Journal article
Structural, functional, and mechanistic insights uncover the fundamental role of orphan connexin-62 in platelets
Blood, Vol.137(6), pp.830-843
02/11/2021
DOI: 10.1182/blood.2019004575
PMCID: PMC7885822
PMID: 32822477
Abstract
Connexins oligomerise to form hexameric hemichannels in the plasma membrane that can further dock together on adjacent cells to form gap junctions and facilitate intercellular trafficking of molecules. In this study, we report the expression and function of an orphan connexin, connexin-62 (Cx62), in human and mouse (Cx57, mouse homolog) platelets. A novel mimetic peptide (62Gap27) was developed to target the second extracellular loop of Cx62, and 3-dimensional structural models predicted its interference with gap junction and hemichannel function. The ability of 62Gap27 to regulate both gap junction and hemichannel-mediated intercellular communication was observed using fluorescence recovery after photobleaching analysis and flow cytometry. Cx62 inhibition by 62Gap27 suppressed a range of agonist-stimulated platelet functions and impaired thrombosis and hemostasis. This was associated with elevated protein kinase A-dependent signaling in a cyclic adenosine monophosphate-independent manner and was not observed in Cx57-deficient mouse platelets (in which the selectivity of 62Gap27 for this connexin was also confirmed). Notably, Cx62 hemichannels were observed to function independently of Cx37 and Cx40 hemichannels. Together, our data reveal a fundamental role for a hitherto uncharacterized connexin in regulating the function of circulating cells.
Details
- Title: Subtitle
- Structural, functional, and mechanistic insights uncover the fundamental role of orphan connexin-62 in platelets
- Creators
- Khaled A Sahli - University of ReadingGagan D Flora - University of IowaParvathy Sasikumar - University of ReadingAli H Maghrabi - University of ReadingLisa-Marie Holbrook - King's College LondonSarah K AlOuda - University of ReadingAmro Elgheznawy - University of ReadingTanya Sage - University of ReadingAlexander R Stainer - University of ReadingRecep Adiyaman - University of ReadingMohammad AboHassan - University of ReadingMarilena Crescente - University of ReadingNeline Kriek - University of ReadingSakthivel Vaiyapuri - University of ReadingAlexander P Bye - University of ReadingAmanda J Unsworth - University of ReadingChris I Jones - University of ReadingLiam J McGuffin - University of ReadingJonathan M Gibbins - University of Reading
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.137(6), pp.830-843
- DOI
- 10.1182/blood.2019004575
- PMID
- 32822477
- PMCID
- PMC7885822
- NLM abbreviation
- Blood
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Grant note
- MR/J002666/1 / Medical Research Council RG/09/011/28094 / British Heart Foundation RG/15/2/31224 / British Heart Foundation MR/P023878/1 / Medical Research Council Biotechnology and Biological Sciences Research Council PG/19/62/34593 / British Heart Foundation
- Language
- English
- Date published
- 02/11/2021
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984949466202771
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