-channels-in-neurovascular-coupling
#15
Allanah Kenny, Michael J Plank, Tim David
Neuronal activity evokes a localised change in cerebral blood flow in a response known as neurovascular coupling (NVC). Although NVC has been widely studied the exact mechanisms that mediate this response remain unclear; in particular the role of astrocytic calcium is controversial. Mathematical modelling can be a useful tool for investigating the contribution of various signalling pathways towards NVC and for analysing the underlying cellular mechanisms. The lumped parameter model of a neurovascular unit with both potassium and nitric oxide (NO) signalling pathways and comprised of neurons, astrocytes, and vascular cells has been extended to include the glutamate induced astrocytic calcium pathway with epoxyeicosatrienoic acid (EET) signalling and the stretch dependent TRPV4 calcium channel on the astrocytic endfoot...
November 20, 2017: Journal of Computational Neuroscience
https://www.readbyqxmd.com/read/29145442/downregulation-of-kcnmb4-expression-and-changes-in-bk-channel-subtype-in-hippocampal-granule-neurons-following-seizure-activity
#16
Luke E Whitmire, Ling Ling, Vladslav Bugay, Chase M Carver, Santosh Timilsina, Hui-Hsiu Chuang, David B Jaffe, Mark S Shapiro, Jose E Cavazos, Robert Brenner
A major challenge is to understand maladaptive changes in ion channels that sets neurons on a course towards epilepsy development. Voltage- and calcium-activated K+ (BK) channels contribute to early spike timing in neurons, and studies indicate that the BK channel plays a pathological role in increasing excitability early after a seizure. Here, we have investigated changes in BK channels and their accessory β4 subunit (KCNMB4) in dentate gyrus (DG) granule neurons of the hippocampus, key neurons that regulate excitability of the hippocampus circuit...
2017: PloS One
https://www.readbyqxmd.com/read/29144974/double-nanodomain-coupling-of-calcium-channels-ryanodine-receptors-and-bk-channels-controls-the-generation-of-burst-firing
#17
Tomohiko Irie, Laurence O Trussell
Action potentials clustered into high-frequency bursts play distinct roles in neural computations. However, little is known about ionic currents that control the duration and probability of these bursts. We found that, in cartwheel inhibitory interneurons of the dorsal cochlear nucleus, the likelihood of bursts and the interval between their spikelets were controlled by Ca2+ acting across two nanodomains, one between plasma membrane P/Q Ca2+ channels and endoplasmic reticulum (ER) ryanodine receptors and another between ryanodine receptors and large-conductance, voltage- and Ca2+-activated K+ (BK) channels...
November 15, 2017: Neuron
https://www.readbyqxmd.com/read/29136290/the-role-of-ca-2-dependent-k-channels-at-the-rat-corticostriatal-synapses-revealed-by-paired-pulse-stimulation
#18
Angel A Robles G, Ana V Vega, Carolina Gonzalez-Sandoval, Jaime Barral
Potassium channels play an important role in modulating synaptic activity both at presynaptic and postsynaptic levels. We have shown before that presynaptically located KV and KIR channels modulate the strength of corticostriatal synapses in rat brain, but the role of other types of potassium channels at these synapses remains largely unknown. Here we show that calcium-dependent potassium channels BK-type but not SK-type channels are located presynaptically in corticostriatal synapses. We stimulated cortical neurons in rat brain slices and recorded postsynaptic excitatory potentials (EPSP) in medium spiny neurons (MSN) in dorsal neostriatum...
November 14, 2017: Synapse
https://www.readbyqxmd.com/read/29051185/cgmp-elevating-compounds-and-ischemic-conditioning-provide-cardioprotection-against-ischemia-and-reperfusion-injury-via-cardiomyocyte-specific-bk-channels
#19
Sandra Frankenreiter, Piotr Bednarczyk, Angelina Kniess, Nadja Bork, Julia Straubinger, Piotr Koprowski, Antoni Wrzosek, Eva Mohr, Angela Logan, Michael P Murphy, Meinrad Gawaz, Thomas Krieg, Adam Szewczyk, Viacheslav O Nikolaev, Peter Ruth, Robert Lukowski
Background -The nitric oxide-sensitive guanylyl cyclase (NO-GC)/cyclic guanosine-3',5'-monophosphate (cGMP)/cGMP-dependent protein kinase type I (cGKI)-signaling pathway can afford protection against the ischemia and reperfusion (I/R) injury that occurs during myocardial infarction (MI). Reportedly, voltage and Ca(2+)-activated K(+) channels of the BK-type are stimulated by cGMP/cGKI and recent ex-vivo studies implicated that increased BK activity favors the survival of the myocardium at I/R. It remains unclear, however, whether the molecular events downstream of cGMP involve BK channels present in cardiomyocytes (CMs) or in other cardiac cell types...
October 19, 2017: Circulation
https://www.readbyqxmd.com/read/29050967/role-of-k-channels-in-regulating-spontaneous-activity-in-the-muscularis-mucosae-of-guinea-pig-bladder
#20
Ken Lee, Ayu Isogai, Minori Antoh, Shunichi Kajioka, Masatoshi Eto, Hikaru Hashitani
To explore the roles of various K(+) channels in regulating the spontaneous activity of bladder muscularis mucosae (MM) that is considered to play an important role in maintaining mucosal function. Effects of K(+) channel modulators on electrical and contractile activity in the guinea-pig bladder MM were examined using intracellular microelectrode and isometric tension recording. The MM predominately generated bursting spontaneous action potentials (SAPs) and phasic contractions (SPCs) that were blocked by nifedipine (1µM)...
October 16, 2017: European Journal of Pharmacology
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