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https://www.readbyqxmd.com/read/28619748/pore-polarity-and-charge-determine-differential-block-of-kir1-1-and-kir7-1-potassium-channels-by-the-small-molecule-inhibitor-vu590
#1
Sujay Kharade, Jonathan Sheehan, Eric Figueroa, Jens Meiler, Jerod Denton
VU590 was the first publicly disclosed, sub-micromolar-affinity (IC50=0.2 µM), small-molecule inhibitor of the inward rectifier potassium (Kir) channel, Kir1.1, an emerging diuretic target for the treatment of hypertension. VU590 also inhibits Kir7.1, albeit with 40-fold lower potency (IC50~8 µM), and has been used as a Kir7.1 tool compound to uncover new roles of the channel in regulation of myometrial contractility and melanocortin signaling in the brain. Here, we employed molecular modeling, site-directed mutagenesis, and patch clamp electrophysiology to elucidate the molecular mechanisms underlying inhibition of Kir1...
June 15, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28613412/myoendothelial-coupling-through-cx40-contributes-to-edh-induced-vasodilation-in-murine-renal-arteries-evidence-from-experiments-and-modelling
#2
Jens Christian Brasen, Cor de Wit, Charlotte Mehlin Sorensen
Regulation of renal vascular resistance plays a major role in controlling arterial blood pressure. The endothelium participates in this regulation as endothelial derived hyperpolarization plays a significant role in smaller renal arteries and arterioles but the exact mechanisms are still unknown AIM: to investigate the role of vascular gap junctions and potassium channels in the renal endothelial derived hyperpolarization. METHODS: in interlobar arteries from wild-type and connexin40 knock-out mice we assessed the role of calcium activated small (SK) and intermediate (IK) conductance potassium channels...
June 14, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28600190/understanding-the-checkpoint-blockade-in-lung-cancer-immunotherapy
#3
REVIEW
Maria G Dal Bello, Angela Alama, Simona Coco, Irene Vanni, Francesco Grossi
Immunotherapies have changed the treatment strategy of some types of tumor including melanoma and, more recently, non-small-cell lung cancer (NSCLC). Immune checkpoints are crucial for the maintenance of self-tolerance and it is known that some tumors use checkpoint systems to evade antitumor immune response. The treatment of advanced NSCLC by immune-checkpoint blockade targeting the PD1/PDL1 and CTLA4 pathways has led to significant clinical benefit either as monotherapy or in combination therapy. Moreover, checkpoint receptors such as LAG3, TIM3 and KIRs are also being investigated as potential immunotherapeutic targets...
June 7, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28582449/hiv-1-adaptation-to-nk-cell-mediated-immune-pressure
#4
Marjet Elemans, Lies Boelen, Michael Rasmussen, Søren Buus, Becca Asquith
The observation, by Alter et al., of the enrichment of NK cell "escape" variants in individuals carrying certain Killer-cell Immunoglobulin-like Receptor (KIR) genes is compelling evidence that natural killer (NK) cells exert selection pressure on HIV-1. Alter et al hypothesise that variant peptide, in complex with HLA class I molecules binds KIR receptors and either increases NK cell inhibition or decreases NK cell activation compared to wild type peptide thus leading to virus escape from the NK cell response...
June 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28579987/killer-immunoglobulin-like-receptor-allele-determination-using-next-generation-sequencing-technology
#5
Bercelin Maniangou, Nolwenn Legrand, Mehdi Alizadeh, Ulysse Guyet, Catherine Willem, Gaëlle David, Eric Charpentier, Alexandre Walencik, Christelle Retière, Katia Gagne
The impact of natural killer (NK) cell alloreactivity on hematopoietic stem cell transplantation (HSCT) outcome is still debated due to the complexity of graft parameters, HLA class I environment, the nature of killer cell immunoglobulin-like receptor (KIR)/KIR ligand genetic combinations studied, and KIR(+) NK cell repertoire size. KIR genes are known to be polymorphic in terms of gene content, copy number variation, and number of alleles. These allelic polymorphisms may impact both the phenotype and function of KIR(+) NK cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28536356/hla-c-kir-ligands-determine-the-impact-of-anti-thymocyte-globulin-atg-on-graft-versus-host-and-graft-versus-leukemia-effects-following-hematopoietic-stem-cell-transplantation
#6
Johannes Clausen, Alexandra Böhm, Irene Straßl, Olga Stiefel, Veronika Buxhofer-Ausch, Sigrid Machherndl-Spandl, Josef König, Stefan Schmidt, Hansjörg Steitzer, Martin Danzer, Hedwig Kasparu, Ansgar Weltermann, David Nachbaur
Rabbit anti-thymocyte globulins (ATGs) are widely used for the prevention of acute and chronic graft versus host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). However, most prospective and retrospective studies did not reveal an overall survival (OS) benefit associated with ATG. Homozygosity for human leukocyte antigen (HLA)-C group 1 killer-cell immunoglobulin-like receptor ligands (KIR-L), i.e. C1/1 KIR-L status, was recently shown to be a risk factor for severe aGVHD...
March 28, 2017: Biomedicines
https://www.readbyqxmd.com/read/28528709/association-between-the-killer-cell-immunoglobulin-like-receptor-a-haplotype-and-childhood-acute-lymphoblastic-leukemia
#7
Awad E Osman, Abdullah Aljuryan, Hanan Al-Harthi, Mai Almeshari
Killer immunoglobulin-like receptors (KIRs) have the ability to regulate Natural killer (NK) cell function through inhibition/activation mechanisms. Healthy human cells express HLA class I ligands on their surface, which are recognized by NK cells to avoid spontaneous cell destruction. The associations of KIRs and/or HLA class 1 ligands in leukemic patients have been studied in some populations, with some of these studies demonstrating an association of specific types with leukemia. KIRs and their corresponding HLA class 1 ligands were investigated in Saudi patients with ALL and AML and compared to healthy controls...
May 18, 2017: Human Immunology
https://www.readbyqxmd.com/read/28466469/recipient-donor-kir-ligand-matching-prevents-cmv-reactivation-post-haploidentical-t-cell-replete-transplantation
#8
Xiang-Yu Zhao, Xue-Yi Luo, Xing-Xing Yu, Xiao-Su Zhao, Ting-Ting Han, Ying-Jun Chang, Ming-Rui Huo, Lan-Ping Xu, Xiao-Hui Zhang, Kai-Yan Liu, Dan Li, Zheng-Fan Jiang, Xiao-Jun Huang
Licensed natural killer (NK) cells have been demonstrated to have anti-cytomegalovirus (CMV) activity. We prospectively analysed the human leucocyte antigen typing of donor-recipient pairs and the killer cell immunoglobulin-like receptor (KIR) typing of donors for 180 leukaemia patients to assess the predictive roles of licensed NK cells on CMV reactivation post-T-cell-replete haploidentical stem cell transplantation. Multivariate analysis showed that donor-recipient KIR ligand graft-versus-host or host-versus-graft direction mismatch was associated with increased refractory CMV infection (Hazard ratio = 2·556, 95% confidence interval, 1·377-4·744, P = 0·003) post-transplantation...
June 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28446610/conformational-changes-at-cytoplasmic-intersubunit-interactions-control-kir-channel-gating
#9
Shizhen Wang, William F Borschel, Sarah Heyman, Phillip Hsu, Colin G Nichols
The defining structural feature of inward-rectifier potassium (Kir) channels is the unique Kir cytoplasmic domain. Recently we showed that salt bridges located at the cytoplasmic domain subunit interfaces (CD-Is) of eukaryotic Kir channels control channel gating via stability of a novel inactivated closed state. The cytoplasmic domains of prokaryotic and eukaryotic Kir channels show similar conformational rearrangements to the common gating ligand, phosphatidylinositol bisphosphate (PIP2), although these exhibit opposite coupling to opening and closing transitions...
June 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28425222/class-iii-antiarrhythmic-drugs-amiodarone-and-dronedarone-impair-kir-2-1-backward-trafficking
#10
Yuan Ji, Hiroki Takanari, Muge Qile, Lukas Nalos, Marien J C Houtman, Fee L Romunde, Raimond Heukers, Paul M P van Bergen En Henegouwen, Marc A Vos, Marcel A G van der Heyden
Drug-induced ion channel trafficking disturbance can cause cardiac arrhythmias. The subcellular level at which drugs interfere in trafficking pathways is largely unknown. KIR 2.1 inward rectifier channels, largely responsible for the cardiac inward rectifier current (IK1 ), are degraded in lysosomes. Amiodarone and dronedarone are class III antiarrhythmics. Chronic use of amiodarone, and to a lesser extent dronedarone, causes serious adverse effects to several organs and tissue types, including the heart. Both drugs have been described to interfere in the late-endosome/lysosome system...
April 19, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28424684/modulation-of-human-leukocyte-antigen-c-by-human-cytomegalovirus-stimulates-kir2ds1-recognition-by-natural-killer-cells
#11
Kattria van der Ploeg, Chiwen Chang, Martin A Ivarsson, Ashley Moffett, Mark R Wills, John Trowsdale
The interaction of inhibitory killer cell Ig-like receptors (KIRs) with human leukocyte antigen (HLA) class I molecules has been characterized in detail. By contrast, activating members of the KIR family, although closely related to inhibitory KIRs, appear to interact weakly, if at all, with HLA class I. KIR2DS1 is the best studied activating KIR and it interacts with C2 group HLA-C (C2-HLA-C) in some assays, but not as strongly as KIR2DL1. We used a mouse 2B4 cell reporter system, which carries NFAT-green fluorescent protein with KIR2DS1 and a modified DAP12 adaptor protein...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28397235/-allelic-diversity-of-kir2dl4-gene-and-identification-of-five-novel-alleles-among-southern-han-chinese-population
#12
Guobin Zhang, Zhihui Deng
OBJECTIVE: To study the polymorphisms of the KIR2DL4 gene in a southern Han Chinese population. METHODS: Genomic DNA isolated from 306 unrelated individuals was amplified by using KIR2DL4-specific PCR primers. The PCR products were genotyped for the entire coding sequence by sequencing-based typing (SBT). Assignment of allelic profile was accomplished with an Assign 3.5 software. For samples with inconclusive SBT results, the RT-PCR products covering the entire coding sequence of the KIR2DL4 gene were subjected to cloning and haplotype sequencing...
April 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/28375571/hla-mismatching-favoring-host-versus-graft-nk-cell-activity-via-kir3dl1-is-associated-with-improved-outcomes-following-lung-transplantation
#13
J R Greenland, H Sun, D Calabrese, T Chong, J P Singer, J Kukreja, S R Hays, J A Golden, G H Caughey, J M Venstrom, R Rajalingam
Chronic lung allograft dysfunction (CLAD) is linked to rejection and limits survival following lung transplantation. HLA-Bw4 recipients of HLA-Bw6 grafts have enhanced host-versus-graft (HVG) natural killer (NK) cell activity mediated by killer cell immunoglobulin-like receptor (KIR)3DL1 ligand. Because NK cells may promote tolerance by depleting antigen-presenting cells, we hypothesized improved outcomes for HLA-Bw4 recipients of HLA-Bw6 grafts. We evaluated differences in acute cellular rejection and CLAD-free survival across 252 KIR3DL1+ recipients from University of California, San Francisco (UCSF)...
April 4, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28371470/role-of-renal-vascular-potassium-channels-in-physiology-and-pathophysiology
#14
REVIEW
M Salomonsson, J C Brasen, C M Sorensen
The control of renal vascular tone is important for the regulation of salt and water balance, blood pressure and the protection against damaging elevated glomerular pressure. The K(+) conductance is a major factor in the regulation of the membrane potential (Vm ) in vascular smooth muscle (VSMC) and endothelial cells (EC). The vascular tone is controlled by Vm via its effect on the opening probability of voltage-operated Ca(2+) channels (VOCC) in VSMC. When K(+) conductance increases Vm becomes more negative and vasodilation follows, while deactivation of K(+) channels leads to depolarization and vasoconstriction...
March 30, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28357111/typing-of-killer-cell-immunoglobulin-like-receptors-and-their-cognate-human-leukocyte-antigen-class-i-ligands-predicts-survival-of-chinese-han-patients-with-metastatic-non-small-cell-lung-cancer
#15
Hui Yu, Fang Liu, Benoit Sansas, Bin Kang, Xavier Preville, Xianghua Wu, Jianhua Chang, Romain Micol, Jialei Wang, Xia Meng
Non-small-cell lung cancer (NSCLC) may establish an immunosuppressive tumor microenvironment that is conducive to tumor growth. Natural killer (NK) cells play a pivotal role in immunological surveillance. Activation of NK cells partially depends on the interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands. We herein investigated the association of KIRs and HLA ligands with survival in metastatic NSCLC (mNSCLC) patients treated with chemotherapy in a Chinese Han population...
February 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28293391/gestational-diabetes-leads-to-down-regulation-of-cdk4-prb-e2f1-pathway-genes-in-pancreatic-islets-of-rat-offspring
#16
Zahra Nazari, Mohammad Nabiuni, Mohsen Saeidi, Mohammad Jafar Golalipour
OBJECTIVES: The link between a hyperglycemic intrauterine environment and the development of diabetes later in life has been observed in offspring exposed to gestational diabetes mellitus (GDM), but the underlying mechanisms for this phenomenon are still not clear. Reduced β-cells mass is a determinant in the development of diabetes (type 1 and type 2 diabetes). Some recent studies have provided evidence that the CDK4-pRB-E2F1 regulatory pathway is involved in β-cells proliferation...
February 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28288868/inhibition-of-kir4-1-potassium-channels-by-quinacrine
#17
Leticia G Marmolejo-Murillo, Iván A Aréchiga-Figueroa, Meng Cui, Eloy G Moreno-Galindo, Ricardo A Navarro-Polanco, José A Sánchez-Chapula, Tania Ferrer, Aldo A Rodríguez-Menchaca
Inwardly rectifying potassium (Kir) channels are expressed in many cell types and contribute to a wide range of physiological processes. Particularly, Kir4.1 channels are involved in the astroglial spatial potassium buffering. In this work, we examined the effects of the cationic amphiphilic drug quinacrine on Kir4.1 channels heterologously expressed in HEK293 cells, employing the patch clamp technique. Quinacrine inhibited the currents of Kir4.1 channels in a concentration and voltage dependent manner. In inside-out patches, quinacrine inhibited Kir4...
May 15, 2017: Brain Research
https://www.readbyqxmd.com/read/28202613/the-activating-human-nk-cell-receptor-kir2ds2-recognizes-a-%C3%AE-2-microglobulin-independent-ligand-on-cancer-cells
#18
Lavanya Thiruchelvam-Kyle, Sigurd E Hoelsbrekken, Per C Saether, Elisabeth Gyllensten Bjørnsen, Daniela Pende, Sigbjørn Fossum, Michael R Daws, Erik Dissen
The functions of activating members of the killer cell Ig-like receptor (KIR) family are not fully understood, as the ligands for these receptors are largely unidentified. In this study, we report that KIR2DS2 reporter cells recognize a ligand expressed by cancer cell lines. All cancer targets recognized by KIR2DS2 were also recognized by KIR2DL2 and KIR2DL3 reporters. Trogocytosis of membrane proteins from the cancer targets was observed with responding reporter cells, indicating the formation of KIR2DS2 ligand-specific immunological synapses...
April 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28196473/2-7-million-samples-genotyped-for-hla-by-next-generation-sequencing-lessons-learned
#19
Gerhard Schöfl, Kathrin Lang, Philipp Quenzel, Irina Böhme, Jürgen Sauter, Jan A Hofmann, Julia Pingel, Alexander H Schmidt, Vinzenz Lange
BACKGROUND: At the DKMS Life Science Lab, Next Generation Sequencing (NGS) has been used for ultra-high-volume high-resolution genotyping of HLA loci for the last three and a half years. Here, we report on our experiences in genotyping the HLA, CCR5, ABO, RHD and KIR genes using a direct amplicon sequencing approach on Illumina MiSeq and HiSeq 2500 instruments. RESULTS: Between January 2013 and June 2016, 2,714,110 samples largely from German, Polish and UK-based potential stem cell donors have been processed...
February 14, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28188495/cancer-treatment-and-the-kir-hla-system-an-overview
#20
REVIEW
Patrizia Leone, Valli De Re, Angelo Vacca, Franco Dammacco, Vito Racanelli
Accumulating evidence indicates that the success of cancer therapy depends not only on a combination of adequate procedures (surgery, chemotherapy and radiotherapy) that aim to eliminate all tumor cells, but also on the functional state of the host immune system. HLA and KIR molecules, in particular, are critical to the interactions between tumor cells and both innate and adaptive immune cells such as NK cells and T cells. Different KIR-HLA gene combinations as well as different HLA expression levels on tumor cells associate with variable tumor prognosis and response to treatment...
February 10, 2017: Clinical and Experimental Medicine
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