Dataset Information

The G?1 and G?3 Subunits Differentially Regulate Rat Vascular Kv7 Channels.

ABSTRACT: Within the vasculature Kv7 channels are key regulators of basal tone and contribute to a variety of receptor mediated vasorelaxants. The Kv7.4 isoform, abundant within the vasculature, is key to these processes and was recently shown to have an obligatory requirement of G-protein ?? subunits for its voltage dependent activity. There is an increasing appreciation that with 5 G? subunits and 12 G? subunits described in mammalian cells that different G? x ? x combinations can confer selectivity in G?? effector stimulation. Therefore, we aimed to characterize the G? subunit(s) which basally regulate Kv7.4 channels and native vascular Kv7 channels. In Chinese Hamster Ovary cells overexpressing Kv7.4 and different G?x subunits only G?1, G?3, and G?5 enhanced Kv7.4 currents, increasing the activation kinetics and negatively shifting the voltage dependence of activation. In isolated rat renal artery myocytes, proximity ligation assay detected an interaction of Kv7.4 with G?1 and G?3 subunits, but not other isoforms. Morpholino directed knockdown of G?1 in rat renal arteries did not alter Kv7 dependent currents but reduced Kv7.4 protein expression. Knockdown of G?3 in rat renal arteries resulted in decreased basal K+ currents which were not sensitive to pharmacological inhibition of Kv7 channels. These studies implicate the G?1 subunit in the synthesis or stability of Kv7.4 proteins, whilst revealing that the G?3 isoform is responsible for the basal activity of Kv7 channels in native rat renal myocytes. These findings demonstrate that different G? subunits have important individual roles in ion channel regulation.

SUBMITTER: Greenwood IA

PROVIDER: S-EPMC6971187 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Gβ1 and Gβ3 Subunits Differentially Regulate Rat Vascular Kv7 Channels.

Greenwood Iain A IA Stott Jennifer B JB

Frontiers in physiology 20200114

Within the vasculature Kv7 channels are key regulators of basal tone and contribute to a variety of receptor mediated vasorelaxants. The Kv7.4 isoform, abundant within the vasculature, is key to these processes and was recently shown to have an obligatory requirement of G-protein βγ subunits for its voltage dependent activity. There is an increasing appreciation that with 5 Gβ subunits and 12 Gγ subunits described in mammalian cells that different Gβ x γ x com ...[more]

PMID: 31992990

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Project description:Background and purposeCerebral vasospasm is the persistent constriction of large conduit arteries in the base of the brain. This pathologically sustained contraction of the arterial myocytes has been attributed to locally elevated concentrations of vasoconstrictor agonists (spasmogens). We assessed the presence and function of KCNQ (K(v) 7) potassium channels in rat basilar artery myocytes, and determined the efficacy of K(v) 7 channel activators in relieving spasmogen-induced basilar artery constriction.Experimental approachExpression and function of K(v) 7 channels in freshly isolated basilar artery myocytes were evaluated by reverse transcriptase polymerase chain reaction and whole-cell electrophysiological techniques. Functional responses to K(v) 7 channel modulators were studied in intact artery segments using pressure myography.Key resultsAll five mammalian KCNQ subtypes (KCNQ1-5) were detected in the myocytes. K(v) currents were attributed to K(v) 7 channel activity based on their voltage dependence of activation (V(0.5) ∼-34 mV), lack of inactivation, enhancement by flupirtine (a selective K(v) 7 channel activator) and inhibition by 10,10-bis(pyridin-4-ylmethyl)anthracen-9-one (XE991; a selective K(v) 7 channel blocker). XE991 depolarized the myocytes and constricted intact basilar arteries. Celecoxib, a clinically used anti-inflammatory drug, not only enhanced K(v) 7 currents but also inhibited voltage-sensitive Ca(2+) currents. In arteries pre-constricted with spasmogens, both celecoxib and flupirtine were more effective in dilating artery segments than was nimodipine, a selective L-type Ca(2+) channel blocker.Conclusions and implicationsK(v) 7 channels are important determinants of basilar artery contractile status. Targeting the K(v) 7 channels using flupirtine or celecoxib could provide a novel strategy to relieve basilar artery constriction in patients with cerebral vasospasm.Linked articlesTo view two letters to the Editor regarding this article visit http://dx.doi.org/10.1111/j.1476-5381.2011.01454.x and http://dx.doi.org/10.1111/j.1476-5381.2011.01457.x.

Project description:Lung diseases constitute a global health concern causing disability. According to WHO in 2016, respiratory diseases accounted for 24% of world population mortality, the second cause of death after cardiovascular diseases. The Kv7 channels family is a group of voltage-dependent K+ channels (Kv) encoded by KCNQ genes that are involved in various physiological functions in numerous cell types, especially, cardiac myocytes, smooth muscle cells, neurons, and epithelial cells. Kv7 channel α-subunits are regulated by KCNE1-5 ancillary β-subunits, which modulate several characteristics of Kv7 channels such as biophysical properties, cell-location, channel trafficking, and pharmacological sensitivity. Kv7 channels are mainly expressed in two large groups of lung tissues: pulmonary arteries (PAs) and bronchial tubes. In PA, Kv7 channels are expressed in pulmonary artery smooth muscle cells (PASMCs); while in the airway (trachea, bronchus, and bronchioles), Kv7 channels are expressed in airway smooth muscle cells (ASMCs), airway epithelial cells (AEPs), and vagal airway C-fibers (VACFs). The functional role of Kv7 channels may vary depending on the cell type. Several studies have demonstrated that the impairment of Kv7 channel has a strong impact on pulmonary physiology contributing to the pathophysiology of different respiratory diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, chronic coughing, lung cancer, and pulmonary hypertension. Kv7 channels are now recognized as playing relevant physiological roles in many tissues, which have encouraged the search for Kv7 channel modulators with potential therapeutic use in many diseases including those affecting the lung. Modulation of Kv7 channels has been proposed to provide beneficial effects in a number of lung conditions. Therefore, Kv7 channel openers/enhancers or drugs acting partly through these channels have been proposed as bronchodilators, expectorants, antitussives, chemotherapeutics and pulmonary vasodilators.

Dataset Information

The G?1 and G?3 Subunits Differentially Regulate Rat Vascular Kv7 Channels.

Publications

The Gβ1 and Gβ3 Subunits Differentially Regulate Rat Vascular Kv7 Channels.

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