scholarly journals Cantu syndrome-associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms

2017 ◽  
Author(s):  
Conor McClenaghan ◽  
Alex Hanson ◽  
Monica Sala-Rabanal ◽  
Helen I. Roessler ◽  
Dragana Josifova ◽  
...  
Keyword(s):  
Katp Channel ◽  
Molecular Mechanisms ◽  
Cardiovascular Disorder ◽  
Major Effect ◽  
Channel Activity ◽  
Gain Of Function ◽  
Structural Domains ◽  
Equivalent Position ◽  
Genes Encoding ◽  
Patch Clamp Electrophysiology

AbstractThe complex cardiovascular disorder Cantu Syndrome arises from gain-of-function mutations in either KCNJ8 or ABCC9, the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (KATP) channels. Recent reports indicate that such mutations can increase channel activity by multiple molecular mechanisms. In this study, we determine the mechanism by which KATP function is altered by several mutations in distinct structural domains of SUR2: D207E in the intracellular L0-linker and Y985S, G989E, M1060I, and R1154Q/W in TMD2. Mutations were engineered at their equivalent position in rat SUR2A (D207E, Y981S, G985E, M1056I and R1150Q/W) and functional effects were investigated using macroscopic rubidium (86Rb+) efflux assays and patch clamp electrophysiology. The results show that D207E increases KATP activity by increasing intrinsic stability of the open state, whilst the cluster of Y981S/G985E/M1056I mutations, as well as R1150Q/W, augment Mg-nucleotide activation. The response of mutant channels to inhibition by the sulfonylurea drug glibenclamide, a potential pharmacotherapy for CS, was also tested. There was no major effect on glibenclamide sensitivity for the D207E, Y981S, G985E or M1056I mutations, but glutamine and tryptophan substitution at R1150 resulted in significant decreases in potency.

scholarly journals Differential mechanisms of Cantú syndrome–associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel

2015 ◽  
Vol 146 (6) ◽  
pp. 527-540 ◽  
Author(s):  
Paige E. Cooper ◽  
Monica Sala-Rabanal ◽  
Sun Joo Lee ◽  
Colin G. Nichols
Keyword(s):  
Cell Metabolism ◽  
Katp Channels ◽  
Sulfonylurea Receptor ◽  
Membrane Excitability ◽  
Gain Of Function ◽  
Equivalent Position ◽  
Functional Consequences ◽  
Atp Inhibition ◽  
Patch Clamp Electrophysiology ◽  
Inwardly Rectifying

Cantú syndrome (CS) is a rare disease characterized by congenital hypertrichosis, distinct facial features, osteochondrodysplasia, and cardiac defects. Recent genetic analysis has revealed that the majority of CS patients carry a missense mutation in ABCC9, which codes for the sulfonylurea receptor SUR2. SUR2 subunits couple with Kir6.x, inwardly rectifying potassium pore-forming subunits, to form adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, which link cell metabolism to membrane excitability in a variety of tissues including vascular smooth muscle, skeletal muscle, and the heart. The functional consequences of multiple uncharacterized CS mutations remain unclear. Here, we have focused on determining the functional consequences of three documented human CS-associated ABCC9 mutations: human P432L, A478V, and C1043Y. The mutations were engineered in the equivalent position in rat SUR2A (P429L, A475V, and C1039Y), and each was coexpressed with mouse Kir6.2. Using macroscopic rubidium (86Rb+) efflux assays, we show that KATP channels formed with P429L, A475V, or C1039Y mutants enhance KATP activity compared with wild-type (WT) channels. We used inside-out patch-clamp electrophysiology to measure channel sensitivity to ATP inhibition and to MgADP activation. For P429L and A475V mutants, sensitivity to ATP inhibition was comparable to WT channels, but activation by MgADP was significantly greater. C1039Y-dependent channels were significantly less sensitive to inhibition by ATP or by glibenclamide, but MgADP activation was comparable to WT. The results indicate that these three CS mutations all lead to overactive KATP channels, but at least two mechanisms underlie the observed gain of function: decreased ATP inhibition and enhanced MgADP activation.

Cardiac ATP-sensitive K+ channels: regulation by intracellular nucleotides and K+ channel-opening drugs

1995 ◽  
Vol 269 (3) ◽  
pp. C525-C545 ◽  
Author(s):  
A. Terzic ◽  
A. Jahangir ◽  
Y. Kurachi
Keyword(s):  
Katp Channel ◽  
Molecular Mechanisms ◽  
Enzymatic Reaction ◽  
Katp Channels ◽  
Cardiac Cells ◽  
K Channel ◽  
Channel Activity ◽  
Pharmacological Agents ◽  
Channel Opening ◽  
Main Regulator

ATP-sensitive K+ (KATP) channels are present at high density in membranes of cardiac cells where they regulate cardiac function during cellular metabolic impairment. KATP channels have been implicated in the shortening of the action potential duration and the cellular loss of K+ that occurs during metabolic inhibition. KATP channels have been associated with the cardioprotective mechanism of ischemia-related preconditioning. Intracellular ATP (ATPi) is the main regulator of KATP channels. ATPi has two functions: 1) to close the channel (ligand function) and 2) in the presence of Mg2+, to maintain the activity of KATP channels (presumably through an enzymatic reaction). KATP channel activity is modulated by intracellular nucleoside diphosphates that antagonize the ATPi-induced inhibition of channel opening or induce KATP channels to open. How nucleotides will affect KATP channels depends on the state of the channel. K+ channel-opening drugs are pharmacological agents that enhance KATP channel activity through different mechanisms and have great potential in the management of cardiovascular conditions. KATP channel activity is also modulated by neurohormones. Adenosine, through the activation of a GTP-binding protein, antagonizes the ATPi-induced channel closure. Understanding the molecular mechanisms that underlie KATP channel regulation should prove essential to further define the function of KATP channels and to elucidate the pharmacological regulation of this channel protein. Since the molecular structure of the KATP channel has now become available, it is anticipated that major progress in the KATP channel field will be achieved.

scholarly journals Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Karolina Stępniak ◽  
Magdalena A. Machnicka ◽  
Jakub Mieczkowski ◽  
Anna Macioszek ◽  
Bartosz Wojtaś ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Molecular Mechanisms ◽  
Genome Mapping ◽  
Malignant Gliomas ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Multiple Tumor ◽  
Genes Encoding ◽  
Methylation Patterns

AbstractChromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

scholarly journals Genes encoding putative bicarbonate transporters as a missing molecular link between molt and mineralization in crustaceans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shai Abehsera ◽  
Shmuel Bentov ◽  
Xuguang Li ◽  
Simy Weil ◽  
Rivka Manor ◽  
...  
Keyword(s):  
Calcium Carbonate ◽  
Molecular Mechanisms ◽  
Ph Control ◽  
Functional Genomic ◽  
Single Event ◽  
Tight Coupling ◽  
Molt Cycle ◽  
Mineral Deposition ◽  
Bicarbonate Transporters ◽  
Genes Encoding

AbstractDuring their life, crustaceans undergo several molts, which if theoretically compared to the human body would be equivalent to replacing all bones at a single event. Such a dramatic repetitive event is coupled to unique molecular mechanisms of mineralization so far mostly unknown. Unlike human bone mineralized with calcium phosphate, the crustacean exoskeleton is mineralized mainly by calcium carbonate. Crustacean growth thus necessitates well-timed mobilization of bicarbonate to specific extracellular sites of biomineralization at distinct molt cycle stages. Here, by looking at the crayfish Cherax quadricarinatus at different molting stages, we suggest that the mechanisms of bicarbonate ion transport for mineralization in crustaceans involve the SLC4 family of transporters and that these proteins play a key role in the tight coupling between molt cycle events and mineral deposition. This discovery of putative bicarbonate transporters in a pancrustacean with functional genomic evidence from genes encoding the SLC4 family—mostly known for their role in pH control—is discussed in the context of the evolution of calcium carbonate biomineralization.

scholarly journals Transcriptome Changes Reveal the Molecular Mechanisms of Humic Acid-Induced Salt Stress Tolerance in Arabidopsis

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 782
Author(s):  
Joon-Yung Cha ◽  
Sang-Ho Kang ◽  
Myung Geun Ji ◽  
Gyeong-Im Shin ◽  
Song Yi Jeong ◽  
...  
Keyword(s):  
Salt Stress ◽  
Abiotic Stress ◽  
Humic Acid ◽  
Stress Tolerance ◽  
Plant Development ◽  
Molecular Mechanisms ◽  
Abiotic Stress Tolerance ◽  
Principal Component ◽  
Salt Stress Tolerance ◽  
Genes Encoding

Humic acid (HA) is a principal component of humic substances, which make up the complex organic matter that broadly exists in soil environments. HA promotes plant development as well as stress tolerance, however the precise molecular mechanism for these is little known. Here we conducted transcriptome analysis to elucidate the molecular mechanisms by which HA enhances salt stress tolerance. Gene Ontology Enrichment Analysis pointed to the involvement of diverse abiotic stress-related genes encoding HEAT-SHOCK PROTEINs and redox proteins, which were up-regulated by HA regardless of salt stress. Genes related to biotic stress and secondary metabolic process were mainly down-regulated by HA. In addition, HA up-regulated genes encoding transcription factors (TFs) involved in plant development as well as abiotic stress tolerance, and down-regulated TF genes involved in secondary metabolic processes. Our transcriptome information provided here provides molecular evidences and improves our understanding of how HA confers tolerance to salinity stress in plants.

scholarly journals Analysis of saponins detoxification genes in Ilyonectria mors-panacis G3B inducing root rot of Panax notoginseng by RNA-Seq

2021 ◽  
Author(s):  
Guohong Zeng ◽  
Jin Li ◽  
Yuxiu Ma ◽  
Qian Pu ◽  
Tian Xiao ◽  
...  
Keyword(s):  
Root Rot ◽  
Molecular Mechanisms ◽  
Management Strategies ◽  
Panax Notoginseng ◽  
Glycoside Hydrolases ◽  
Rna Seq ◽  
Host Interaction ◽  
Excellent Starting Point ◽  
Starting Point ◽  
Genes Encoding

AbstractSaponins are kinds of antifungal compounds produced by Panax notoginseng to resist invasion by pathogens. Ilyonectria mors-panacis G3B was the dominant pathogen inducing root rot of P. notoginseng, and the abilities to detoxify saponins were the key to infect P. notoginseng successfully. To research the molecular mechanisms of detoxifying saponins in I. mors-panacis G3B, we used high-throughput RNA-Seq to identify 557 and 1519 differential expression genes (DEGs) in I. mors-panacis G3B with saponins treatments for 4H (Hours) and 12H (Hours) compared with no saponins treatments, respectively. Among these DEGs, we found 93 genes which were simultaneously highly expressed in I. mors-panacis G3B with saponins treatments for 4H and 12H, they mainly belong to genes encoding transporters, glycoside hydrolases, oxidation–reduction enzymes, transcription factors and so on. In addition, there were 21 putative PHI (Pathogen–Host Interaction) genes out of those 93 up-regulated genes. In this report, we analyzed virulence-associated genes in I. mors-panacis G3B which may be related to detoxifying saponins to infect P. notoginseng successfully. They provided an excellent starting point for in-depth study on pathogenicity of I. mors-panacis G3B and developed appropriate root rot disease management strategies in the future.

scholarly journals Cantu syndrome–associated SUR2 (ABCC9) mutations in distinct structural domains result in KATPchannel gain-of-function by differential mechanisms

2017 ◽  
Vol 293 (6) ◽  
pp. 2041-2052 ◽  
Author(s):  
Conor McClenaghan ◽  
Alex Hanson ◽  
Monica Sala-Rabanal ◽  
Helen I. Roessler ◽  
Dragana Josifova ◽  
...  
Keyword(s):  
Gain Of Function ◽  
Structural Domains

scholarly journals In silico identification of Capsicum type III polyketide synthase genes and expression patterns in Capsicum annuum

2020 ◽  
Vol 15 (1) ◽  
pp. 753-762
Author(s):  
Delong Kan ◽  
Di Zhao ◽  
Pengfei Duan
Keyword(s):  
Molecular Mechanisms ◽  
Polyketide Synthase ◽  
Expression Patterns ◽  
Class Ii ◽  
Chili Pepper ◽  
Type Iii Polyketide Synthase ◽  
Type Iii ◽  
Genes Encoding ◽  
Duplication Events ◽  
Pepper Leaves

AbstractStudies have shown that abundant and various flavonoids accumulate in chili pepper (Capsicum), but there are few reports on the genes that govern chili pepper flavonoid biosynthesis. Here, we report the comprehensive identification of genes encoding type III polyketide synthase (PKS), an important enzyme catalyzing the generation of flavonoid backbones. In total, 13, 14 and 13 type III PKS genes were identified in each genome of C. annuum, C. chinense and C. baccatum, respectively. The phylogeny topology of Capsicum PKSs is similar to those in other plants, as it showed two classes of genes. Within each class, clades can be further identified. Class II genes likely encode chalcone synthase (CHS) as they are placed together with the Arabidopsis CHS gene, which experienced extensive expansions in the genomes of Capsicum. Interestingly, 8 of the 11 Class II genes form three clusters in the genome of C. annuum, which is likely the result of tandem duplication events. Four genes are not expressed in the tissues of C. annuum, three of which are located in the clusters, indicating that a portion of genes was pseudogenized after tandem duplications. Expression of two Class I genes was complementary to each other, and all the genes in Class II were not expressed in roots of C. annuum. Two Class II genes (CA00g90790 and CA05g17060) showed upregulated expression as the chili pepper leaves matured, and two Class II genes (CA05g17060 and CA12g20070) showed downregulated expression with the maturation of fruits, consistent with flavonoid accumulation trends in chili pepper as reported previously. The identified genes, sequences, phylogeny and expression information collected in this article lay the groundwork for future studies on the molecular mechanisms of chili pepper flavonoid metabolism.

scholarly journals The Primary Causes of Muscle Dysfunction Associated with the Point Mutations in Tpm3.12; Conformational Analysis of Mutant Proteins as a Tool for Classification of Myopathies

2018 ◽  
Vol 19 (12) ◽  
pp. 3975 ◽  
Author(s):  
Yurii Borovikov ◽  
Olga Karpicheva ◽  
Armen Simonyan ◽  
Stanislava Avrova ◽  
Elena Rogozovets ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Fiber Type ◽  
Point Mutations ◽  
Nemaline Myopathy ◽  
Muscle Dysfunction ◽  
Thin Filaments ◽  
Mutant Proteins ◽  
Strong Binding ◽  
Genes Encoding

Point mutations in genes encoding isoforms of skeletal muscle tropomyosin may cause nemaline myopathy, cap myopathy (Cap), congenital fiber-type disproportion (CFTD), and distal arthrogryposis. The molecular mechanisms of muscle dysfunction in these diseases remain unclear. We studied the effect of the E173A, R90P, E150A, and A155T myopathy-causing substitutions in γ-tropomyosin (Tpm3.12) on the position of tropomyosin in thin filaments, and the conformational state of actin monomers and myosin heads at different stages of the ATPase cycle using polarized fluorescence microscopy. The E173A, R90P, and E150A mutations produced abnormally large displacement of tropomyosin to the inner domains of actin and an increase in the number of myosin heads in strong-binding state at low and high Ca2+, which is characteristic of CFTD. On the contrary, the A155T mutation caused a decrease in the amount of such heads at high Ca2+ which is typical for mutations associated with Cap. An increase in the number of the myosin heads in strong-binding state at low Ca2+ was observed for all mutations associated with high Ca2+-sensitivity. Comparison between the typical conformational changes in mutant proteins associated with different myopathies observed with α-, β-, and γ-tropomyosins demonstrated the possibility of using such changes as tests for identifying the diseases.

scholarly journals Vascular Dysfunction in Preeclampsia

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3055
Author(s):  
Megan A. Opichka ◽  
Matthew W. Rappelt ◽  
David D. Gutterman ◽  
Justin L. Grobe ◽  
Jennifer J. McIntosh
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Treatment Options ◽  
Cardiovascular Disorder ◽  
Endothelial Damage ◽  
Spiral Artery ◽  
Mitochondrial Stress ◽  
Inflammatory State ◽  
Life Threatening

Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and placental vascular dysfunction plays a role in the pathogenesis and can persist into the postpartum period. Potential abnormalities include impaired placentation, incomplete spiral artery remodeling, and endothelial damage, which are further propagated by immune factors, mitochondrial stress, and an imbalance of pro- and antiangiogenic substances. While the field has progressed, current gaps in knowledge include detailed initial molecular mechanisms and effective treatment options. Newfound evidence indicates that vasopressin is an early mediator and biomarker of the disorder, and promising future therapeutic avenues include mitigating mitochondrial dysfunction, excess oxidative stress, and the resulting inflammatory state. In this review, we provide a detailed overview of vascular defects present during preeclampsia and connect well-established notions to newer discoveries at the molecular, cellular, and whole-organism levels.

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