Regulation of the voltage-gated K+ channels KCNQ2/3 and KCNQ3/5 by serum- and glucocorticoid-regulated kinase-1

2008 ◽  
Vol 295 (1) ◽  
pp. C73-C80 ◽  
Author(s):  
Friderike Schuetz ◽  
Sharad Kumar ◽  
Philip Poronnik ◽  
David J. Adams
Keyword(s):  
Cell Membrane ◽  
Cell Surface ◽  
Ion Transport ◽  
Ubiquitin Ligase ◽  
Xenopus Oocytes ◽  
Neuronal Excitability ◽  
Potential Mechanism ◽  
K Channels ◽  
Kcnq Channels ◽  
Voltage Gated

The voltage-gated KCNQ2/3 and KCNQ3/5 K+ channels regulate neuronal excitability. We recently showed that KCNQ2/3 and KCNQ3/5 channels are regulated by the ubiquitin ligase Nedd4-2. Serum- and glucocorticoid-regulated kinase-1 (SGK-1) plays an important role in regulation of epithelial ion transport. SGK-1 phosphorylation of Nedd4-2 decreases the ability of Nedd4-2 to ubiquitinate the epithelial Na+ channel, which increases the abundance of channel protein in the cell membrane. In this study, we investigated the mechanism(s) of SGK-1 regulation of M-type KCNQ channels expressed in Xenopus oocytes. SGK-1 significantly upregulated the K+ current amplitudes of KCNQ2/3 and KCNQ3/5 channels ∼1.4- and ∼1.7-fold, respectively, whereas the kinase-inactive SGK-1 mutant had no effect. The cell surface levels of KCNQ2-hemagglutinin/3 were also increased by SGK-1. Deletion of the KCNQ3 channel COOH terminus in the presence of SGK-1 did not affect the K+ current amplitude of KCNQ2/3/5-mediated currents. Coexpression of Nedd4-2 and SGK-1 with KCNQ2/3 or KCNQ3/5 channels did not significantly alter K+ current amplitudes. Only the Nedd4-2 mutant S448ANedd4-2 exhibited a significant downregulation of the KCNQ2/3/5 K+ current amplitudes. Taken together, these results demonstrate a potential mechanism for regulation of KCNQ2/3 and KCNQ3/5 channels by SGK-1 regulation of the activity of the ubiquitin ligase Nedd4-2.

scholarly journals Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Nina E Ottosson ◽  
Xiongyu Wu ◽  
Andreas Nolting ◽  
Urban Karlsson ◽  
Per-Eric Lund ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Resin Acid ◽  
K Channels ◽  
Voltage Gated

scholarly journals Major diversification of voltage-gated K+ channels occurred in ancestral parahoxozoans

2015 ◽  
Vol 112 (9) ◽  
pp. E1010-E1019 ◽  
Author(s):  
Xiaofan Li ◽  
Hansi Liu ◽  
Jose Chu Luo ◽  
Sarah A. Rhodes ◽  
Liana M. Trigg ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Neuronal Excitability ◽  
Common Ancestor ◽  
Gene Families ◽  
Subunit Structure ◽  
K Channels ◽  
Voltage Gated ◽  
Basal Metazoan ◽  
A Subunit ◽  
Distinct Subunit

We examined the origins and functional evolution of the Shaker and KCNQ families of voltage-gated K+ channels to better understand how neuronal excitability evolved. In bilaterians, the Shaker family consists of four functionally distinct gene families (Shaker, Shab, Shal, and Shaw) that share a subunit structure consisting of a voltage-gated K+ channel motif coupled to a cytoplasmic domain that mediates subfamily-exclusive assembly (T1). We traced the origin of this unique Shaker subunit structure to a common ancestor of ctenophores and parahoxozoans (cnidarians, bilaterians, and placozoans). Thus, the Shaker family is metazoan specific but is likely to have evolved in a basal metazoan. Phylogenetic analysis suggested that the Shaker subfamily could predate the divergence of ctenophores and parahoxozoans, but that the Shab, Shal, and Shaw subfamilies are parahoxozoan specific. In support of this, putative ctenophore Shaker subfamily channel subunits coassembled with cnidarian and mouse Shaker subunits, but not with cnidarian Shab, Shal, or Shaw subunits. The KCNQ family, which has a distinct subunit structure, also appears solely within the parahoxozoan lineage. Functional analysis indicated that the characteristic properties of Shaker, Shab, Shal, Shaw, and KCNQ currents evolved before the divergence of cnidarians and bilaterians. These results show that a major diversification of voltage-gated K+ channels occurred in ancestral parahoxozoans and imply that many fundamental mechanisms for the regulation of action potential propagation evolved at this time. Our results further suggest that there are likely to be substantial differences in the regulation of neuronal excitability between ctenophores and parahoxozoans.

scholarly journals SGK3 Sensitivity of Voltage Gated K+ Channel Kv1.5 (KCNA5)

2016 ◽  
Vol 38 (1) ◽  
pp. 359-367 ◽  
Author(s):  
Musaab Ahmed ◽  
Myriam Fezai ◽  
Nestor L. Uzcategui ◽  
Zohreh Hosseinzadeh ◽  
Florian Lang
Keyword(s):  
Ubiquitin Ligase ◽  
Xenopus Oocytes ◽  
Cardiac Action Potential ◽  
K Channel ◽  
Channel Activity ◽  
Wild Type ◽  
Voltage Gated ◽  
Cardiac Action ◽  
Electrode Voltage ◽  
Potential Activity

Background: The serum & glucocorticoid inducible kinase isoform SGK3 is a powerful regulator of several transporters, ion channels and the Na+/K+ ATPase. Targets of SGK3 include the ubiquitin ligase Nedd4-2, which is in turn a known regulator of the voltage gated K+ channel Kv1.5 (KCNA5). The present study thus explored whether SGK3 modifies the activity of the voltage gated K+ channel KCNA5, which participates in the regulation of diverse functions including atrial cardiac action potential, activity of vascular smooth muscle cells, insulin release and tumour cell proliferation. Methods: cRNA encoding KCNA5 was injected into Xenopus oocytes with and without additional injection of cRNA encoding wild-type SGK3, constitutively active S419DSGK3, inactive K191NSGK3 and/or wild type Nedd4-2. Voltage gated K+ channel activity was quantified utilizing dual electrode voltage clamp. Results: Voltage gated current in KCNA5 expressing Xenopus oocytes was significantly enhanced by wild-type SGK3 and S419DSGK3, but not by K191NSGK3. SGK3 was effective in the presence of ouabain (1 mM) and thus did not require Na+/K+ ATPase activity. Coexpression of Nedd4-2 decreased the voltage gated current in KCNA5 expressing Xenopus oocytes, an effect largely reversed by additional coexpression of SGK3. Conclusion: SGK3 is a positive regulator of KCNA5, which is at least partially effective by abrogating the effect of Nedd4-2.

scholarly journals Up-Regulation of Voltage Gated K+ Channels Kv1.3 and Kv1.5 by Protein Kinase PKB/Akt

2015 ◽  
Vol 37 (6) ◽  
pp. 2454-2463 ◽  
Author(s):  
Jamshed Warsi ◽  
Myriam Fezai ◽  
Mireia Fores ◽  
Bernat Elvira ◽  
Florian Lang
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase ◽  
Cell Membrane ◽  
Brefeldin A ◽  
Xenopus Laevis Oocytes ◽  
K Channels ◽  
Voltage Gated ◽  
Electrode Voltage ◽  
And Function ◽  
K Currents

Background: The voltage gated K+ channels Kv1.3 and Kv1.5 contribute to the orchestration of cell proliferation. Kinases participating in the regulation of cell proliferation include protein kinase B (PKB/Akt). The present study thus explored whether PKB/Akt modifies the abundance and function of Kv1.3 and Kv1.5. Methods: Kv1.3 or Kv1.5 was expressed in Xenopus laevis oocytes with or without wild-type PKB/Akt, constitutively active T308D/S473DPKB/Akt or inactive T308A/S473APKB/Akt. The channel activity was quantified utilizing dual electrode voltage clamp. Moreover, HA-tagged Kv1.5 protein was determined utilizing chemiluminescence. Results: Voltage gated K+ currents were observed in Kv1.3 or Kv1.5 expressing oocytes but not in water-injected oocytes or in oocytes expressing PKB/Akt alone. Co-expression of PKB/Akt or T308D/S473DPKB/Akt, but not co-expression of T308A/S473APKB/Akt significantly increased the voltage gated current in both Kv1.3 and Kv1.5 expressing oocytes. As shown for Kv1.5, co-expression of PKB/Akt enhanced the channel protein abundance in the cell membrane. In Kv1.5 expressing oocytes voltage gated current decreased following inhibition of carrier insertion by brefeldin A (5 µM) to similarly low values in the absence and presence of PKB/Akt, suggesting that PKB/Akt stimulated carrier insertion into rather than inhibiting carrier retrieval from the cell membrane. Conclusion: PKB/Akt up-regulates both, Kv1.3 and Kv1.5 K+ channels.

scholarly journals Development of the L-type CaV / BK Complex Simulator (II): estimation of the distance between the channels

2021 ◽  
Vol 2 (2) ◽  
pp. 1258-1265
Author(s):  
Marleni Reyes Monreal ◽  
Jessica Quintero Pérez ◽  
Miguel Pérez Escalera ◽  
Arturo Reyes Lazalde ◽  
María Eugenia Pérez Bonilla
Keyword(s):  
Cell Membrane ◽  
Mathematical Models ◽  
Visual Basic ◽  
Bk Channel ◽  
Excitable Cells ◽  
K Channels ◽  
Voltage Gated ◽  
Ca2 Channels ◽  
High Conductance

The presence, in the cell membrane, of high-conductance K+ channels and voltage-gated Ca2+ channels (CaV) forming complexes has been reported. These complexes have important functions in excitable cells. The [Ca2+]i at the mouth of the CaV channel decreases with distance and with the concentration of chelators. For the BK channel to be activated with internal Ca2, a concentration of the order of M is necessary and this implies a closeness between the BK-CaV channels. A simulator of the decay of Ca2+ in the presence of BAPTA to estimate the distance between the channels was developed. The mathematical models were implemented in Visual Basic® 6.0 and were solved numerically. The results indicate the coexistence of L-type CaV channel and BK grouped in nanodomains with a distance between channels of ~30 nm.

scholarly journals The Sodium Channel Accessory Subunit Nav 1 Regulates Neuronal Excitability through Modulation of Repolarizing Voltage-Gated K+ Channels

2012 ◽  
Vol 32 (17) ◽  
pp. 5716-5727 ◽  
Author(s):  
C. Marionneau ◽  
Y. Carrasquillo ◽  
A. J. Norris ◽  
R. R. Townsend ◽  
L. L. Isom ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Neuronal Excitability ◽  
K Channels ◽  
Voltage Gated ◽  
Accessory Subunit

Hypoxia-induced inhibition of whole cell membrane currents and ion transport of A549 cells

2004 ◽  
Vol 286 (6) ◽  
pp. L1154-L1160 ◽  
Author(s):  
Christoph Karle ◽  
Tobias Gehrig ◽  
Ralf Wodopia ◽  
Sabine Höschele ◽  
Volker A. W. Kreye ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Ion Transport ◽  
A549 Cells ◽  
Membrane Depolarization ◽  
Membrane Currents ◽  
K Channel ◽  
Transport Activity ◽  
Whole Cell ◽  
K Channels ◽  
Transport Inhibition

In excitable cells, hypoxia inhibits K channels, causes membrane depolarization, and initiates complex adaptive mechanisms. It is unclear whether K channels of alveolar epithelial cells reveal a similar response to hypoxia. A549 cells were exposed to hypoxia during whole cell patch-clamp measurements. Hypoxia reversibly inhibited a voltage-dependent outward current, consistent with a K current, because tetraethylamonium (TEA; 10 mM) abolished this effect; however, iberiotoxin (0.1 μM) does not. In normoxia, TEA and iberiotoxin inhibited whole cell current (−35%), whereas the K-channel inhibitors glibenclamide (1 μM), barium (1 mM), chromanol B293 (10 μM), and 4-aminopyridine (1 mM) were ineffective. 86Rb uptake was measured to see whether K-channel modulation also affected transport activity. TEA, iberiotoxin, and 4-h hypoxia (1.5% O2) inhibited total 86Rb uptake by 40, 20, and 35%, respectively. Increased extracellular K also inhibited 86Rb uptake in a dose-dependent way. The K-channel opener 1-ethyl-2-benzimidazolinone (1 mM) increased 86Rb uptake by 120% in normoxic and hypoxic cells by activation of Na-K pumps (+60%) and Na-K-2Cl cotransport (+170%). However, hypoxic transport inhibition was also seen in the presence of 1-ethyl-2-benzimidazolinone, TEA, and iberiotoxin. These results indicate that hypoxia, membrane depolarization, and K-channel inhibition decrease whole cell membrane currents and transport activity. It appears, therefore, that a hypoxia-induced change in membrane conductance and membrane potential might be a link between hypoxia and alveolar ion transport inhibition.

scholarly journals SUMO modification of cell surface Kv2.1 potassium channels regulates the activity of rat hippocampal neurons

2011 ◽  
Vol 137 (5) ◽  
pp. 441-454 ◽  
Author(s):  
Leigh D. Plant ◽  
Evan J. Dowdell ◽  
Irina S. Dementieva ◽  
Jeremy D. Marks ◽  
Steve A.N. Goldstein
Keyword(s):  
Potassium Channels ◽  
Cell Surface ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Voltage Gated ◽  
Sumo Modification ◽  
Maximal Activation ◽  
Sumo Pathway ◽  
Activity Dependent ◽  
The Brain

Voltage-gated Kv2.1 potassium channels are important in the brain for determining activity-dependent excitability. Small ubiquitin-like modifier proteins (SUMOs) regulate function through reversible, enzyme-mediated conjugation to target lysine(s). Here, sumoylation of Kv2.1 in hippocampal neurons is shown to regulate firing by shifting the half-maximal activation voltage (V1/2) of channels up to 35 mV. Native SUMO and Kv2.1 are shown to interact within and outside channel clusters at the neuronal surface. Studies of single, heterologously expressed Kv2.1 channels show that only K470 is sumoylated. The channels have four subunits, but no more than two non-adjacent subunits carry SUMO concurrently. SUMO on one site shifts V1/2 by 15 mV, whereas sumoylation of two sites produces a full response. Thus, the SUMO pathway regulates neuronal excitability via Kv2.1 in a direct and graded manner.

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