Kv1.5-Kvβ Interactions: Molecular Determinants and Pharmacological Consequences

@article{Gonzalez2010Kv15KvIM,
  title={Kv1.5-Kv$\beta$ Interactions: Molecular Determinants and Pharmacological Consequences},
  author={T. Gonzalez and M. David and Cristina Moreno and A. Macias and C. Valenzuela},
  journal={Mini-reviews in Medicinal Chemistry},
  year={2010},
  volume={10},
  pages={635-642}
}
Kv1.5 channels are homotetramers of α-pore subunits mainly present in human atrium and pulmonary vasculature. Thus, Kv1.5 is a pharmacological target for cardiovascular diseases. Kvβ1.3 assemblies with Kvα1.5 and modifies its gating and pharmacology. A further knowledge of α-β interactions and pharmacology will lead a better design of new drugs. 
PKC inhibition results in a Kv1.5 + Kvβ1.3 pharmacology closer to Kv1.5 channels
TLDR
The aim of the present study was to investigate the effects of PKC inhibition on bupivacaine and quinidine block of Kv1.5 + Kvβ1.3 channels, resulting in the formation of a functional channelosome. Expand
KV1.5–KVβ1.3 Recycling Is PKC-Dependent
TLDR
The results suggest that the trafficking regulation of KV1.5–KVβ1.3 channels is dependent on phosphorylation by PKC and, therefore, they could represent a clinically relevant issue, mainly in those diseases that exhibit modifications in PKC activity. Expand
Ultra-rapid delayed rectifier channels: molecular basis and therapeutic implications.
TLDR
An overview of the properties of I(Kur) channels in expression systems and native cardiomyocytes is provided and their efficacy in treatment of atrial fibrillation (AF) is discussed. Expand
Effects of dapoxetine on cloned Kv1.5 channels expressed in CHO cells
TLDR
Results indicate that dapoxetine blocks Kv1.5 currents by interacting with the channel in both the open and inactivated states of the channel, which correspond to the voltage range of channel activation. Expand
Carvedilol blocks the cloned cardiac Kv1.5 channels in a β-adrenergic receptor-independent manner.
TLDR
The results indicate that carvedilol blocks Kv1.5 in a reversible, concentration, voltage, time, and use-dependent manner, but only at concentrations slightly higher than therapeutic plasma concentrations in humans. Expand
SGK3 Sensitivity of Voltage Gated K+ Channel Kv1.5 (KCNA5)
TLDR
SGK3 is a positive regulator of KCNA5, which is at least partially effective by abrogating the effect of Nedd4-2, and thus did not require Na+/K+ ATPase activity. Expand
Regulation of Voltage-Gated K+ Channel Kv1.5 by the Janus Kinase JAK3
TLDR
JAK3 contributes to the regulation of membrane Kv1.5 protein abundance and activity, an effect sensitive to ouabain and thus possibly involving Na+/K+ ATPase activity. Expand
Up-Regulation of Voltage Gated K+ Channels Kv1.3 and Kv1.5 by Protein Kinase PKB/Akt
TLDR
PKB/Akt up-regulates both, Kv 1.3 and Kv1.5 K+ channels, and enhances the channel protein abundance in the cell membrane. Expand
SPAK and OSR1 Sensitivity of Voltage-Gated K+ Channel Kv1.5
TLDR
Both, SPAK and OSR1 decrease cell membrane Kv1.5 protein abundance and activity and modify the expression and/or activity of the voltage-gated K+ channel, which participates in the regulation of diverse functions including atrial cardiac action potential and tumor cell proliferation. Expand
Novel molecular targets for atrial fibrillation therapy
TLDR
This Review focuses on the mechanistic rationale for the development of new anti-atrial fibrillation drugs, on the molecular and structural motifs that they target and on the results obtained so far in experimental and clinical studies. Expand
...
1
2
...

References

SHOWING 1-10 OF 59 REFERENCES
Assembly with the Kvbeta1.3 subunit modulates drug block of hKv1.5 channels.
TLDR
The results suggest that the Kvbeta1.3 subunit does not modify the affinity of the charged bupivacaine for its external receptor site but markedly reduces the affinity and quinidine for their internal receptor site in hKv1.5 channels. Expand
Molecular Basis for Kv1.5 Channel Block
TLDR
A novel and potent inhibitor of Kv1.5 potassium channels, N-benzyl-N-pyridin-3-yl-methyl-2-(toluene-4-sulfonylamino)-benzamide hydrochloride (S0100176), which exhibits features consistent with preferential block of the open state. Expand
Kvβ1.3 Reduces the Degree of Stereoselective Bupivacaine Block of Kv1.5 Channels
TLDR
The findings support an overlapping binding site for drugs and Kvβ1.3, which modifies the gating and the pharmacology of Kv1.5 channels, decreasing their sensitivity to block induced by drugs, and competes with them for a binding site at Kv2.3. Expand
Structural determinants of Kvβ1.3‐induced channel inactivation: a hairpin modulated by PIP2
TLDR
Findings indicate that inactivation of Kv1.5 is mediated by an equilibrium binding of the N terminus of K vβ1.3 between phosphoinositides (PIPs) and the inner pore region of the channel. Expand
Structural Basis for Competition between Drug Binding and Kvβ1.3 Accessory Subunit-Induced N-Type Inactivation of Kv1.5 Channels
TLDR
None of the Ala mutations prevented the Kvβ1.3-induced negative shifts in the voltage dependence of activation or slow C-type inactivation, suggesting that these gating effects are mediated by an interaction other than the one for N- type inactivation. Expand
Comparison of Binding and Block Produced by Alternatively Spliced Kvβ1 Subunits*
  • Zhiguo Wang, J. Kiehn, Qing Yang, Arthur M. Brown, B. Wible
  • Biology, Medicine
  • The Journal of Biological Chemistry
  • 1996
TLDR
It is suggested that different Kvβ subunits extend the range over which distinct Kv1α subunits are modulated and may provide a variable mechanism for adjusting K+ currents in response to alterations in cellular conditions. Expand
Binding Site of a Novel Kv1.5 Blocker: A “Foot in the Door” against Atrial Fibrillation
TLDR
The mechanisms of action of 2′-{[2-(4-methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide (AVE0118) on Kv1.5 channels heterologously expressed in Xenopus laevis oocytes are characterized. Expand
Crystal Structure of a Mammalian Voltage-Dependent Shaker Family K+ Channel
TLDR
Electrostatic properties of the side portals and positions of the T1 domain and β sub unit are consistent with electrophysiological studies of inactivation gating and with the possibility of K+ channel regulation by the β subunit. Expand
Alteration of voltage-dependence of Shaker potassium channel by mutations in the S4 sequence
TLDR
Voltage-dependent potassium, sodium and calcium ion channels may share a common mechanism of activation, in which the conserved S4 sequence acts as the primary voltage sensor, and electrophysiological analysis suggest that voltage-dependent activation involves the S4 sequences but is not solely due to electrostatic interactions. Expand
Blocker protection in the pore of a voltage-gated K+ channel and its structural implications
TLDR
The ability of blockers to protect against chemical modification of cysteines introduced at sites in transmembrane segment S6, which contributes to the intracellular entrance, is investigated. Expand
...
1
2
3
4
5
...