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    The lipidated connexin mimetic peptide SRPTEKT-Hdc is a potent inhibitor of Cx43 channels with specificity for the pS368 phospho-isoform

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    Cotter et al for open access at ...
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    Final Accepted Manuscript
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    Author
    Cotter, Maura L
    Boitano, Scott
    Lampe, Paul D
    Solan, Joell L
    Vagner, Josef
    Ek-Vitorin, Jose F
    Burt, Janis M
    Affiliation
    Univ Arizona, Dept Pharmacol
    Univ Arizona, Bio5 Inst
    Univ Arizona, Asthma & Airway Dis Res Ctr
    Univ Arizona, Dept Physiol
    Issue Date
    2019-10-07
    Keywords
    Ca2+-wave propagation
    conformation-specific gap junction channel inhibitor
    connexin 43
    hemichannel inhibitor
    
    Metadata
    Show full item record
    Publisher
    AMER PHYSIOLOGICAL SOC
    Citation
    Cotter, Maura L., et al. "The lipidated connexin mimetic peptide SRPTEKT-Hdc is a potent inhibitor of Cx43 channels with specificity for the pS368 phospho-isoform." American Journal of Physiology-Cell Physiology 317.4 (2019): C825-C842.
    Journal
    AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
    Rights
    Copyright © 2019 the American Physiological Society.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Connexin (Cx) mimetic peptides derived from extracellular loop II sequences (e.g., Gap27: SRPTEKTIFII; Peptide5: VDCFLSRPTEKT) have been used as reversible, Cx-specific blockers of hemichannel (HCh) and gap junction channel (GJCh) function. These blockers typically require high concentrations (~5 µM, <1 h for HCh; ~100 µM, >1 h for GJCh) to achieve inhibition. We have shown that addition of a hexadecyl (Hdc) lipid tail to the conserved SRPTEKT peptide sequence (SRPTEKT-Hdc) results in a novel, highly efficacious, and potent inhibitor of mechanically induced Ca2+-wave propagation (IC50 64.8 pM) and HCh-mediated dye uptake (IC50 45.0 pM) in Madin-Darby canine kidney cells expressing rat Cx43 (MDCK43). The lack of similar effect on dye coupling (NBD-MTMA) suggested channel conformation-specific inhibition. Here we report that SRPTEKT-Hdc inhibition of Ca2+-wave propagation, dye coupling, and dye uptake depended on the functional configuration of Cx43 as determined by phosphorylation at serine 368 (S368). Ca2+-wave propagation was enhanced in MDCK cells expressing single-site mutants of Cx43 that mimicked (MDCK43-S368D) or favored (MDCK43-S365A) phosphorylation at S368. Furthermore, SRPTEKT-Hdc potently inhibited GJCh-mediated Ca2+-wave propagation (IC50 230.4 pM), dye coupling, and HCh-mediated dye uptake in MDCK43-S368D and -S365A cells. In contrast, Ca2+-wave propagation, dye coupling, and dye uptake were largely unaffected (IC50 12.3 μM) by SRPTEKT-Hdc in MDCK43-S368A and -S365D cells, mutations that mimic or favor dephosphorylation at S368. Together, these data indicate that SRPTEKT-Hdc is a potent inhibitor of physiological Ca2+-wave signaling mediated specifically by the pS368 phosphorylated form of Cx43.
    Note
    12 month embargo; published online: 7 October 2019
    ISSN
    0363-6143
    PubMed ID
    31365296
    DOI
    10.1152/ajpcell.00160.2019
    Version
    Final accepted manuscript
    Sponsors
    United States Department of Health & Human Services National Institutes of Health (NIH) - USA [HL-058732, HL-131712, HL-007249, NS-073664, GM-055632]
    ae974a485f413a2113503eed53cd6c53
    10.1152/ajpcell.00160.2019
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