Molecular expression and pharmacological identification of a role for K<sub>v</sub>7 channels in murine vascular reactivity

Yeung, Shuk Yin; Pucovský, Vladimír; Moffatt, James D.; Saldanha, Luiz Balthazar; Schwake, Michael; Ohya, Susumu; Greenwood, Iain A.

doi:10.1038/sj.bjp.0707284

Cited by 172 publications

(297 citation statements)

References 32 publications

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“…39 -41 The importance of K V 7 channels to vascular reactivity has also been repeatedly demonstrated. 18,20 Immunohistochemistry data also provide some insight into the potential impact of altered K V 7 channel composition. The distribution of KCNQ3 and KCNE5 protein was not as localized to vascular regions as might be expected.…”

Section: Discussionmentioning

confidence: 99%

“…35,36 KCNQ3, along with KCNQ5, is highly expressed in bladder smooth muscle. 37 KCNE5 is highly expressed in the femoral artery 20 and can modulate KCNQ1-encoded channels with respect to the voltage and time-dependent functions of the channel. 38 Such channel complex-specific activity makes it difficult to predict how different K V 7 channels may influence placental/vascular function.…”

Section: Discussionmentioning

confidence: 99%

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Novel Expression and Regulation of Voltage-Dependent Potassium Channels in Placentas From Women With Preeclampsia

et al. 2011

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Abstract-Preeclampsia is associated with structural/functional alterations in placental and maternal vasculature.Voltage-dependant potassium channels encoded by KCNQ1-5 genes have been detected in several types of blood vessels where they promote vascular relaxation. Voltage-dependant potassium channel function can be modulated by KCNE1-5-encoded accessory proteins. The aim of this study was to determine whether KCNQ and KCNE genes are differentially expressed in placentas from women with preeclampsia compared with normotensive controls and to examine any differences in those who delivered preterm (Ͻ37 weeks) or term. Key Words: potassium channel Ⅲ placenta Ⅲ preeclampsia Ⅲ KCNQ Ⅲ KCNE P reeclampsia is a pregnancy-specific condition affecting 2% to 7% of women and is associated with maternal multiorgan dysfunction. 1 This disorder, which is responsible for Ϸ60 000 maternal deaths each year worldwide, 2 increases perinatal mortality 5-fold 3 and is commonly associated with preterm delivery and fetal growth restriction. 4 Women who develop preeclampsia and their infants are at increased risk of hypertension, metabolic disorders, cardiovascular disease, and cardiovascular death in later life. 5,6 The pathophysiology underpinning the disorder is complex. Impaired placentation almost certainly plays a part. Placental and maternal oxidative stress and generalized systemic inflammatory activation 7 are main components of the syndrome. 8 Altered maternal and placental vascular reactivity and endothelial cell function have been implicated in the clinical manifestations of preeclampsia, for example, an increase in total peripheral vascular resistance, 9,10 hypertension, and altered hemodynamics.There is emerging evidence to suggest that potassium channels play important roles in the feto-placental vasculature. 11-15 Specifically, it is proposed that suppression of voltage-dependant potassium channel function may increase vascular tone and, hence, be a mechanism affecting perfusion in placentas from women with preeclampsia.The subfamilies of voltage-gated K V 7 channels (potassium channel complexes encoded by KCNQ1-5 and KCNE1-5 genes) are of particular interest, because preliminary data indicate the presence of functional K V 7 channels in human chorionic plate arteries. 15 K V 7 channel activity is generally associated with outwardly rectifying, voltage-dependent K ϩ

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Novel Expression and Regulation of Voltage-Dependent Potassium Channels in Placentas From Women With Preeclampsia

et al. 2011

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“…In vascular smooth muscle cells, KCNQ1, KCNQ4 and KCNQ5 are predominantly expressed with a minimal contribution of KCNQ2 and KCNQ3. [46][47][48] In addition, Jepps et al 49 recently demonstrated that KCNQ channel activators induce arterial relaxation, and the expression of KCNQ4 is decreased in the vascular smooth muscle cells of hypertensive rodent models. The present study also suggested that perivascular sympathetic neurotransmission might also be influenced by KCNQ channels in rat mesenteric arteries.…”

Section: Kcnq Channels In Perivascular Sympathetic Nerves Y Kansui Et Almentioning

confidence: 99%

Facilitation of sympathetic neurotransmission by phosphatidylinositol-4,5-bisphosphate-dependent regulation of KCNQ channels in rat mesenteric arteries

et al. 2012

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Sympathetic nerves regulate vascular tone by releasing neurotransmitters into the vasculature. We previously demonstrated that bradykinin facilitates sympathetic neurotransmission in rat mesenteric arteries. Although little is known about the intracellular mechanism modulating this neurotransmission, recent cell line experiments have shown that the KCNQ channel, which is inhibited by the depletion of membrane phosphatidylinositol-4,5-bisphosphate (PIP 2 ), participates in the control of neurotransmission by bradykinin. In the present study, we examined the mechanism regulating neurotransmitter release from rat perivascular sympathetic nerves. Excitatory junction potentials (EJPs) elicited by repetitive nerve stimulation (1 Hz, 11 pulses, 20 ls, 20-50 V), a measure of sympathetic purinergic neurotransmission, were recorded with a conventional microelectrode technique in rat mesenteric arteries. Bradykinin (10 À7 mol l À1 ) significantly enhanced the amplitude of EJPs (n ¼ 22, Po0.05). This enhancing effect was abolished by N-type calcium-channel inhibition with x-conotoxin GVIA (2 Â 10 À9 mol l À1 , n ¼ 8). The blockade of phospholipase C with U-73122 (10 À6 mol l À1 , n ¼ 17) also eliminated the facilitatory effect of bradykinin. In addition, the effects of bradykinin were diminished by the prevention of PIP 2 resynthesis with wortmannin (10 À5 mol l À1 n ¼ 7) or KCNQ channel inhibition with XE-991 (10 À5 mol l À1 , n ¼ 7). On the other hand, depletion of intracellular calcium stores with cyclopiazonic acid (3 Â 10 À6 mol l À1 , n ¼ 6) or the inhibition of protein kinase C with bisindolylmaleimide-I (10 À6 mol l À1 , n ¼ 9) did not alter the action of bradykinin. These data demonstrate that the hydrolysis of PIP 2 by phospholipase C, which is activated by G q/11 -coupled receptors, and subsequent KCNQ channel inhibition enhance sympathetic purinergic neurotransmission presumably via the activation of N-type calcium channels in rat mesenteric arteries.

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“…There are five Kv7 isoforms (Kv7.1-Kv7.5) of which Kv7.1, Kv7.4, and Kv7.5 are consistently expressed within VSM, where the predominant molecular architecture is a Kv7.4/Kv7.5 heterotetramer (2,3). Activation of Kv7 channels produces relaxation of numerous arteries (4)(5)(6)(7)(8), whereas blockade of Kv7 channels results in contraction of vessels at rest (7,(9)(10)(11) or an inhibition of endogenously derived vasorelaxations (2,(11)(12)(13). In addition, molecular reduction of Kv7.4 reduces responses to various Gs-coupled vasodilators in a number of arteries (2,11).…”

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confidence: 99%

G-protein βγ subunits are positive regulators of Kv7.4 and native vascular Kv7 channel activity

Stott¹,

Povstyan²,

Carr³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Kv7.4 channels are a crucial determinant of arterial diameter both at rest and in response to endogenous vasodilators. However, nothing is known about the factors that ensure effective activity of these channels. We report that G-protein βγ subunits increase the amplitude and activation rate of whole-cell voltage-dependent K + currents sensitive to the Kv7 blocker linopirdine in HEK cells heterologously expressing Kv7.4, and in rat renal artery myocytes. In excised patch recordings, Gβγ subunits (2-250 ng /mL) enhanced the open probability of Kv7.4 channels without changing unitary conductance. Kv7 channel activity was also augmented by stimulation of G-protein-coupled receptors. Gallein, an inhibitor of Gβγ subunits, prevented these stimulatory effects. Moreover, gallein and two other structurally different Gβγ subunit inhibitors (GRK2i and a β-subunit antibody) abolished Kv7 channel currents in the absence of either Gβγ subunit enrichment or G-protein-coupled receptor stimulation. Proximity ligation assay revealed that Kv7.4 and Gβγ subunits colocalized in HEK cells and renal artery smooth muscle cells. Gallein disrupted this colocalization, contracted whole renal arteries to a similar degree as the Kv7 inhibitor linopirdine, and impaired isoproterenol-induced relaxations. Furthermore, mSIRK, which disassociates Gβγ subunits from α subunits without stimulating nucleotide exchange, relaxed precontracted arteries in a linopirdine-sensitive manner. These results reveal that Gβγ subunits are fundamental for Kv7.4 activation and crucial for vascular Kv7 channel activity, which has major consequences for the regulation of arterial tone.Kv7 channels | KCNQ genes | G-protein beta gamma subunits | electrophysiology | vascular biology

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Molecular expression and pharmacological identification of a role for K_v7 channels in murine vascular reactivity

Cited by 172 publications

References 32 publications

Novel Expression and Regulation of Voltage-Dependent Potassium Channels in Placentas From Women With Preeclampsia

Novel Expression and Regulation of Voltage-Dependent Potassium Channels in Placentas From Women With Preeclampsia

Facilitation of sympathetic neurotransmission by phosphatidylinositol-4,5-bisphosphate-dependent regulation of KCNQ channels in rat mesenteric arteries

G-protein βγ subunits are positive regulators of Kv7.4 and native vascular Kv7 channel activity

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Molecular expression and pharmacological identification of a role for Kv7 channels in murine vascular reactivity

Cited by 172 publications

References 32 publications

Novel Expression and Regulation of Voltage-Dependent Potassium Channels in Placentas From Women With Preeclampsia

Novel Expression and Regulation of Voltage-Dependent Potassium Channels in Placentas From Women With Preeclampsia

Facilitation of sympathetic neurotransmission by phosphatidylinositol-4,5-bisphosphate-dependent regulation of KCNQ channels in rat mesenteric arteries

G-protein βγ subunits are positive regulators of Kv7.4 and native vascular Kv7 channel activity

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Molecular expression and pharmacological identification of a role for K_v7 channels in murine vascular reactivity