keyword
https://read.qxmd.com/read/38042986/structural-mapping-of-patient-associated-kcnma1-gene-variants
#1
JOURNAL ARTICLE
Hans J Moldenhauer, Kelly Tammen, Andrea L Meredith
KCNMA1-linked channelopathy is a neurological disorder characterized by seizures, motor abnormalities, and neurodevelopmental disabilities. The disease mechanisms are predicted to result from alterations in KCNMA1-encoded BK K+ channel activity; however, only a subset of the patient-associated variants have been functionally studied. The localization of these variants within the tertiary structure or evaluation by pathogenicity algorithms has not been systematically assessed. In this study, 82 nonsynonymous patient-associated KCNMA1 variants were mapped within the BK channel protein...
December 1, 2023: Biophysical Journal
https://read.qxmd.com/read/37958656/down-regulation-of-cyp3a4-by-the-k-ca-1-1-inhibition-is-responsible-for-overcoming-resistance-to-doxorubicin-in-cancer-spheroid-models
#2
JOURNAL ARTICLE
Susumu Ohya, Junko Kajikuri, Hiroaki Kito, Miki Matsui
The large-conductance Ca2+ -activated K+ channel, KCa 1.1, plays a pivotal role in cancer progression, metastasis, and the acquisition of chemoresistance. Previous studies indicated that the pharmacological inhibition of KCa 1.1 overcame resistance to doxorubicin (DOX) by down-regulating multidrug resistance-associated proteins in the three-dimensional spheroid models of human prostate cancer LNCaP, osteosarcoma MG-63, and chondrosarcoma SW-1353 cells. Investigations have recently focused on the critical roles of intratumoral, drug-metabolizing cytochrome P450 enzymes (CYPs) in chemoresistance...
October 27, 2023: International Journal of Molecular Sciences
https://read.qxmd.com/read/37937323/meta-analysis-of-microarray-data-to-determine-gene-indicators-involved-in-the-cisplatin-resistance-in-ovarian-cancer
#3
JOURNAL ARTICLE
Somayeh Hashemi Sheikhshabani, Zeinab Amini-Farsani, Nesa Kazemifard, Parastoo Modarres, Zahra Amini-Farsani, Mir Davood Omrani, Soudeh Ghafouri-Fard
BACKGROUND: Significant miss-expressed gene indicators contributing to cisplatin resistance in ovarian cancer have not been completely understood. It seems that several regulatory genes and signaling pathways are associated with the emergence of the chemo-resistant phenotype. AIMS: Here, a meta-analysis approach was adopted to assess deregulated genes involved in relapse after the first line of chemotherapy (cisplatin). METHODS AND RESULTS: To do so, six ovarian cancer libraries were gathered from GEO repository...
December 2023: Cancer reports
https://read.qxmd.com/read/37686437/selective-inhibition-of-pulmonary-vein-excitability-by-constitutively-active-girk-channels-blockade-in-rats
#4
JOURNAL ARTICLE
Ian Findlay, Côme Pasqualin, Angèle Yu, Véronique Maupoil, Pierre Bredeloux
Pulmonary veins (PV) are the main source of ectopy, triggering atrial fibrillation. This study investigated the roles of G protein-coupled inwardly rectifying potassium (GIRK) channels in the PV and the left atrium (LA) of the rat. Simultaneous intracellular microelectrode recording from the LA and the PV of the rat found that in the presence or absence of acetylcholine, the GIRK channel blocker tertiapin-Q induced AP duration elongation in the LA and the loss of over-shooting AP in the PV, suggesting the presence of constitutively active GIRK channels in these tissues...
September 4, 2023: International Journal of Molecular Sciences
https://read.qxmd.com/read/37632788/an-integrated-approach-for-early-in-vitro-seizure-prediction-utilising-hipsc-neurons-and-human-ion-channel-assays
#5
JOURNAL ARTICLE
Kimberly Rockley, Ruth Roberts, Hannah Jennings, Karen Jones, Myrtle Davis, Paul Levesque, Michael Morton
Seizure liability remains a significant cause of attrition throughout drug development. Advances in stem cell biology coupled with an increased understanding of the role of ion channels in seizure offer an opportunity for a new paradigm in screening. We assessed the activity of 15 pro-seizurogenic compounds (7 CNS active therapies, 4 GABA receptor antagonists and 4 other reported seizurogenic compounds) using automated electrophysiology against a panel of 14 ion channels (Nav1.1, Nav1.2, Nav1.6, Kv7.2/7.3, Kv7...
August 26, 2023: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://read.qxmd.com/read/37057569/erectile-dysfunction-and-altered-contribution-of-kca1-1-and-kca2-3-channels-in-the-penile-tissue-of-type-2-diabetic-db-db-mice
#6
JOURNAL ARTICLE
Simon Comerma-Steffensen, Judit Prat-Duran, Susie Mogensen, Rafael Fais, Estéfano Pinilla, Ulf Simonsen
BACKGROUND: Activation of endothelial small conductance calcium-activated K+ channels (KCa2.3) and intermediate conductance calcium-activated K+ channels (KCa3.1) leads to vascular relaxation. We found endothelial KCa2.3 down-regulation in the corpus cavernosum diminishes erectile function. AIM: We hypothesized that in type-2 diabetic mice, the function of KCa2.3 and KCa1.1 channels is impaired in erectile tissue. METHODS: Erectile function was measured, and corpus cavernosum strips were mounted for functional studies and processed for qPCR and immunoblotting...
May 1, 2022: Journal of Sexual Medicine
https://read.qxmd.com/read/36838628/interaction-of-some-asymmetrical-porphyrins-with-u937-cell-membranes-in-vitro-and-in-silico-studies
#7
JOURNAL ARTICLE
Dragos Paul Mihai, Rica Boscencu, Gina Manda, Andreea Mihaela Burloiu, Georgiana Vasiliu, Ionela Victoria Neagoe, Radu Petre Socoteanu, Dumitru Lupuliasa
The aim of the present study was to assess the effects exerted in vitro by three asymmetrical porphyrins (5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin, 5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrinatozinc(II), and 5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrinatocopper(II)) on the transmembrane potential and the membrane anisotropy of U937 cell lines, using bis-(1,3-dibutylbarbituric acid)trimethine oxonol (DiBAC4(3)) and 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p-toluenesulfonate (TMA-DPH), respectively, as fluorescent probes for fluorescence spectrophotometry...
February 8, 2023: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/36752210/intestinal-distension-orchestrates-neuronal-activity-in-the-enteric-nervous-system-of-adult-mice
#8
JOURNAL ARTICLE
Jean-Baptiste Cavin, Preedajit Wongkrasant, Joel B Glover, Onesmo B Balemba, Wallace K MacNaughton, Keith A Sharkey
The enteric nervous system (ENS) regulates the motor, secretory and defensive functions of the gastrointestinal tract. Enteric neurons integrate mechanical and chemical inputs from the gut lumen to generate complex motor outputs. How intact enteric neural circuits respond to changes in the gut lumen is not well understood. We recorded intracellular calcium in live-cell confocal recordings in neurons from intact segments of mouse intestine in order to investigate neuronal response to luminal mechanical and chemical stimuli...
February 8, 2023: Journal of Physiology
https://read.qxmd.com/read/36326690/kca1-1-channels-contribute-to-optogenetically-driven-post-stimulation-silencing-in-cerebellar-molecular-layer-interneurons
#9
JOURNAL ARTICLE
Merouann Kassa, Jonathan Bradley, Abdelali Jalil, Isabel Llano
Using cell-attached recordings from molecular layer interneurons (MLI) of the cerebellar cortex of adult mice expressing channel rhodopsin 2, we show that wide-field optical activation induces an increase in firing rate during illumination and a firing pause when the illumination ends (post-stimulation silencing; PSS). Significant spike rate changes with respect to basal firing rate were observed for optical activations lasting 200 ms and 1 s as well as for 1 s long trains of 10 ms pulses at 50 Hz. For all conditions, the net effect of optical activation on the integrated spike rate is significantly reduced because of PSS...
January 2, 2023: Journal of General Physiology
https://read.qxmd.com/read/36203817/effect-of-an-autism-associated-kcnmb2-variant-g124r-on-bk-channel-properties
#10
JOURNAL ARTICLE
Hans J Moldenhauer, Ria L Dinsdale, Sara Alvarez, Alberto Fernández-Jaén, Andrea L Meredith
BK K+ channels are critical regulators of neuron and muscle excitability, comprised of a tetramer of pore-forming αsubunits from the KCNMA1 gene and cell- and tissue-selective β subunits ( KCNMB1-4 ). Mutations in KCNMA1 are associated with neurological disorders, including autism. However, little is known about the role of neuronal BK channel β subunits in human neuropathology. The β2 subunit is expressed in central neurons and imparts inactivation to BK channels, as well as altering activation and deactivation gating...
2022: Current research in physiology
https://read.qxmd.com/read/36142445/the-heag1-k-channel-inhibitor-astemizole-stimulates-ca-2-deposition-in-saos-2-and-mg-63-osteosarcoma-cultures
#11
JOURNAL ARTICLE
Beáta Mészáros, Agota Csoti, Tibor G Szanto, Andrea Telek, Katalin Kovács, Agnes Toth, Julianna Volkó, Gyorgy Panyi
The hEag1 (Kv10.1) K+ channel is normally found in the brain, but it is ectopically expressed in tumor cells, including osteosarcoma. Based on the pivotal role of ion channels in osteogenesis, we tested whether pharmacological modulation of hEag1 may affect osteogenic differentiation of osteosarcoma cell lines. Using molecular biology (RT-PCR), electrophysiology (patch-clamp) and pharmacology (astemizole sensitivity, IC50 = 0.135 μM) we demonstrated that SaOS-2 osteosarcoma cells also express hEag1 channels...
September 11, 2022: International Journal of Molecular Sciences
https://read.qxmd.com/read/36007181/ion-channels-and-channelopathies-in-glomeruli
#12
REVIEW
Alexander Staruschenko, Rong Ma, Oleg Palygin, Stuart E Dryer
An essential step in renal function entails the formation of an ultrafiltrate that is delivered to the renal tubules for subsequent processing. This process, known as glomerular filtration, is controlled by intrinsic regulatory systems and by paracrine, neuronal, and endocrine signals that converge onto glomerular cells. In addition, the characteristics of glomerular fluid flow, such as the glomerular filtration rate and the glomerular filtration fraction, play an important role in determining blood flow to the rest of the kidney...
August 25, 2022: Physiological Reviews
https://read.qxmd.com/read/36005518/novel-labdane-diterpenes-based-synthetic-derivatives-identification-of-a-bifunctional-vasodilator-that-inhibits-ca-v-1-2-and-stimulates-k-ca-1-1-channels
#13
JOURNAL ARTICLE
Gabriele Carullo, Simona Saponara, Amer Ahmed, Beatrice Gorelli, Sarah Mazzotta, Alfonso Trezza, Beatrice Gianibbi, Giuseppe Campiani, Fabio Fusi, Francesca Aiello
Sesquiterpenes such as leucodin and the labdane-type diterpene manool are natural compounds endowed with remarkably in vitro vasorelaxant and in vivo hypotensive activities. Given their structural similarity with the sesquiterpene lactone (+)-sclareolide, this molecule was selected as a scaffold to develop novel vasoactive agents. Functional, electrophysiology, and molecular dynamics studies were performed. The opening of the five-member lactone ring in the (+)-sclareolide provided a series of labdane-based small molecules, promoting a significant in vitro vasorelaxant effect...
August 13, 2022: Marine Drugs
https://read.qxmd.com/read/35889386/vietnamese-dalbergia-tonkinensis-a-promising-source-of-mono-and-bifunctional-vasodilators
#14
JOURNAL ARTICLE
Nguyen Manh Cuong, Ninh The Son, Ngu Truong Nhan, Yoshiyasu Fukuyama, Amer Ahmed, Simona Saponara, Alfonso Trezza, Beatrice Gianibbi, Ginevra Vigni, Ottavia Spiga, Fabio Fusi
Hypertension is a risk factor for cardiovascular diseases, which are the main cause of morbidity and mortality in the world. In the search for new molecules capable of targeting KCa 1.1 and CaV 1.2 channels, the expression of which is altered in hypertension, the in vitro vascular effects of a series of flavonoids extracted from the heartwoods, roots, and leaves of Dalbergia tonkinensis Prain, widely used in traditional medicine, were assessed. Rat aorta rings, tail artery myocytes, and docking and molecular dynamics simulations were used to analyse their effect on these channels...
July 14, 2022: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/35699659/cm28-a-scorpion-toxin-having-a-unique-primary-structure-inhibits-kv1-2-and-kv1-3-with-high-affinity
#15
JOURNAL ARTICLE
Muhammad Umair Naseem, Edson Carcamo-Noriega, José Beltrán-Vidal, Jesus Borrego, Tibor G Szanto, Fernando Z Zamudio, Gustavo Delgado-Prudencio, Lourival D Possani, Gyorgy Panyi
The Cm28 in the venom of Centruroides margaritatus is a short peptide consisting of 27 amino acid residues with a mol wt of 2,820 D. Cm28 has <40% similarity with other known α-KTx from scorpions and lacks the typical functional dyad (lysine-tyrosine) required to block KV channels. However, its unique sequence contains the three disulfide-bond traits of the α-KTx scorpion toxin family. We propose that Cm28 is the first example of a new subfamily of α-KTxs, registered with the systematic number α-KTx32...
August 1, 2022: Journal of General Physiology
https://read.qxmd.com/read/35321830/erectile-dysfunction-and-altered-contribution-of-kca1-1-and-kca2-3-channels-in-the-penile-tissue-of-type-2-diabetic-db-db-mice
#16
JOURNAL ARTICLE
Simon Comerma-Steffensen, Judit Prat-Duran, Susie Mogensen, Rafael Fais, Estéfano Pinilla, Ulf Simonsen
BACKGROUND: Activation of endothelial small conductance calcium-activated K+ channels (KCa2.3) and intermediate conductance calcium-activated K+ channels (KCa3.1) leads to vascular relaxation. We found endothelial KCa2.3 down-regulation in the corpus cavernosum diminishes erectile function. AIM: We hypothesized that in type-2 diabetic mice, the function of KCa2.3 and KCa1.1 channels is impaired in erectile tissue. METHODS: Erectile function was measured, and corpus cavernosum strips were mounted for functional studies and processed for qPCR and immunoblotting...
May 2022: Journal of Sexual Medicine
https://read.qxmd.com/read/35141357/lisdexamfetamine-therapy-in-paroxysmal-non-kinesigenic-dyskinesia-associated-with-the-kcnma1-n999s-variant
#17
Sotirios Keros, Jennifer Heim, Wejdan Hakami, Efrat Zohar-Dayan, Bruria Ben-Zeev, Zach Grinspan, Michael C Kruer, Andrea L Meredith
BACKGROUND: KCNMA1 -linked channelopathy is a rare movement disorder first reported in 2005. Paroxysmal non-kinesigenic dyskinesia (PNKD) in KCNMA1 -linked channelopathy is the most common symptom in patients harboring the KCNMA1 -N999S mutation. PNKD episodes occur up to hundreds of times daily with significant morbidity and limited treatment options, often in the context of epilepsy. CASES: We report 6 cases with the KCNMA1 -N999S variant treated with lisdexamfetamine (0...
February 2022: Movement Disorders Clinical Practice
https://read.qxmd.com/read/35102550/the-vrac-blocker-dcpib-directly-gates-the-bk-channels-and-increases-intracellular-ca-2-in-melanoma-and-pancreatic-duct-adenocarcinoma-pdac-cell-lines
#18
JOURNAL ARTICLE
Paolo Zuccolini, Loretta Ferrera, Alessia Remigante, Cristiana Picco, Raffaella Barbieri, Sara Bertelli, Oscar Moran, Paola Gavazzo, Michael Pusch
BACKGROUND AND PURPOSE: The Volume Regulated Anion Channel (VRAC) is known to be involved in different aspects of cancer cell behavior and response to therapies. For this reason, we investigated the effect of DCPIB, a presumably specific blocker of VRAC, in two types of cancer: pancreatic duct adenocarcinoma (PDAC) and melanoma. EXPERIMENTAL APPROACH: For this investigation, we used patch-clamp electrophysiology, supported by Ca2+ imaging, gene expression analysis, docking simulation and mutagenesis...
January 31, 2022: British Journal of Pharmacology
https://read.qxmd.com/read/34948357/k-ca-1-1-k-channel-inhibition-overcomes-resistance-to-antiandrogens-and-doxorubicin-in-a-human-prostate-cancer-lncap-spheroid-model
#19
JOURNAL ARTICLE
Susumu Ohya, Junko Kajikuri, Kyoko Endo, Hiroaki Kito, Miki Matsui
Several types of K+ channels play crucial roles in tumorigenicity, stemness, invasiveness, and drug resistance in cancer. Spheroid formation of human prostate cancer (PC) LNCaP cells with ultra-low attachment surface cultureware induced the up-regulation of cancer stem cell markers, such as NANOG, and decreased the protein degradation of the Ca2+ -activated K+ channel KCa 1.1 by down-regulating the E3 ubiquitin ligase, FBXW7, compared with LNCaP monolayers. Accordingly, KCa 1.1 activator-induced hyperpolarizing responses were larger in isolated cells from LNCaP spheroids...
December 17, 2021: International Journal of Molecular Sciences
https://read.qxmd.com/read/34826228/citral-inhibits-the-nociception-in-the-rat-formalin-test-effect-of-metformin-and-blockers-of-opioid-receptor-and-the-no-cgmp-k-channel-pathway
#20
JOURNAL ARTICLE
Mario I Ortiz, Raquel Cariño-Cortés, Víctor M Muñoz-Pérez, Carlo Eduardo Medina-Solís, Gilberto Castañeda-Hernández
The objective of the present study was to scrutinize the effect of nitric oxide (NO), cyclic GMP (cGMP), potassium channel blockers, and metformin on the citral-produced peripheral antinociception. The rat paw 1% formalin test was used to assess nociception and antinociception. Rats were treated with local peripheral administration of citral (10-100 µg/paw). The antinociception of citral (100 µg/paw) was evaluated with and without the local pretreatment of naloxone, NG-L-nitro-arginine methyl ester (L-NAME, a NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor), metformin, opioid receptors antagonists, and K+ channel blockers...
April 2022: Canadian Journal of Physiology and Pharmacology
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