keyword
https://read.qxmd.com/read/37546746/structural-mapping-of-patient-associated-kcnma1-gene-variants
#21
Hans J Moldenhauer, Kelly Tammen, Andrea L Meredith
KCNMA1 -linked channelopathy is a neurological disorder produced by malfunctioning of the BK channel, characterized by seizure, motor abnormalities, and neurodevelopmental disability. Twenty-one KCNMA1 patient-associated variants have been classified as gain-of-function (GOF) or loss-of-function (LOF) in BK channel activity, and the remaining ∼40% are variants of uncertain significance (VUS). To address the physical relationships, this study analyzed KCNMA1 missense variants within the context of BK channel cryoEM structures...
July 28, 2023: bioRxiv
https://read.qxmd.com/read/37513884/neuroprotection-in-an-experimental-model-of-multiple-sclerosis-via-opening-of-big-conductance-calcium-activated-potassium-channels
#22
JOURNAL ARTICLE
Gareth Pryce, Sofia Sisay, Gavin Giovannoni, David L Selwood, David Baker
Big conductance calcium-activated (BK) channel openers can inhibit pathologically driven neural hyperactivity to control symptoms via hyperpolarizing signals to limit neural excitability. We hypothesized that BK channel openers would be neuroprotective during neuroinflammatory, autoimmune disease. The neurodegenerative disease was induced in a mouse experimental autoimmune encephalomyelitis model with translational value to detect neuroprotection in multiple sclerosis. Following the treatment with the BK channel openers, BMS-204253 and VSN16R, neuroprotection was assessed using subjective and objective clinical outcomes and by quantitating spinal nerve content...
July 7, 2023: Pharmaceuticals
https://read.qxmd.com/read/37425916/incorporating-physics-to-overcome-data-scarcity-in-predictive-modeling-of-protein-function-a-case-study-of-bk-channels
#23
Erik Nordquist, Guohui Zhang, Shrishti Barethiya, Nathan Ji, Kelli M White, Lu Han, Zhiguang Jia, Jingyi Shi, Jianmin Cui, Jianhan Chen
UNLABELLED: Machine learning has played transformative roles in numerous chemical and biophysical problems such as protein folding where large amount of data exists. Nonetheless, many important problems remain challenging for data-driven machine learning approaches due to the limitation of data scarcity. One approach to overcome data scarcity is to incorporate physical principles such as through molecular modeling and simulation. Here, we focus on the big potassium (BK) channels that play important roles in cardiovascular and neural systems...
June 26, 2023: bioRxiv
https://read.qxmd.com/read/37365840/mas-receptor-a-potential-strategy-in-the-management-of-ischemic-cardiovascular-diseases
#24
REVIEW
Ali Molaei, Emad Molaei, A Wallace Hayes, Gholamreza Karimi
MasR is a critical element in the RAS accessory pathway that protects the heart against myocardial infarction, ischemia-reperfusion injury, and pathological remodeling by counteracting the effects of AT1R. This receptor is mainly stimulated by Ang 1-7, which is a bioactive metabolite of the angiotensin produced by ACE2. MasR activation attenuates ischemia-related myocardial damage by facilitating vasorelaxation, improving cell metabolism, reducing inflammation and oxidative stress, inhibiting thrombosis, and stabilizing atherosclerotic plaque...
July 2023: Cell Cycle
https://read.qxmd.com/read/37333104/bk-ca-nitrosylation-is-associated-with-cerebral-microvascular-dysfunction-in-female-5x-fad-mice
#25
Josiane F Silva, Felipe D Polk, Andrea Savu, Allison M Kath, Michael T Gee, Paulo W Pires
UNLABELLED: Cerebral microvascular dysfunction and nitro-oxidative stress are present in patients with Alzheimer's disease (AD) and may contribute to disease progression and severity. Large conductance Ca 2+ -activated K + channels (BK Ca ) play an essential role in vasodilatory responses and maintenance of myogenic tone in resistance arteries. BK Ca can be modified in a pro-nitro-oxidative environment, resulting in decreased activity and vascular hyper-contractility, which can compromise cerebral blood flow regulation...
June 8, 2023: bioRxiv
https://read.qxmd.com/read/37223477/striatal-cdk5-regulates-cholinergic-neuron-activation-and-dyskinesia-like-behaviors-through-bk-channels
#26
JOURNAL ARTICLE
Chu Tong, Peng-Xiang Min, Qian Zhang, Ru-Xin Gu, Yao-Hai Wen, Yi Shi, Yu-Huan Bao, Xiang Chen, Yi-Xuan Zhang, Xing-Feng Mao, Hao-Yang Yuan, Xiu-Xiu Liu, Takuya Sasaki, Li Zhang, Feng Han, Ying-Mei Lu
Disturbance of the cholinergic system plays a crucial role in the pathological progression of neurological diseases that cause dyskinesia-like behaviors. However, the molecular mechanisms underlying this disturbance remain elusive. Here, we showed that cyclin-dependent kinase 5 ( Cdk5 ) was reduced in cholinergic neurons of midbrain according to the single-nucleus RNA sequencing analysis. Serum levels of CDK5 also decreased in patients with Parkinson's disease accompanied by motor symptoms. Moreover, Cdk5 deficiency in cholinergic neurons triggered paw tremors, abnormal motor coordination, and motor balance deficits in mice...
2023: Research: a science partner journal
https://read.qxmd.com/read/37171794/peroxisome-deficiency-in-cochlear-hair-cells-causes-hearing-loss-by-deregulating-bk-channels
#27
JOURNAL ARTICLE
Xiaolong Fu, Peifeng Wan, Ling Lu, Yingcui Wan, Ziyi Liu, Guodong Hong, Shengda Cao, Xiuli Bi, Jing Zhou, Ruifeng Qiao, Siwei Guo, Yu Xiao, Bingzheng Wang, Miao Chang, Wen Li, Peipei Li, Aizhen Zhang, Jin Sun, Renjie Chai, Jiangang Gao
The peroxisome is a ubiquitous organelle in rodent cells and plays important roles in a variety of cell types and tissues. It is previously indicated that peroxisomes are associated with auditory function, and patients with peroxisome biogenesis disorders (PBDs) are found to have hearing dysfunction, but the specific role of peroxisomes in hearing remains unclear. In this study, two peroxisome-deficient mouse models (Atoh1-Pex5-/- and Pax2-Pex5-/- ) are established and it is found that peroxisomes mainly function in the hair cells of cochleae...
July 2023: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
https://read.qxmd.com/read/37161185/a-double-channel-multiscale-depthwise-separable-convolutional-neural-network-for-abnormal-gait-recognition
#28
JOURNAL ARTICLE
Xiaoguang Liu, Yubo Wu, Meng Chen, Tie Liang, Fei Han, Xiuling Liu
Abnormal gait recognition is important for detecting body part weakness and diagnosing diseases. The abnormal gait hides a considerable amount of information. In order to extract the fine, spatial feature information in the abnormal gait and reduce the computational cost arising from excessive network parameters, this paper proposes a double-channel multiscale depthwise separable convolutional neural network (DCMSDSCNN) for abnormal gait recognition. The method designs a multiscale depthwise feature extraction block (MDB), uses depthwise separable convolution (DSC) instead of standard convolution in the module and introduces the Bottleneck (BK) structure to optimize the MDB...
February 23, 2023: Mathematical Biosciences and Engineering: MBE
https://read.qxmd.com/read/37047767/ca-2-activated-k-channels-in-progenitor-cells-of-musculoskeletal-tissues-a-narrative-review
#29
REVIEW
Roland Takács, Patrik Kovács, Rana Abdelsattar Ebeid, János Almássy, János Fodor, László Ducza, Richard Barrett-Jolley, Rebecca Lewis, Csaba Matta
Musculoskeletal disorders represent one of the main causes of disability worldwide, and their prevalence is predicted to increase in the coming decades. Stem cell therapy may be a promising option for the treatment of some of the musculoskeletal diseases. Although significant progress has been made in musculoskeletal stem cell research, osteoarthritis, the most-common musculoskeletal disorder, still lacks curative treatment. To fine-tune stem-cell-based therapy, it is necessary to focus on the underlying biological mechanisms...
April 5, 2023: International Journal of Molecular Sciences
https://read.qxmd.com/read/36890646/potassium-activates-mtorc2-dependent-sgk1-phosphorylation-to-stimulate-enac-role-in-rapid-renal-responses-to-dietary-potassium
#30
JOURNAL ARTICLE
Bidisha Saha, Waheed Shabbir, Enzo Takagi, Xin-Peng Duan, Deise Carla Almeida Leite Dellova, John Demko, Anna Manis, Dominique Loffing-Cueni, Johannes Loffing, Mads Vaarby Sørensen, Wen-Hui Wang, David Pearce
BACKGROUND: Increasing evidence implicates the signaling kinase mTOR complex-2 (mTORC2) in rapid renal responses to changes in plasma potassium concentration [K+]. However, the underlying cellular and molecular mechanisms that are relevant in vivo for these responses remain controversial. METHODS: We used Cre-Lox-mediated knockout of rapamycin-insensitive companion of TOR (Rictor) to inactivate mTORC2 in kidney tubule cells of mice. In a series of time-course experiments in wild-type and knockout mice, we assessed urinary and blood parameters and renal expression and activity of signaling molecules and transport proteins following a K+ load via gavage...
March 9, 2023: Journal of the American Society of Nephrology: JASN
https://read.qxmd.com/read/36800503/aluminum-alters-excitability-by-inhibiting-calcium-sodium-and-potassium-currents-in-bovine-chromaffin-cells
#31
JOURNAL ARTICLE
Andrés M Baraibar, Ricardo de Pascual, Victoria Jiménez Carretero, Ninfa Liccardi, Natalia Hernández Juárez, Jesús M Hernández-Guijo
Aluminum (Al3+ ) has long been related to neurotoxicity and neurological diseases. This study aims to describe the specific actions of this metal on cellular excitability and neurotransmitter release in primary culture of bovine chromaffin cells. Using voltage-clamp and current clamp recordings with the whole-cell configuration of the patch clamp technique, on-line measurement of catecholamine release and measurements of [Ca2+ ]c with Fluo-4-AM we have observed that Al3+ reduced intracellular calcium concentrations around 25% and decreased catecholamine secretion in a dose-dependent manner, with an IC50 of 89...
February 17, 2023: Journal of Neurochemistry
https://read.qxmd.com/read/36530331/use-of-cheminformatics-to-determine-potential-drug-interactions-between-popular-barbadian-botanical-medicines-and-antihypertensive-drugs
#32
JOURNAL ARTICLE
Andraniek Evadgian, Ambadasu Bharatha, Damian Cohall
Barbados has a rich traditional use of medicinal plants, especially among the older population who may have a chronic noncommunicable disease. This study aims to identify possible drug-herb interactions between popular herbal remedies used to manage elevated blood pressure and conventional antihypertensive drugs. In this study, in silico molecular docking experiments with AutoDock Vina (Scripps Research Institute, La Jolla, CA), a part of Yasara Structure software, version 20.12.24, were used to screen 30 potential phytochemicals for drug interactions from 11 popular plants in Barbados that are used for high blood pressure and could influence the pharmacology of the most prescribed antihypertensive drugs in Barbados...
December 13, 2022: ACS Omega
https://read.qxmd.com/read/36514218/deletion-of-large-conductance-calcium-activated-potassium-channels-promotes-vascular-remodelling-through-the-ctrp7-mediated-pi3k-akt-signaling-pathway
#33
JOURNAL ARTICLE
Jing Bi, Yanru Duan, Meili Wang, Chunyu He, Xiaoyue Li, Xi Zhang, Yan Tao, Yunhui Du, Huirong Liu
The large-conductance calcium-activated potassium (BK) channel is a critical regulator and potential therapeutic target of vascular tone and architecture, and abnormal expression or dysfunction of this channel is linked to many vascular diseases. Vascular remodelling is the early pathological basis of severe vascular diseases. Delaying the progression of vascular remodelling can reduce cardiovascular events, but the pathogenesis remains unclear. To clarify the role of BK channels in vascular remodelling, we use rats with BK channel α subunit knockout (BK α ‒/‒ )...
December 25, 2022: Acta Biochimica et Biophysica Sinica
https://read.qxmd.com/read/36503451/kca-related-neurological-disorders-phenotypic-spectrum-and-therapeutic-indications
#34
JOURNAL ARTICLE
Aqeela Zahra, Ru Liu, Wenzhe Han, Hui Meng, Qun Wan, YunFu Wang, Susan L Campbel, Jianping Wu
Although potassium channelopathies have been linked to a wide range of neurological con- ditions, the underlying pathogenic mechanism is not always clear, and a systematic summary of clini- cal manifestation is absent. Several neurological disorders have been associated with alterations of calcium-activated potassium channels (KCa channels), such as loss- or gain-of-function mutations, post-transcriptional modification, etc. Here, we outlined the current understanding of the molecular and cellular properties of three subtypes of KCa channels, including big conductance KCa channels (BK), small conductance KCa channels (SK), and the intermediate conductance KCa channels (IK)...
December 8, 2022: Current Neuropharmacology
https://read.qxmd.com/read/36393851/the-modulation-of-potassium-channels-by-estrogens-facilitates-neuroprotection
#35
REVIEW
Xian-Tao Li
Estrogens, the sex hormones, have the potential to govern multiple cellular functions, such as proliferation, apoptosis, differentiation, and homeostasis, and to exert numerous beneficial influences for the cardiovascular system, nervous system, and bones in genomic and/or non-genomic ways. Converging evidence indicates that estrogens serve a crucial role in counteracting neurodegeneration and ischemic injury; they are thereby being considered as a potent neuroprotectant for preventing neurological diseases such as Alzheimer's disease and stroke...
2022: Frontiers in Cell and Developmental Biology
https://read.qxmd.com/read/36379094/amyloid-%C3%AE-oligomers-disrupt-piriform-cortical-output-via-a-serotonergic-pathway
#36
JOURNAL ARTICLE
Xiaojie Wang, Mengxi Hu, Qian Xie, Chi Geng, Chen Jin, Wei Ren, Jiangpeng Fan, Tengfei Ma, Bin Hu
Although olfactory deficits have been found in patients with early-stage Alzheimer's disease (AD), the underlying mechanisms remain unclear. Here we investigated whether and how human amyloid β (Aβ) oligomers affect neural activity in the piriform cortex (PC) slices of adult mice. We found that oligomeric Aβ1-42 decreased the excitability of pyramidal neurons in the anterior PC. The effect was not blocked by glutamate or GABAA receptor antagonists, suggesting that Aβ1-42-induced hypoactivity is independent of glutamatergic and GABAergic transmission...
September 23, 2022: Neurobiology of Aging
https://read.qxmd.com/read/36368250/diethylcarbamazine-mediated-potentiation-of-emodepside-induced-paralysis-requires-trp-2-in-adult-brugia-malayi
#37
JOURNAL ARTICLE
Sudhanva S Kashyap, Mark A McHugh, Alan P Robertson, Richard J Martin
Human and veterinary filarial nematode infections are a major health concern in tropical countries. They are transmitted by biting insects and mosquitoes. Lymphatic filariasis, a group of filarial infections caused by Brugia spp. and Wucheria bancrofti affect more than 120 million people worldwide. Infected individuals develop swollen limbs and disfigurement, leading to an inability to work and ostracization from society. Control and prophylaxis for these infections involve mass drug administration combinations of anthelmintics including diethylcarbamazine (DEC)...
October 29, 2022: International Journal for Parasitology, Drugs and Drug Resistance
https://read.qxmd.com/read/36365155/bk-ca-activator-ns1619-improves-the-structure-and-function-of-skeletal-muscle-mitochondria-in-duchenne-dystrophy
#38
JOURNAL ARTICLE
Mikhail V Dubinin, Vlada S Starinets, Natalia V Belosludtseva, Irina B Mikheeva, Yuliya A Chelyadnikova, Anastasia D Igoshkina, Aliya B Vafina, Alexander A Vedernikov, Konstantin N Belosludtsev
Duchenne muscular dystrophy (DMD) is a progressive hereditary disease caused by the absence of the dystrophin protein. This is secondarily accompanied by a dysregulation of ion homeostasis, in which mitochondria play an important role. In the present work, we show that mitochondrial dysfunction in the skeletal muscles of dystrophin-deficient mdx mice is accompanied by a reduction in K+ transport and a decrease in its content in the matrix. This is associated with a decrease in the expression of the mitochondrial large-conductance calcium-activated potassium channel (mitoBKCa ) in the muscles of mdx mice, which play an important role in cytoprotection...
October 29, 2022: Pharmaceutics
https://read.qxmd.com/read/36213221/vascular-smooth-muscle-ion-channels-in-essential-hypertension
#39
REVIEW
Nuria Daghbouche-Rubio, José Ramón López-López, María Teresa Pérez-García, Pilar Cidad
Hypertension is a highly prevalent chronic disease and the major risk factor for cardiovascular diseases, the leading cause of death worldwide. Hypertension is characterized by an increased vascular tone determined by the contractile state of vascular smooth muscle cells that depends on intracellular calcium levels. The interplay of ion channels determine VSMCs membrane potential and thus intracellular calcium that controls the degree of contraction, vascular tone and blood pressure. Changes in ion channels expression and function have been linked to hypertension, but the mechanisms and molecular entities involved are not completely clear...
2022: Frontiers in Physiology
https://read.qxmd.com/read/36139381/neurodegenerative-lysosomal-storage-disorders-tpc2-comes-to-the-rescue
#40
REVIEW
Sandra Prat Castro, Veronika Kudrina, Dawid Jaślan, Julia Böck, Anna Scotto Rosato, Christian Grimm
Lysosomal storage diseases (LSDs) resulting from inherited gene mutations constitute a family of disorders that disturb lysosomal degradative function leading to abnormal storage of macromolecular substrates. In most LSDs, central nervous system (CNS) involvement is common and leads to the progressive appearance of neurodegeneration and early death. A growing amount of evidence suggests that ion channels in the endolysosomal system play a crucial role in the pathology of neurodegenerative LSDs. One of the main basic mechanisms through which the endolysosomal ion channels regulate the function of the endolysosomal system is Ca2+ release, which is thought to be essential for intracellular compartment fusion, fission, trafficking and lysosomal exocytosis...
September 8, 2022: Cells
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