scholarly journals Heritable arrhythmias associated with abnormal function of cardiac potassium channels

2020 ◽  
Vol 116 (9) ◽  
pp. 1542-1556 ◽  
Author(s):  
Lia Crotti ◽  
Katja E Odening ◽  
Michael C Sanguinetti
Keyword(s):  
Potassium Channels ◽  
Genetic Basis ◽  
Resting Membrane Potential ◽  
Therapeutic Approaches ◽  
Functional Roles ◽  
Cellular Models ◽  
Sodium Calcium ◽  
Disease Mechanisms ◽  
Genes Encoding ◽  
Action Potential Repolarization

Abstract Cardiomyocytes express a surprisingly large number of potassium channel types. The primary physiological functions of the currents conducted by these channels are to maintain the resting membrane potential and mediate action potential repolarization under basal conditions and in response to changes in the concentrations of intracellular sodium, calcium, and ATP/ADP. Here, we review the diversity and functional roles of cardiac potassium channels under normal conditions and how heritable mutations in the genes encoding these channels can lead to distinct arrhythmias. We briefly review atrial fibrillation and J-wave syndromes. For long and short QT syndromes, we describe their genetic basis, clinical manifestation, risk stratification, traditional and novel therapeutic approaches, as well as insights into disease mechanisms provided by animal and cellular models.

scholarly journals Inherited cataracts: molecular genetics, clinical features, disease mechanisms and novel therapeutic approaches

2020 ◽  
Vol 104 (10) ◽  
pp. 1331-1337 ◽  
Author(s):  
Vanita Berry ◽  
Michalis Georgiou ◽  
Kaoru Fujinami ◽  
Roy Quinlan ◽  
Anthony Moore ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
Pharmacological Treatments ◽  
Therapeutic Approaches ◽  
Disease Mechanisms ◽  
Molecular Genetic Basis ◽  
Infancy And Early Childhood ◽  
Novel Therapeutic ◽  
Made In

Cataract is the most common cause of blindness in the world; during infancy and early childhood, it frequently results in visual impairment. Congenital cataracts are phenotypically and genotypically heterogeneous and can occur in isolation or in association with other systemic disorders. Significant progress has been made in identifying the molecular genetic basis of cataract; 115 genes to date have been found to be associated with syndromic and non-syndromic cataract and 38 disease-causing genes have been identified to date to be associated with isolated cataract. In this review, we briefly discuss lens development and cataractogenesis, detail the variable cataract phenotypes and molecular mechanisms, including genotype–phenotype correlations, and explore future novel therapeutic avenues including cellular therapies and pharmacological treatments.

scholarly journals ALS-linked FUS mutants affect the localization of U7 snRNP and replication-dependent histone gene expression in human cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ankur Gadgil ◽  
Agnieszka Walczak ◽  
Agata Stępień ◽  
Jonas Mechtersheimer ◽  
Agnes Lumi Nishimura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Histone Gene ◽  
Cytoplasmic Inclusions ◽  
Cellular Models ◽  
Histone Gene Expression ◽  
Genes Encoding ◽  
U7 Snrnp ◽  
Processing Event ◽  
Fus Protein

AbstractGenes encoding replication-dependent histones lack introns, and the mRNAs produced are a unique class of RNA polymerase II transcripts in eukaryotic cells that do not end in a polyadenylated tail. Mature mRNAs are thus formed by a single endonucleolytic cleavage that releases the pre-mRNA from the DNA and is the only processing event necessary. U7 snRNP is one of the key factors that determines the cleavage site within the 3ʹUTR of replication-dependent histone pre-mRNAs. We have previously showed that the FUS protein interacts with U7 snRNA/snRNP and regulates the expression of histone genes by stimulating transcription and 3ʹ end maturation. Mutations in the FUS gene first identified in patients with amyotrophic lateral sclerosis (ALS) lead to the accumulation of the FUS protein in cytoplasmic inclusions. Here, we report that mutations in FUS lead to disruption of the transcriptional activity of FUS and mislocalization of U7 snRNA/snRNP in cytoplasmic aggregates in cellular models and primary neurons. As a consequence, decreased transcriptional efficiency and aberrant 3ʹ end processing of histone pre-mRNAs were observed. This study highlights for the first time the deregulation of replication-dependent histone gene expression and its involvement in ALS.

Advances in the Biology and Genetics of the Podocytopathies: Implications for Diagnosis and Therapy

2009 ◽  
Vol 133 (2) ◽  
pp. 201-216 ◽  
Author(s):  
Laura Barisoni ◽  
H. William Schnaper ◽  
Jeffrey B. Kopp
Keyword(s):  
Current Knowledge ◽  
Diffuse Mesangial Sclerosis ◽  
Therapeutic Approaches ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Collapsing Glomerulopathy ◽  
Novel Approach ◽  
Genes Encoding ◽  
Glomerular Morphology

AbstractContext.—Etiologic factors and pathways leading to altered podocyte phenotype are clearly numerous and involve the activity of different cellular function.Objective.—To focus on recent discoveries in podocyte biology and genetics and their relevance to these human glomerular diseases, named podocytopathies.Data Sources.—Genetic mutations in genes encoding for proteins in the nucleus, slit diaphragm, podocyte cytoplasm, and cell membrane are responsible for podocyte phenotype and functional abnormalities. Podocyte injury may also derive from secondary stimuli, such as mechanical stress, infections, or use of certain medications. Podocytes can respond to injury in a limited number of ways, which include (1) effacement, (2) apoptosis, (3) arrest of development, and (4) dedifferentiation. Each of these pathways results in a specific glomerular morphology: minimal change nephropathy, focal segmental glomerulosclerosis, diffuse mesangial sclerosis, and collapsing glomerulopathy.Conclusions.—Based on current knowledge of podocyte biology, we organized etiologic factors and morphologic features in a taxonomy of podocytopathies, which provides a novel approach to the classification of these diseases. Current and experimental therapeutic approaches are also discussed.

Molecular physiology of cardiac potassium channels

1996 ◽  
Vol 76 (1) ◽  
pp. 49-67 ◽  
Author(s):  
K. K. Deal ◽  
S. K. England ◽  
M. M. Tamkun
Keyword(s):  
Potassium Channels ◽  
Action Potential ◽  
Single Channel ◽  
Resting Membrane Potential ◽  
Molecular Physiology ◽  
K Channels ◽  
Relative Contribution ◽  
Outward Currents ◽  
Important Challenge ◽  
Heterologous Expression Systems

The cardiac action potential results from the complex, but precisely regulated, movement of ions across the sarcolemmal membrane. Potassium channels represent the most diverse class of ion channels in heart and are the targets of several antiarrhythmic drugs. Potassium currents in the myocardium can be classified into one of two general categories: 1) inward rectifying currents such as IK1, IKACh, and IKATP; and 2) primarily voltage-gated currents such as IKs, IKr, IKp, IKur, and Ito. The inward rectifier currents regulate the resting membrane potential, whereas the voltage-activated currents control action potential duration. The presence of these multiple, often overlapping, outward currents in native cardiac myocytes has complicated the study of individual K+ channels; however, the application of molecular cloning technology to these cardiovascular K+ channels has identified the primary structure of these proteins, and heterologous expression systems have allowed a detailed analysis of the function and pharmacology of a single channel type. This review addresses the progress made toward understanding the complex molecular physiology of K+ channels in mammalian myocardium. An important challenge for the future is to determine the relative contribution of each of these cloned channels to cardiac function.

Blocking Mechanisms of Ketamine and Its Enantiomers in Enzymatically Demyelinated Peripheral Nerve as Revealed by Single-channel Experiments

1997 ◽  
Vol 86 (2) ◽  
pp. 394-404 ◽  
Author(s):  
Michael E. Brau ◽  
Frank Sander ◽  
Werner Vogel ◽  
Gunter Hempelmann
Keyword(s):  
Potassium Channels ◽  
Peripheral Nerve ◽  
Ion Channel ◽  
Single Channel ◽  
Resting Potential ◽  
K Channel ◽  
Resting Membrane Potential ◽  
Na Channel ◽  
Ic50 Values ◽  
Sodium And Potassium

Background Ketamine shows, besides its general anesthetic effect, a local anesthetic-like action that is due to blocking of peripheral nerve sodium currents. In this study, the stereoselectivity of the blocking effects of the ketamine enantiomers S(+) and R(-) was investigated in sodium and potassium channels in peripheral nerve membranes. Methods Ion channel blockade of ketamine was investigated in enzymatically dissociated Xenopus sciatic nerves in multiple-channel and in single-channel outside-out patches. Results Concentration-effect curves for the Na+ peak current revealed half-maximal inhibiting concentrations (IC50) of 347 microM and 291 microM for S(+) and R(-) ketamine, respectively. The potential-dependent K+ current was less sensitive than the Na+ current with IC50 values of 982 microM and 942 microM. The most sensitive ion channel was the flickering background K+ channel, with IC50 values of 168 microM and 146 microM for S(+) and R(-) ketamine. Competition experiments suggest one binding site at the flicker K+ channel, with specific binding affinities for each of the enantiomers. For the Na+ channel, the block was weaker in acidic (pH = 6.6) than in neutral (pH = 7.4) and basic (pH = 8.2) solutions; for the flicker K+ channel, the block was weaker in acidic and stronger in basic solutions. Conclusions Ketamine blockade of sodium and potassium channels in peripheral nerve membranes shows no stereoselectivity except for the flicker K+ channel, which showed a very weak stereoselectivity in favor of the R(-) form. This potential-insensitive flicker K+ channel may contribute to the resting potential. Block of this channel and subsequent depolarization of the resting membrane potential leads, besides to direct Na+ channel block, to inexcitability via Na+ channel inactivation.

scholarly journals Ceramide modulates HERG potassium channel gating by translocation into lipid rafts

2010 ◽  
Vol 299 (1) ◽  
pp. C74-C86 ◽  
Author(s):  
Sindura B. Ganapathi ◽  
Todd E. Fox ◽  
Mark Kester ◽  
Keith S. Elmslie
Keyword(s):  
Potassium Channels ◽  
Action Potential ◽  
Lipid Rafts ◽  
Negative Impact ◽  
Cardiac Action Potential ◽  
Cholesterol Depletion ◽  
Cardiac Action ◽  
Herg Channels ◽  
The Impact ◽  
Action Potential Repolarization

Human ether-à-go-go-related gene (HERG) potassium channels play an important role in cardiac action potential repolarization, and HERG dysfunction can cause cardiac arrhythmias. However, recent evidence suggests a role for HERG in the proliferation and progression of multiple types of cancers, making it an attractive target for cancer therapy. Ceramide is an important second messenger of the sphingolipid family, which due to its proapoptotic properties has shown promising results in animal models as an anticancer agent . Yet the acute effects of ceramide on HERG potassium channels are not known. In the present study we examined the effects of cell-permeable C6-ceramide on HERG potassium channels stably expressed in HEK-293 cells. C6-ceramide (10 μM) reversibly inhibited HERG channel current (IHERG) by 36 ± 5%. Kinetically, ceramide induced a significant hyperpolarizing shift in the current-voltage relationship (Δ V1/2 = −8 ± 0.5 mV) and increased the deactivation rate (43 ± 3% for τfast and 51 ± 3% for τslow). Mechanistically, ceramide recruited HERG channels within caveolin-enriched lipid rafts. Cholesterol depletion and repletion experiments and mathematical modeling studies confirmed that inhibition and gating effects are mediated by separate mechanisms. The ceramide-induced hyperpolarizing gating shift (raft mediated) could offset the impact of inhibition (raft independent) during cardiac action potential repolarization, so together they may nullify any negative impact on cardiac rhythm. Our results provide new insights into the effects of C6-ceramide on HERG channels and suggest that C6-ceramide can be a promising therapeutic for cancers that overexpress HERG.

scholarly journals A new source of root-knot nematode resistance from Arachis stenosperma incorporated into allotetraploid peanut (Arachis hypogaea)

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Carolina Ballén-Taborda ◽  
Ye Chu ◽  
Peggy Ozias-Akins ◽  
Patricia Timper ◽  
C. Corley Holbrook ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Snp Array ◽  
Nematode Resistance ◽  
Major Effect ◽  
Root Knot Nematode ◽  
Breeding Programs ◽  
Genes Encoding ◽  
In The Wild ◽  
Arachis Batizocoi ◽  
Lrr Protein

AbstractRoot-knot nematode is a very destructive pathogen, to which most peanut cultivars are highly susceptible. Strong resistance is present in the wild diploid peanut relatives. Previously, QTLs controlling nematode resistance were identified on chromosomes A02, A04 and A09 of Arachis stenosperma. Here, to study the inheritance of these resistance alleles within the genetic background of tetraploid peanut, an F2 population was developed from a cross between peanut and an induced allotetraploid that incorporated A. stenosperma, [Arachis batizocoi x A. stenosperma]4×. This population was genotyped using a SNP array and phenotyped for nematode resistance. QTL analysis allowed us to verify the major-effect QTL on chromosome A02 and a secondary QTL on A09, each contributing to a percentage reduction in nematode multiplication up to 98.2%. These were validated in selected F2:3 lines. The genome location of the large-effect QTL on A02 is rich in genes encoding TIR-NBS-LRR protein domains that are involved in plant defenses. We conclude that the strong resistance to RKN, derived from the diploid A. stenosperma, is transferrable and expressed in tetraploid peanut. Currently it is being used in breeding programs for introgressing a new source of nematode resistance and to widen the genetic basis of agronomically adapted peanut lines.

scholarly journals Selective expression of KCNA5 and KCNB1 genes in gastric and colorectal carcinoma

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Azer Farah ◽  
Maria Kabbage ◽  
Salsabil Atafi ◽  
Amira Jaballah Gabteni ◽  
Mouadh Barbirou ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Cancer Progression ◽  
Clinical Stage ◽  
Inflammatory Cells ◽  
Tumour Cells ◽  
Malignant Tumours ◽  
Genes Encoding ◽  
First Time ◽  
Formalin Fixed

Abstract Background Gastric and colorectal cancers are the most common malignant tumours, leading to a significant number of cancer-related deaths worldwide. Recently, increasing evidence has demonstrated that cancer cells exhibit a differential expression of potassium channels and this can contribute to cancer progression. However, their expression and localisation at the somatic level remains uncertain. In this study, we have investigated the expression levels of KCNB1 and KCNA5 genes encoding ubiquitous Kv2.1 and Kv1.5 potassium channels in gastric and colorectal tumours. Methods Gastric and colorectal tumoral and peritumoral tissues were collected to evaluate the expression of KCNB1 and KCNA5 mRNA by quantitative PCR. Moreover, the immunohistochemical staining profile of Kv2.1 and Kv1.5 was assessed on 40 Formalin-Fixed and Paraffin-Embedded (FFPE) gastric carcinoma tissues. Differences in gene expression between tumoral and peritumoral tissues were compared statistically with the Mann-Whitney U test. The association between the clinicopathological features of the GC patients and the expression of both Kv proteins was investigated with χ2 and Fisher’s exact tests. Results The mRNA fold expression of KCNB1 and KCNA5 genes showed a lower mean in the tumoral tissues (0.06 ± 0.17, 0.006 ± 0.009) compared to peritumoral tissues (0.08 ± 0.16, 0.16 ± 0.48, respectively) without reaching the significance rate (p = 0.861, p = 0.152, respectively). Interestingly, Kv2.1 and Kv1.5 immunostaining was detectable and characterised by a large distribution in peritumoral and tumoral epithelial cells. More interestingly, inflammatory cells were also stained. Surprisingly, Kv2.1 and Kv1.5 staining was undoubtedly and predominantly detected in the cytoplasm compartment of tumour cells. Indeed, the expression of Kv2.1 in tumour cells revealed a significant association with the early gastric cancer clinical stage (p = 0.026). Conclusion The data highlight, for the first time, the potential role of Kv1.5 and Kv2.1 in gastrointestinal-related cancers and suggests they may be promising prognostic markers for these tumours.

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