Constitutive SRC-mediated phosphorylation of pannexin 1 at tyrosine 198 occurs at the plasma membrane

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dc.contributor.authorDeLalio, Leon J.
dc.contributor.authorBillaud, Marie
dc.contributor.authorRuddiman, Claire A.
dc.contributor.authorJohnstone, Scott R.
dc.contributor.authorButcher, Joshua T.
dc.contributor.authorWolpe, Abigail G.
dc.contributor.authorJin, Xueyao
dc.contributor.authorStevenson Keller, T. C. IV
dc.contributor.authorKeller, Alexander S.
dc.contributor.authorRivière, Thibaud
dc.contributor.authorGood, Miranda E.
dc.contributor.authorBest, Angela K.
dc.contributor.authorLohman, Alexander W.
dc.contributor.authorSwayne, Leigh Anne
dc.contributor.authorPenuela, Silvia
dc.contributor.authorThompson, Roger J.
dc.contributor.authorLampe, Paul D.
dc.contributor.authorYeager, Mark
dc.contributor.authorIsakson, Brant E.
dc.date.accessioned2021-01-28T23:42:27Z
dc.date.available2021-01-28T23:42:27Z
dc.date.copyright2019en_US
dc.date.issued2019
dc.description.abstractPannexin 1 (PANX1)-mediated ATP release in vascular smooth muscle coordinates α1-adrenergic receptor (α1-AR) vasoconstriction and blood pressure homeostasis. We recently identified amino acids 198–200 (YLK) on the PANX1 intracellular loop that are critical for α1-AR–mediated vasoconstriction and PANX1 channel function. We report herein that the YLK motif is contained within an SRC homology 2 domain and is directly phosphorylated by SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) at Tyr198. We demonstrate that PANX1-mediated ATP release occurs independently of intracellular calcium but is sensitive to SRC family kinase (SFK) inhibition, suggestive of channel regulation by tyrosine phosphorylation. Using a PANX1 Tyr198–specific antibody, SFK inhibitors, SRC knockdown, temperature-dependent SRC cells, and kinase assays, we found that PANX1-mediated ATP release and vasoconstriction involves constitutive phosphorylation of PANX1 Tyr198 by SRC. We specifically detected SRC-mediated Tyr198 phosphorylation at the plasma membrane and observed that it is not enhanced or induced by α1-AR activation. Last, we show that PANX1 immunostaining is enriched in the smooth muscle layer of arteries from hypertensive humans and that Tyr198 phosphorylation is detectable in these samples, indicative of a role for membrane-associated PANX1 in small arteries of hypertensive humans. Our discovery adds insight into the regulation of PANX1 by post-translational modifications and connects a significant purinergic vasoconstriction pathway with a previously identified, yet unexplored, tyrosine kinase–based α1-AR constriction mechanism. This work implicates SRC-mediated PANX1 function in normal vascular hemodynamics and suggests that Tyr198-phosphorylated PANX1 is involved in hypertensive vascular pathology.en_US
dc.description.reviewstatusRevieweden_US
dc.description.scholarlevelFacultyen_US
dc.identifier.citationDeLalio, L. J., Billaud, M., Ruddiman, C. A., Johnstone, S. R., Butcher, J. T., Swayne, L. A., … Isakson, B. E. (2019). Constitutive SRC-mediated phosphorylation of pannexin 1 at tyrosine 198 occurs at the plasma membrane. Journal of Biological Chemistry, 294(17), 6940-6956. https://doi.org/10.1074/jbc.RA118.006982.en_US
dc.identifier.urihttps://doi.org/10.1074/jbc.RA118.006982
dc.identifier.urihttp://hdl.handle.net/1828/12617
dc.language.isoenen_US
dc.publisherJournal of Biological Chemistryen_US
dc.subjectpannexin 1 (PANX1)
dc.subjectSRC
dc.subjectsmooth muscle
dc.subjectATP
dc.subjectATP release
dc.subjectvascular biology
dc.subjectadrenergic receptor
dc.subjecthypertension
dc.subjectvasoconstriction
dc.subjectSRC family kinase (SFK)
dc.subjectkinase signaling
dc.subjectmuscle contraction
dc.subjectmembrane channel
dc.subjectCentre for Biomedical Research
dc.subject.departmentDivision of Medical Sciences
dc.subject.departmentSchool of Medical Sciences
dc.titleConstitutive SRC-mediated phosphorylation of pannexin 1 at tyrosine 198 occurs at the plasma membraneen_US
dc.typeArticleen_US

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