Differential Protein Kinase C-dependent Modulation of Kv7.4 and Kv7.5 Subunits of Vascular Kv7 Channels

Brueggemann, Lioubov I.; Mackie, Alexander R; Cribbs, Leanne L.; Freda, Jessica; Abhishek, Tripathi; Majetschak, Matthias; Byron, Kenneth L.

doi:10.1074/jbc.m113.527820

Cited by 61 publications

(91 citation statements)

References 48 publications

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“…We sought to evaluate whether heteromeric complexes between α 1 -AR and CXCR4 are expressed on the cell surface of VSMC. Thus, we used proximity ligation assays (PLA) to visualize individual receptors and receptorreceptor interactions (39)(40)(41). PLA have been previously used to observe individual proteins and interactions between individual endogenous proteins at a single-molecule resolution (39).…”

Section: Resultsmentioning

confidence: 99%

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Heteromerization of chemokine (C-X-C motif) receptor 4 with α_1A/B-adrenergic receptors controls α₁-adrenergic receptor function

Abhishek

Vana

Chavan

et al. 2015

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

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118

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Recent evidence suggests that chemokine (C-X-C motif) receptor 4 (CXCR4) contributes to the regulation of blood pressure through interactions with α 1 -adrenergic receptors (ARs) in vascular smooth muscle. The underlying molecular mechanisms, however, are unknown. Using proximity ligation assays to visualize single-molecule interactions, we detected that α 1A/B -ARs associate with CXCR4 on the cell surface of rat and human vascular smooth muscle cells (VSMC). Furthermore, α 1A/B -AR could be coimmunoprecipitated with CXCR4 in a HeLa expression system and in human VSMC. A peptide derived from the second transmembrane helix of CXCR4 induced chemical shift changes in the NMR spectrum of CXCR4 in membranes, disturbed the association between α 1A/B -AR and CXCR4, and inhibited Ca 2+ mobilization, myosin light chain (MLC) 2 phosphorylation, and contraction of VSMC upon α 1 -AR activation. CXCR4 silencing reduced α 1A/B -AR:CXCR4 heteromeric complexes in VSMC and abolished phenylephrine-induced Ca 2+ fluxes and MLC2 phosphorylation. Treatment of rats with CXCR4 agonists (CXCL12, ubiquitin) reduced the EC 50 of the phenylephrineinduced blood pressure response three-to fourfold. These observations suggest that disruption of the quaternary structure of α 1A/B -AR:CXCR4 heteromeric complexes by targeting transmembrane helix 2 of CXCR4 and depletion of the heteromeric receptor complexes by CXCR4 knockdown inhibit α 1 -AR-mediated function in VSMC and that activation of CXCR4 enhances the potency of α 1 -AR agonists. Our findings extend the current understanding of the molecular mechanisms regulating α 1 -AR and provide an example of the importance of G protein-coupled receptor (GPCR) heteromerization for GPCR function. Compounds targeting the α 1A/B -AR:CXCR4 interaction could provide an alternative pharmacological approach to modulate blood pressure.CXCL12 | ubiquitin | AMD3100 | phenylephrine | blood pressure

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Section: Resultsmentioning

confidence: 99%

“…Duolink proximity ligation assays were performed as described previously (40,41). In brief, VSMC and A7r5 cells were grown and fixed on eight-well tissue culture slides.…”

Section: Methodsmentioning

confidence: 99%

Heteromerization of chemokine (C-X-C motif) receptor 4 with α_1A/B-adrenergic receptors controls α₁-adrenergic receptor function

Abhishek

Vana

Chavan

et al. 2015

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

Self Cite

118

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“…77,78 KCNQ4 seems to fulfil specific functions in the inner ear and in peripheral sensors, while KCNQ4/Q5 heteromers are important for vessel smooth muscle diameter control and in the vestibular system. [79][80][81] KCNQ5 has further been identified as a neuronal KCNQ member. [82][83][84] A complex molecular network is regulating the expression, localization, and gating of KCNQ channels.…”

Section: Kcnq Structure and Regulation By B-subunitsmentioning

confidence: 99%

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

et al. 2016

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b-site APP-cleaving enzyme 1 (BACE1) has become infamous for its pivotal role in the pathogenesis of Alzheimer's disease (AD). Consequently, BACE1 represents a prime target in drug development. Despite its detrimental involvement in AD, it should be quite obvious that BACE1 is not primarily present in the brain to drive mental decline. In fact, additional functions have been identified. In this review, we focus on the regulation of ion channels, specifically voltage-gated sodium and KCNQ potassium channels, by BACE1. These studies provide evidence for a highly unexpected feature in the functional repertoire of BACE1. Although capable of cleaving accessory channel subunits, BACE1 exerts many of its physiologically significant effects through direct, non-enzymatic interactions with main channel subunits. We discuss how the underlying mechanisms can be conceived and develop scenarios how the regulation of ion conductances by BACE1 might shape electric activity in the intact and diseased brain and heart.

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“…4 isoform, in particular, has a fundamental role in this process. 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).…”

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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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Differential Protein Kinase C-dependent Modulation of Kv7.4 and Kv7.5 Subunits of Vascular Kv7 Channels

Cited by 61 publications

References 48 publications

Heteromerization of chemokine (C-X-C motif) receptor 4 with α_1A/B-adrenergic receptors controls α₁-adrenergic receptor function

Heteromerization of chemokine (C-X-C motif) receptor 4 with α_1A/B-adrenergic receptors controls α₁-adrenergic receptor function

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

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

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Differential Protein Kinase C-dependent Modulation of Kv7.4 and Kv7.5 Subunits of Vascular Kv7 Channels

Cited by 61 publications

References 48 publications

Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

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

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Heteromerization of chemokine (C-X-C motif) receptor 4 with α_1A/B-adrenergic receptors controls α₁-adrenergic receptor function

Heteromerization of chemokine (C-X-C motif) receptor 4 with α_1A/B-adrenergic receptors controls α₁-adrenergic receptor function