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MARCKS mediates vascular contractility through regulating interactions between voltage-gated Ca2+ channels and PIP2.

Jahan, KS; Shi, J; Greenberg, HZE; Khavandi, S; Baudel, MM-A; Barrese, V; Greenwood, IA; Albert, AP (2020) MARCKS mediates vascular contractility through regulating interactions between voltage-gated Ca2+ channels and PIP2. Vascul Pharmacol, 132. p. 106776. ISSN 1879-3649 https://doi.org/10.1016/j.vph.2020.106776
SGUL Authors: Albert, Anthony Paul Greenwood, Iain Andrew

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Abstract

Phosphatidylinositol 4,5-bisphosphate (PIP2) acts as substrate and unmodified ligand for Gq-protein-coupled receptor signalling in vascular smooth muscle cells (VSMCs) that is central for initiating contractility. The present work investigated how PIP2 might perform these two potentially conflicting roles by studying the effect of myristoylated alanine-rich C kinase substrate (MARCKS), a PIP2-binding protein, on vascular contractility in rat and mouse mesenteric arteries. Using wire myography, MANS peptide (MANS), a MARCKS inhibitor, produced robust contractions with a pharmacological profile suggesting a predominantly role for L-type (CaV1.2) voltage-gated Ca2+ channels (VGCC). Knockdown of MARCKS using morpholino oligonucleotides reduced contractions induced by MANS and stimulation of α1-adrenoceptors and thromboxane receptors with methoxamine (MO) and U46619 respectively. Immunocytochemistry and proximity ligation assays demonstrated that MARCKS and CaV1.2 proteins co-localise at the plasma membrane in unstimulated tissue, and that MANS and MO reduced these interactions and induced translocation of MARCKS from the plasma membrane to the cytosol. Dot-blots revealed greater PIP2 binding to MARCKS than CaV1.2 in unstimulated tissue, with this binding profile reversed following stimulation by MANS and MO. MANS evoked an increase in peak amplitude and shifted the activation curve to more negative membrane potentials of whole-cell voltage-gated Ca2+ currents, which were prevented by depleting PIP2 levels with wortmannin. This present study indicates for the first time that MARCKS is important regulating vascular contractility and suggests that disinhibition of MARCKS by MANS or vasoconstrictors may induce contraction through releasing PIP2 into the local environment where it increases voltage-gated Ca2+ channel activity.

Item Type: Article
Additional Information: © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/)
Keywords: Contractility, MARCKS, PIP(2), Voltage-gated Ca(2+) channels, Cardiovascular System & Hematology, 1115 Pharmacology and Pharmaceutical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Vascul Pharmacol
ISSN: 1879-3649
Language: eng
Dates:
DateEvent
September 2020Published
21 July 2020Published Online
17 July 2020Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
FS/15/44/31570British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
BB/J007226/1Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/M018350/1Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
PubMed ID: 32707323
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/112163
Publisher's version: https://doi.org/10.1016/j.vph.2020.106776

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