Revisiting the Large-Conductance Calcium-Activated Potassium (BKCa) Channels in the Pulmonary Circulation
Abstract
:1. Introduction
2. The Pulmonary Circulation, a System with Many Unique Features
3. Structure and Gating of the Large-Conductance Calcium (Ca2+)-Activated Potassium (BKCa) Channels
4. The Role of the α-Subunit in the Pulmonary Circulation
5. β-Subunit or the Modulatory Subunit of the BKCa Channel
6. γ-Subunit or the Auxiliary Subunit of the BKCa Channel
7. Perspective
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | (Disease) Model | Effect on BKCa | Effects in the Model | Potential Mechanisms | References |
---|---|---|---|---|---|
NS1619 and C-type natriuretic peptide | Normotensive rats | Activation | Enhanced endothelium-dependent PA ring dilation and PA pressure reduction ex vivo; hyperpolarised and increased NO production in PMVECs in vivo | Direct activation of the channel in PMVECs | [63] |
Compound X | Monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) rat model | Activation | Reduced pulmonary vascular remodelling, pulmonary flow resistance, RV hypertrophy and afterload in PAH model in vivo strongly vasodilated PA rings ex vivo | Direct activation of the channel in PASMCs | [64] |
Docosahexaenoic acid (DHA) | IPAH patients normotensive rats chronic hypoxia-induced PH mouse model Kcnma1−/− mouse | Activation | Reduced RV pressure in the PH animal model to normal in vivo enhanced endothelium-dependent PA ring dilation and PA pressure reduction ex vivo; dose-dependently activated BKCa current and hyperpolarised human IPAH-PASMCs to normal in vivo | Direct activation of the channel in PASMCs | [57] |
Dehydroepiandrosterone (DHEA) | Chronic hypoxia-induced PH rat model | Activation | Reduced RV pressure, RV wall thickness and PA remodelling in the PH animal model in vivo restored the PA-pressure response to acute hypoxia in the PH animal model in vivo. Decreased intracellular [Ca2+] under hypoxia in PASMCs in vitro Increased BKCa channel activity and expression in PA in the PH animal model in vitro | Dual effect: (i) Activation of the channel in PA by changing the redox balance toward a more oxidative state (ii) Upregulated BKCa mRNA and protein in PASMCs of the chronic hypoxic PH model | [60] |
Echinacoside | Normotensive rats | Activation | Reduced noradrenaline-induced contraction of PA in extracellular [Ca2+]-dependent manner ex vivo | Activated NO-cGMP-PKG pathway with subsequent hyperpolarisation and decrease of intracellular free [Ca2+] in PASMCs | [59] |
Forskolin and cAMP activators | Fawn-hooded rat employed in chronic hypoxia-induced PH rat model | Activation | Increased open probability of BKCa channels in fawn-hooded PH animal PASMCs in vitro | Direct activation of the channel in PASMCs | [50] |
NS1619 | Monocrotaline (MCT)-induced PAH rat model | Activation | Reduced RV pressure, carbon monoxide and improved oxygenation in the PAH animal model in vivo reduced PDGF-induced PASMC proliferation in vitro | Direct activation of the channel | [53] |
JAK2 inhibitors | IPF patients bleomycin-induced lung fibrosis and PH rat model | Activation | Reduced RV pressure and PA Remodelling in vivo Reduced V/Q mismatch in animal model in vivo Promoted relaxant and anticontractile effects on IPF-PA ex vivo Inhibited effect of TGFβ1-induced loss of endothelial markers and upregulation of the PA remodelling markers in vitro Activated BKCa current in vitro | Unknown | [65] |
Iloprost and treprostinil | Primary human PASMCs | Activation | Enhanced PA ring dilation ex vivo Enhanced BKCa current in vitro | (PKA)-induced phosphorylation of BKCa | [47] |
NS1619 | Chronic hypoxia-induced PH rat model | Activation | Enhanced NO-dependent PA pressure reduction ex vivo | Direct activation of the channel | [52] |
Compound | (Disease) Model | Effect on BKCa | Effects in the Model | Potential Mechanisms | References |
---|---|---|---|---|---|
Knocking down KCNMB1 | Chronic hypoxia-induced PH mouse model employing Kcnmb1−/− mouse | Inhibition | Increased pulmonary vascular response to acute and chronic hypoxia and increased RV pressure in vivo Increased focal complex expression in PASMCs in vitro | Downregulates BKCa channels (mRNA, protein and function) in PASMCs | [77] |
Knocking down HIF-1α or KCNMB1 | Subacute hypoxia in hPASMCs | Inhibits upregulation of KCNMB1 in response to hypoxia | Potentiated the hypoxic-mediated increase in [Ca2+]i in vitro Strongly vasodilated PA rings ex vivo | Downregulates BKCa channels (mRNA, protein and function) in PASMCs | [79] |
Overexpression or inhibition of miR-29b | Healthy and IPAH PASMCs | Inhibition or activation, respectively | Decreased BKCa channel currents and downregulated KCNMB1 in normal PASMCs in vitro Increased BKCa channel activity and upregulated KCNMB1 in IPAH-PASMC in vitro | Downregulation or activation of the channel in PASMCs | [80] |
Upregulated KCNMB1 | IPF fibroblasts | Activation | Increased BKCa channel activity in vitro | Upregulated BKCa mRNA and protein in IPF fibroblasts | [83] |
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Guntur, D.; Olschewski, H.; Enyedi, P.; Csáki, R.; Olschewski, A.; Nagaraj, C. Revisiting the Large-Conductance Calcium-Activated Potassium (BKCa) Channels in the Pulmonary Circulation. Biomolecules 2021, 11, 1629. https://doi.org/10.3390/biom11111629
Guntur D, Olschewski H, Enyedi P, Csáki R, Olschewski A, Nagaraj C. Revisiting the Large-Conductance Calcium-Activated Potassium (BKCa) Channels in the Pulmonary Circulation. Biomolecules. 2021; 11(11):1629. https://doi.org/10.3390/biom11111629
Chicago/Turabian StyleGuntur, Divya, Horst Olschewski, Péter Enyedi, Réka Csáki, Andrea Olschewski, and Chandran Nagaraj. 2021. "Revisiting the Large-Conductance Calcium-Activated Potassium (BKCa) Channels in the Pulmonary Circulation" Biomolecules 11, no. 11: 1629. https://doi.org/10.3390/biom11111629