Kv7.5 Potassium Channel Subunits Are the Primary Targets for PKA-Dependent Enhancement of Vascular Smooth Muscle Kv7 Currents

Mani, Bharath K.; Robakowski, Christina; Brueggemann, Lyubov I.; Cribbs, Leanne L.; Abhishek, Tripathi; Majetschak, Matthias; Byron, Kenneth L.

doi:10.1124/mol.115.101758

Cited by 57 publications

(88 citation statements)

References 64 publications

(90 reference statements)

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“…Kv7 channels, particularly Kv7.4 and Kv7.5, are important regulators of vascular tone (3, 6-15, 25, 26). These channels have been shown extensively to be expressed and functionally important in several human and rodent arteries.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, this study highlights a novel role for the KCNE4 subunit in mediating β-adrenoceptor responses in the mesenteric artery. Kv7 channels in the vasculature contribute to different Gs-coupled receptor mediated relaxations, yet the exact signaling mechanisms are still unclear (7, 11, 12, 14, 15). Following Gs coupled-receptor activation, a cAMP-dependent mechanism (11) and the βγ-subunits (15) have both been shown to enhance Kv7.4/Kv7.5 channel activity.…”

Section: Discussionmentioning

confidence: 99%

“…Kv7 channels in the vasculature contribute to different Gs-coupled receptor mediated relaxations, yet the exact signaling mechanisms are still unclear (7, 11, 12, 14, 15). Following Gs coupled-receptor activation, a cAMP-dependent mechanism (11) and the βγ-subunits (15) have both been shown to enhance Kv7.4/Kv7.5 channel activity. The current study confirms that isoprenaline effects in the mesenteric artery are sensitive to Kv7 blockade (linopirdine) and reveals an important role for KCNE4 in mediating these vasorelaxant effects in the mesenteric arteries of both males and females.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Kv7 channel blockade, or Kv7.4 channel knockdown, impairs various receptor-mediated vasorelaxations in different arteries. Thus, the vascular Kv7 channels are regarded as functional mediators of different receptor-activated vasodilatations (7, 11-15). …”

Section: Introductionmentioning

confidence: 99%

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Kcne4 Deletion Sex-Dependently Alters Vascular Reactivity

Abbott

Jepps²

2016

J Vasc Res

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Voltage-gated potassium (Kv) channels formed by Kv7 (KCNQ) α-subunits are recognized as crucial for vascular smooth muscle function, in addition to their established roles in the heart (Kv7.1) and the brain (Kv7.2-5). In vivo, Kv7 α-subunits are often regulated by KCNE subfamily ancillary (β) subunits. We investigated the effects of targeted germline Kcne4 deletion on mesenteric artery reactivity in adult male and female mice. Kcne4 deletion increased mesenteric artery contractility in response to α-adrenoceptor agonist methoxamine, and decreased responses to Kv7.2-7.5 channel activator ML213, in male but not female mice. In contrast, Kcne4 deletion markedly decreased vasorelaxation in response to isoprenaline in both male and female mice. Kcne4 expression was 2-fold lower in the female versus the male mouse mesenteric artery, and Kcne4 deletion elicited only moderate changes of other Kcne transcripts, with no striking sex-specific differences. However, Kv7.4 protein expression in females was twice that in males, and was reduced in both sexes by Kcne4 deletion. Our findings confirm a crucial role for KCNE4 in regulation of Kv7 channel activity to modulate vascular tone, and provide the first known molecular mechanism for sex-specificity of this modulation that has important implications for vascular reactivity and may underlie sex-specific susceptibility to cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Kcne4 Deletion Sex-Dependently Alters Vascular Reactivity

Abbott

Jepps²

2016

J Vasc Res

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“…We recently found that the activity of homomeric Kv7.5 but not homomeric Kv7.4 channels in VSMCs was strongly enhanced via the activation of the βAR/G s /cAMP/PKA pathway and this effect was associated with PKA-dependent phosphorylation of Kv7.5 channel α-subunits [8]. The PKA phosphorylation sites of Kv7.5 channels and mechanisms underlying the phosphorylation-induced increase in currents remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of PKA-Dependent Potentiation of Kv7.5 Channel Activity in Human Airway Smooth Muscle Cells

Brueggemann

Cribbs

Schwartz

et al. 2018

IJMS

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β-adrenergic receptor (βAR) activation promotes relaxation of both vascular and airway smooth muscle cells (VSMCs and ASMCs, respectively), though the signaling mechanisms have not been fully elucidated. We previously found that the activity of Kv7.5 voltage-activated potassium channels in VSMCs is robustly enhanced by activation of βARs via a mechanism involving protein kinase A (PKA)-dependent phosphorylation. We also found that enhancement of Kv7 channel activity in ASMCs promotes airway relaxation. Here we provide evidence that Kv7.5 channels are natively expressed in primary cultures of human ASMCs and that they conduct currents which are robustly enhanced in response to activation of the βAR/cyclic adenosine monophosphate (cAMP)/PKA pathway. MIT Scansite software analysis of putative PKA phosphorylation sites on Kv7.5 identified 8 candidate serine or threonine residues. Each residue was individually mutated to an alanine to prevent its phosphorylation and then tested for responses to βAR activation or to stimuli that elevate cAMP levels. Only the mutation of serine 53 (S53A), located on the amino terminus of Kv7.5, significantly reduced the increase in Kv7.5 current in response to these stimuli. A phospho-mimic mutation (S53D) exhibited characteristics of βAR-activated Kv7.5. Serine-to-alanine mutations of 6 putative PKA phosphorylation sites on the Kv7.5 C-terminus, individually or in combination, did not significantly reduce the enhancement of the currents in response to forskolin treatment (to elevate cAMP levels). We conclude that phosphorylation of S53 on the amino terminus of Kv7.5 is essential for PKA-dependent enhancement of channel activity in response to βAR activation in vascular and airway smooth muscle cells.

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Inhibition of voltage‐dependent K⁺ channels by iloperidone in coronary arterial smooth muscle cells

Seo

Jung

et al. 2020

J of Applied Toxicology

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Iloperidone, a second‐generation atypical antipsychotic drug, is widely used in the treatment of schizophrenia. However, the side‐effects of iloperidone on vascular K+ channels remain to be determined. Therefore, we explored the effect of iloperidone on voltage‐dependent K+ (Kv) channels in rabbit coronary arterial smooth muscle cells using the whole‐cell patch‐clamp technique. Iloperidone inhibited vascular Kv channels in a concentration‐dependent manner with a half‐maximal inhibitory concentration (IC50) of 2.11 ± 0.5 μM and a Hill coefficient of 0.68 ± 0.03. Iloperidone had no effect on the steady‐state inactivation kinetics. However, it shifted the steady‐state activation curve to the right, indicating that iloperidone inhibited Kv channels by influencing the voltage sensors. Application of 20 repetitive depolarizing pulses (1 and 2 Hz) progressively increased the inhibition of the Kv current in the presence of iloperidone. Furthermore, iloperidone increased the recovery time constant from Kv channel inactivation, suggesting that iloperidone‐induced inhibition of Kv channels is use (state)‐dependent. Pretreatment with a Kv1.5 inhibitor (diphenyl phosphine oxide 1 [DPO‐1]) inhibited the Kv current to a level similar to that with iloperidone alone. However, pretreatment with a Kv2.1 or Kv7.X inhibitor (guangxitoxin or linopirdine) did not affect the inhibitory effect of iloperidone on Kv channels. Therefore, iloperidone directly inhibits Kv channels in a concentration‐ and use (state)‐dependent manner independently of its antagonism of serotonin and dopamine receptors. Furthermore, the primary target of iloperidone is the Kv1.5 subtype.

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Kv7.5 Potassium Channel Subunits Are the Primary Targets for PKA-Dependent Enhancement of Vascular Smooth Muscle Kv7 Currents

Cited by 57 publications

References 64 publications

Kcne4 Deletion Sex-Dependently Alters Vascular Reactivity

Kcne4 Deletion Sex-Dependently Alters Vascular Reactivity

Mechanisms of PKA-Dependent Potentiation of Kv7.5 Channel Activity in Human Airway Smooth Muscle Cells

Inhibition of voltage‐dependent K⁺ channels by iloperidone in coronary arterial smooth muscle cells

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Kv7.5 Potassium Channel Subunits Are the Primary Targets for PKA-Dependent Enhancement of Vascular Smooth Muscle Kv7 Currents

Cited by 57 publications

References 64 publications

Kcne4 Deletion Sex-Dependently Alters Vascular Reactivity

Kcne4 Deletion Sex-Dependently Alters Vascular Reactivity

Mechanisms of PKA-Dependent Potentiation of Kv7.5 Channel Activity in Human Airway Smooth Muscle Cells

Inhibition of voltage‐dependent K+ channels by iloperidone in coronary arterial smooth muscle cells

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Inhibition of voltage‐dependent K⁺ channels by iloperidone in coronary arterial smooth muscle cells