scholarly journals Functional Consequences of the Variable Stoichiometry of the Kv1.3-KCNE4 Complex

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1128
Author(s):  
Laura Solé ◽  
Daniel Sastre ◽  
Magalí Colomer-Molera ◽  
Albert Vallejo-Gracia ◽  
Sara R. Roig ◽  
...  
Keyword(s):  
Fine Tuning ◽  
Cell Physiology ◽  
Channel Activity ◽  
Membrane Expression ◽  
Ongoing Debate ◽  
Voltage Gated ◽  
Kv Channels ◽  
Functional Consequences ◽  
The Subject ◽  
Variable Stoichiometry

The voltage-gated potassium channel Kv1.3 plays a crucial role during the immune response. The channel forms oligomeric complexes by associating with several modulatory subunits. KCNE4, one of the five members of the KCNE family, binds to Kv1.3, altering channel activity and membrane expression. The association of KCNEs with Kv channels is the subject of numerous studies, and the stoichiometry of such associations has led to an ongoing debate. The number of KCNE4 subunits that can interact and modulate Kv1.3 is unknown. KCNE4 transfers important elements to the Kv1.3 channelosome that negatively regulate channel function, thereby fine-tuning leukocyte physiology. The aim of this study was to determine the stoichiometry of the functional Kv1.3-KCNE4 complex. We demonstrate that as many as four KCNE4 subunits can bind to the same Kv1.3 channel, indicating a variable Kv1.3-KCNE4 stoichiometry. While increasing the number of KCNE4 subunits steadily slowed the activation of the channel and decreased the abundance of Kv1.3 at the cell surface, the presence of a single KCNE4 peptide was sufficient for the cooperative enhancement of the inactivating function of the channel. This variable architecture, which depends on KCNE4 availability, differentially affects Kv1.3 function. Therefore, our data indicate that the physiological remodeling of KCNE4 triggers functional consequences for Kv1.3, thus affecting cell physiology.

Inhibition of voltage-gated K+ channels in dendritic cells by rapamycin

2010 ◽  
Vol 299 (6) ◽  
pp. C1379-C1385 ◽  
Author(s):  
Leonid Tyan ◽  
Mentor Sopjani ◽  
Miribane Dërmaku-Sopjani ◽  
Evi Schmid ◽  
Wenting Yang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Xenopus Oocytes ◽  
Statistical Significance ◽  
Immunosuppressive Drug ◽  
Channel Activity ◽  
Voltage Gated ◽  
Kv Channel ◽  
Kv Channels ◽  
Channel Inactivation ◽  
Kv1.3 Channel

Rapamycin, an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR), is a widely used immunosuppressive drug. Rapamycin affects the function of dendritic cells (DCs), antigen-presenting cells participating in the initiation of primary immune responses and the establishment of immunological memory. Voltage-gated K+ (Kv) channels are expressed in and impact on the function of DCs. The present study explored whether rapamycin influences Kv channels in DCs. To this end, DCs were isolated from murine bone marrow and ion channel activity was determined by whole cell patch clamp. To more directly analyze an effect of mTOR on Kv channel activity, Kv1.3 and Kv1.5 were expressed in Xenopus oocytes with or without the additional expression of mTOR and voltage-gated currents were determined by dual-electrode voltage clamp. As a result, preincubation with rapamycin (0–50 nM) led to a gradual decline of Kv currents in DCs, reaching statistical significance within 6 h and 50 nM of rapamycin. Rapamycin accelerated Kv channel inactivation. Coexpression of mTOR upregulated Kv1.3 and Kv1.5 currents in Xenopus oocytes. Furthermore, mTOR accelerated Kv1.3 channel activation and slowed down Kv1.3 channel inactivation. In conclusion, mTOR stimulates Kv channels, an effect contributing to the immunomodulating properties of rapamycin in DCs.

Upregulation of voltage-gated Na+ channels by long-term activation of the ghrelin-growth hormone secretagogue receptor in clonal GC somatotropes

2009 ◽  
Vol 296 (5) ◽  
pp. E1148-E1156 ◽  
Author(s):  
Belisario Dominguez ◽  
Ricardo Felix ◽  
Eduardo Monjaraz
Keyword(s):  
Growth Hormone ◽  
Hormone Secretion ◽  
Cell Physiology ◽  
Dependent Manner ◽  
Membrane Expression ◽  
Growth Hormone Secretagogue ◽  
Gh Secretagogues ◽  
Voltage Gated ◽  
Channel Expression

A central question in adenohypophyseal cell physiology concerns the role of transmembrane ionic fluxes in the initiation of the hormone secretion process. In the current report, we investigated the effects of the growth hormone (GH) secretagogues ghrelin and GH-releasing peptide-6 (GHRP-6) on the regulation of the functional expression of voltage-gated Na+ channels using the tumoral somatotrope GC cell line as a model. Cells were cultured under control conditions or in presence of the GH secretagogues (GHS) for 96 h, and Na+ currents ( INa) were characterized in whole cell patch-clamp experiments. GHS treatment significantly increased INa density in a dose-dependent manner. The effects of GHRP-6 were accompanied by an augment in conductance without changes in the kinetics and the voltage dependence of the currents, suggesting an increase in the number of channels in the cell membrane. Sustained inhibition of L-type Ca2+ channel activity decreased INa density and prevented the effects of the GHS, whereas long-term exposure to an L-channel agonist increased INa density and enhanced the actions of GHRP-6, indicating that Ca2+ entry through these channels plays a role in the regulation of Na+ channel expression. Likewise, GHRP-6 failed to enhance Na+ channel expression in the presence of membrane-permeable inhibitors of protein kinases A and C, as well as the Ca2+/calmodulin-dependent kinase II. Conversely, treatment with a cAMP analog or a protein kinase C activator enhanced both basal and GHS-induced secretion of GH measured by enzyme-linked immunoassay, suggesting that GHRP-6 acting through the ghrelin receptor and different signaling pathways enhances Na+ channel membrane expression, which favors hormone release from GC somatotropes.

scholarly journals Bcl-2 decreases voltage-gated K+channel activity and enhances survival in vascular smooth muscle cells

2001 ◽  
Vol 281 (1) ◽  
pp. C157-C165 ◽  
Author(s):  
Daryoush Ekhterae ◽  
Oleksandr Platoshyn ◽  
Stefanie Krick ◽  
Ying Yu ◽  
Sharon S. McDaniel ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Channel Activity ◽  
Voltage Gated ◽  
Kv Channel ◽  
Kv Channels ◽  
Volume Decrease

Cell shrinkage is an incipient hallmark of apoptosis in a variety of cell types. The apoptotic volume decrease has been demonstrated to attribute, in part, to K+efflux; blockade of plasmalemmal K+channels inhibits the apoptotic volume decrease and attenuates apoptosis. Using combined approaches of gene transfection, single-cell PCR, patch clamp, and fluorescence microscopy, we examined whether overexpression of Bcl-2, an anti-apoptotic oncoprotein, inhibits apoptosis in pulmonary artery smooth muscle cells (PASMC) by diminishing the activity of voltage-gated K+(Kv) channels. A human bcl-2gene was infected into primary cultured rat PASMC using an adenoviral vector. Overexpression of Bcl-2 significantly decreased the amplitude and current density of Kv currents ( IKv). In contrast, the apoptosis inducer staurosporine (ST) enhanced IKv. In bcl-2-infected cells, however, the ST-induced increase in IKvwas completely abolished, and the ST-induced apoptosis was significantly inhibited compared with cells infected with an empty adenovirus (− bcl-2). Blockade of Kv channels in control cells (− bcl-2) by 4-aminopyridine also inhibited the ST-induced increase in IKvand apoptosis. Furthermore, overexpression of Bcl-2 accelerated the inactivation of IKvand downregulated the mRNA expression of the pore-forming Kv channel α-subunits (Kv1.1, Kv1.5, and Kv2.1). These results suggest that inhibition of Kv channel activity may serve as an additional mechanism involved in the Bcl-2-mediated anti-apoptotic effect on vascular smooth muscle cells.

Atypical sialylated N-glycan structures are attached to neuronal voltage-gated potassium channels

2009 ◽  
Vol 29 (5) ◽  
pp. 301-313 ◽  
Author(s):  
Tara A. Cartwright ◽  
Ruth A. Schwalbe
Keyword(s):  
Potassium Channels ◽  
Neuroblastoma Cells ◽  
Fine Tuning ◽  
Mammalian Brain ◽  
Migration Patterns ◽  
Voltage Gated ◽  
Adult Rat ◽  
Electrophoretic Migration ◽  
Kv Channels ◽  
Rat Brain Membranes

Mammalian brains contain relatively high amounts of common and uncommon sialylated N-glycan structures. Sialic acid linkages were identified for voltage-gated potassium channels, Kv3.1, 3.3, 3.4, 1.1, 1.2 and 1.4, by evaluating their electrophoretic migration patterns in adult rat brain membranes digested with various glycosidases. Additionally, their electrophoretic migration patterns were compared with those of NCAM (neural cell adhesion molecule), transferrin and the Kv3.1 protein heterologously expressed in B35 neuroblastoma cells. Metabolic labelling of the carbohydrates combined with glycosidase digestion reactions were utilized to show that the N-glycan of recombinant Kv3.1 protein was capped with an oligo/poly-sialyl unit. All three brain Kv3 glycoproteins, like NCAM, were terminated with α2,3-linked sialyl residues, as well as atypical α2,8-linked sialyl residues. Additionally, at least one of their antennae was terminated with an oligo/poly-sialyl unit, similar to recombinant Kv3.1 and NCAM. In contrast, brain Kv1 glycoproteins consisted of sialyl residues with α2,8-linkage, as well as sialyl residues linked to internal carbohydrate residues of the carbohydrate chains of the N-glycans. This type of linkage was also supported for Kv3 glycoproteins. To date, such a sialyl linkage has only been identified in gangliosides, not N-linked glycoproteins. We conclude that all six Kv channels (voltage-gated K+ channels) contribute to the α2,8-linked sialylated N-glycan pool in mammalian brain and furthermore that their N-glycan structures contain branched sialyl residues. Identification of these novel and unique sialylated N-glycan structures implicate a connection between potassium channel activity and atypical sialylated N-glycans in modulating and fine-tuning the excitable properties of neurons in the nervous system.

Turkey's Physicians' Attitudes Toward Euthanasia: A Brief Research Report

2004 ◽  
Vol 49 (2) ◽  
pp. 109-115 ◽  
Author(s):  
Erdem Özkara ◽  
Hamit Hanci ◽  
Murat Civaner ◽  
Coskun Yorulmaz ◽  
Mustafa Karagöz ◽  
...  
Keyword(s):  
Assisted Suicide ◽  
Turkish Population ◽  
Legal Aspects ◽  
Research Report ◽  
Ongoing Debate ◽  
The Subject

Euthanasia and assisted suicide are subject to an ongoing debate and discussed with various aspects. Because physicians are in a profession closely related to euthanasia, their attitudes toward this subject are significant. Thus, research intending to explore their opinions is carried out in many countries. In this study, opinions of the physicians regarding euthanasia's definition, contents, legal aspects, and acceptable conditions for its application are addressed. The questionnaire was given to 949 physicians, more than 1% of the total working in Turkey. Of the physicians who participated in the study, 49.9% agreed with the opinion that euthanasia should be legal in certain circumstances. In addition, 19% had come across a euthanasia request and the majority of physicians (55.9%) believed that euthanasia is applied secretly in the country despite the prohibitory legislation. In conclusion, the authors infer from the study itself and believe that euthanasia should be legal in certain circumstances and that the subject, which is not in the agenda of the Turkish population, should continue to be examined.

The Ethics of Accepting Gifts from Pharmaceutical Companies

PEDIATRICS ◽  
1991 ◽  
Vol 88 (6) ◽  
pp. 1233-1237
Author(s):  
Lewis H. Margolis
Keyword(s):  
Pharmaceutical Industry ◽  
Medical Community ◽  
Pharmaceutical Companies ◽  
Ongoing Debate ◽  
The Subject

How physicians respond to the promotional activities of the pharmaceutical industry is the subject of ongoing debate and controversy. This paper postulates that the acceptance of gifts in virtually any form violates fundamental duties of the physician of nonmaleficence, fidelity, justice, and self-improvement. The medical community must articulate this position clearly, and it should act accordingly.

Mechanisms and Physiological Implications of Cooperative Gating of Ion Channels Clusters

2021 ◽  
Author(s):  
Rose Ellen Dixon ◽  
Manuel F. Navedo ◽  
Marc D Binder ◽  
L. Fernando Santana
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Transient Receptor Potential ◽  
Imaging Techniques ◽  
Ryanodine Receptors ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Cardiac Cells ◽  
Fine Tuning ◽  
Voltage Gated

Ion channels play a central role in the regulation of nearly every cellular process. Dating back to the classic 1952 Hodgkin-Huxley model of the generation of the action potential, ion channels have always been thought of as independent agents. A myriad of recent experimental findings exploiting advances in electrophysiology, structural biology, and imaging techniques, however, have posed a serious challenge to this long-held axiom as several classes of ion channels appear to open and close in a coordinated, cooperative manner. Ion channel cooperativity ranges from variable-sized oligomeric cooperative gating in voltage-gated, dihydropyridine-sensitive Cav1.2 and Cav1.3 channels to obligatory dimeric assembly and gating of voltage-gated Nav1.5 channels. Potassium channels, transient receptor potential channels, hyperpolarization cyclic nucleotide-activated channels, ryanodine receptors (RyRs), and inositol trisphosphate receptors (IP3Rs) have also been shown to gate cooperatively. The implications of cooperative gating of these ion channels range from fine tuning excitation-contraction coupling in muscle cells to regulating cardiac function and vascular tone, to modulation of action potential and conduction velocity in neurons and cardiac cells, and to control of pace-making activity in the heart. In this review, we discuss the mechanisms leading to cooperative gating of ion channels, their physiological consequences and how alterations in cooperative gating of ion channels may induce a range of clinically significant pathologies.

Comparisons of voltage-gated sodium channel structures with open and closed gates and implications for state-dependent drug design

2018 ◽  
Vol 46 (6) ◽  
pp. 1567-1575 ◽  
Author(s):  
Giulia Montini ◽  
Jennifer Booker ◽  
Altin Sula ◽  
B.A. Wallace
Keyword(s):  
Drug Design ◽  
Sodium Channels ◽  
Rational Drug Design ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
State Dependent ◽  
Rational Drug ◽  
Sequence Homologies ◽  
Arcobacter Butzleri ◽  
Functional Consequences

Voltage-gated sodium channels (Navs) are responsible for the initiation of the action potential in excitable cells. Several prokaryotic sodium channels, most notably NavMs from Magnetococcus marinus and NavAb from Arcobacter butzleri, have been shown to be good models for human sodium channels based on their sequence homologies and high levels of functional similarities, including ion flux, and functional consequences of critical mutations. The complete full-length crystal structures of these prokaryotic sodium channels captured in different functional states have now revealed the molecular natures of changes associated with the gating process. These include the structures of the intracellular gate, the selectivity filter, the voltage sensors, the intra-membrane fenestrations, and the transmembrane (TM) pore. Here we have identified for the first time how changes in the fenestrations in the hydrophobic TM region associated with the opening of the intracellular gate could modulate the state-dependent ingress and binding of drugs in the TM cavity, in a way that could be exploited for rational drug design.

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