Advertisement

α-Subunit Tyrosine Phosphorylation Is Required for Activation of the Large Conductance Ca2+-Activated Potassium Channel in the Rabbit Sphincter of Oddi

  • Dan Feng
    Affiliations
    Department of Radiology and Functional and Molecular Imaging Key Lab of Shaanxi Province, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Search for articles by this author
  • Yan-Yan Guo
    Affiliations
    Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Search for articles by this author
  • Wen Wang
    Affiliations
    Department of Radiology and Functional and Molecular Imaging Key Lab of Shaanxi Province, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Search for articles by this author
  • Lin-Feng Yan
    Affiliations
    Department of Radiology and Functional and Molecular Imaging Key Lab of Shaanxi Province, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Search for articles by this author
  • Ting Sun
    Affiliations
    Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Search for articles by this author
  • Qing-Qing Liu
    Affiliations
    Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Search for articles by this author
  • Guang-Bin Cui
    Correspondence
    Address correspondence to Hai-Yan Nan, M.D., or Guang-Bin Cui, M.D., Tangdu Hospital, No. 1 Xinsi Rd., Baqiao District, Xi'an 710038, China.
    Affiliations
    Department of Radiology and Functional and Molecular Imaging Key Lab of Shaanxi Province, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Search for articles by this author
  • Hai-Yan Nan
    Correspondence
    Address correspondence to Hai-Yan Nan, M.D., or Guang-Bin Cui, M.D., Tangdu Hospital, No. 1 Xinsi Rd., Baqiao District, Xi'an 710038, China.
    Affiliations
    Department of Radiology and Functional and Molecular Imaging Key Lab of Shaanxi Province, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Search for articles by this author
Published:September 20, 2022DOI:https://doi.org/10.1016/j.ajpath.2022.08.005
      Large conductance Ca2+-activated potassium (BKCa) channels are regulated by intracellular free Ca2+ concentrations ([Ca2+]i) and channel protein phosphorylation. In hypercholesterolemia (HC), motility impairment of the sphincter of Oddi (SO) is associated with abnormal [Ca2+]i accumulation in smooth muscle cells of the rabbit SO (RSOSMCs), which is closely related to BKCa channel activity. However, the underlying mechanisms regulating channel activity remain unclear. In this study, an HC rabbit model was generated and used to investigate BKCa channel activity of RSOSMCs via SO muscle tone measurement in vitro and manometry in vivo, electrophysiological recording, intracellular calcium measurement, and Western blot analyses. BKCa channel activity was decreased, which correlated with [Ca2+]i overload and reduced tyrosine phosphorylation of the BKCa α-subunit in the HC group. The abnormal [Ca2+]i accumulation and decreased BKCa channel activity were partially restored by Na3VO4 pretreatment but worsened by genistein in RSOSMCs in the HC group. This study suggests that α-subunit tyrosine phosphorylation is required for [Ca2+]i to activate BKCa channels, and there is a negative feedback between the BKCa channel and the L-type voltage-dependent Ca2+ channel that regulates [Ca2+]i. This study provides direct evidence that tyrosine phosphorylation of BKCa α-subunits is required for [Ca2+]i to activate BKCa channels in RSOSMCs, which may be the underlying physiological and pathologic mechanism regulating the activity of BKCa channels in SO cells.

      Graphical abstract

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Pathology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Zhang X.Y.
        • Cui G.B.
        • Ma K.J.
        • Wang S.
        • Wei Y.N.
        • Du P.
        • Chen B.Y.
        • Guo W.
        • Wang X.J.
        • Huang H.D.
        • Wang J.H.
        • Huang X.F.
        • Wang C.M.
        • Wang Y.M.
        • Wei J.G.
        Sphincter of Oddi dysfunction in hypercholesterolemic rabbits.
        Eur J Gastroenterol Hepatol. 2008; 20: 202-208
        • Din S.A.
        • Naimi I.
        • Beg M.
        Sphincter of Oddi dysfunction: a perplexing presentation.
        Case Rep Gastroenterol. 2016; 10: 714-719
        • Rong Z.H.
        • Chen H.Y.
        • Wang X.X.
        • Wang Z.Y.
        • Xian G.Z.
        • Ma B.Z.
        • Qin C.K.
        • Zhang Z.H.
        Effects of sphincter of Oddi motility on the formation of cholesterol gallstones.
        World J Gastroenterol. 2016; 22: 5540-5547
        • Kyanam Kabir Baig K.R.
        • Wilcox C.M.
        Translational and clinical perspectives on sphincter of Oddi dysfunction.
        Clin Exp Gastroenterol. 2016; 9: 191-195
        • Jun C.H.
        • Park C.H.
        • Jeon J.
        • Park I.H.
        • Lee H.J.
        • Park S.Y.
        • Kim H.S.
        • Choi S.K.
        • Rew J.S.
        Feasibility of self-expandable metal stents for preservation of sphincter of Oddi function in patients with common bile duct stones: a pilot study.
        Gastrointest Endosc. 2015; 82: 719-723
        • Hanzawa T.
        • Matsunaga T.
        • Koike T.
        • Kanno A.
        • Masamune A.
        • Iijima K.
        • Shimosegawa T.
        • Haga Y.
        A new manometry device for evaluating the sphincter of Oddi using a fiber-optic pressure sensor.
        Minim Invasive Ther Allied Technol. 2018; 27: 226-232
        • Sonoda Y.
        • Takahata S.
        • Jabar F.
        • Schloithe A.C.
        • Grivell M.A.
        • Woods C.M.
        • Simula M.E.
        • Toouli J.
        • Saccone G.T.
        Electrical activation of common bile duct nerves modulates sphincter of Oddi motility in the Australian possum.
        HPB (Oxford). 2005; 7: 303-312
        • Wang X.J.
        • Wei J.G.
        • Wang C.M.
        • Wang Y.C.
        • Wu Q.Z.
        • Xu J.K.
        • Yang X.X.
        Effect of cholesterol liposomes on calcium mobilization in muscle cells from the rabbit sphincter of Oddi.
        World J Gastroenterol. 2002; 8: 144-149
        • Wei J.G.
        • Wang Y.C.
        • Du F.
        • Yu H.J.
        Dynamic and ultrastructural study of sphincter of Oddi in early-stage cholelithiasis in rabbits with hypercholesterolemia.
        World J Gastroenterol. 2000; 6: 102-106
        • Saeki T.
        • Suzuki Y.
        • Yamamura H.
        • Takeshima H.
        • Imaizumi Y.
        A junctophilin-caveolin interaction enables efficient coupling between ryanodine receptors and BKCa channels in the Ca(2+) microdomain of vascular smooth muscle.
        J Biol Chem. 2019; 294: 13093-13105
        • Horiuchi T.
        • Dietrich H.H.
        • Tsugane S.
        • Dacey Jr., R.G.
        Role of potassium channels in regulation of brain arteriolar tone: comparison of cerebrum versus brain stem.
        Stroke. 2001; 32: 218-224
        • Yin X.C.
        • Zhang S.L.
        • Liu H.R.
        Multiple regulatory effects of angiotensin II on the large-conductance Ca(2+)- and voltage-activated potassium channel in vascular smooth muscle cells.
        Sheng Li Xue Bao. 2019; 71: 187-195
        • Hu X.Q.
        • Zhang L.
        Function and regulation of large conductance Ca(2+)-activated K+ channel in vascular smooth muscle cells.
        Drug Discov Today. 2012; 17: 974-987
        • Tykocki N.R.
        • Boerman E.M.
        • Jackson W.F.
        Smooth muscle ion channels and regulation of vascular tone in resistance arteries and arterioles.
        Compr Physiol. 2017; 7: 485-581
        • Kyle B.D.
        • Braun A.P.
        The regulation of BK channel activity by pre- and post-translational modifications.
        Front Physiol. 2014; 5: 316
        • Shipston M.J.
        • Tian L.
        Posttranscriptional and posttranslational regulation of BK channels.
        Int Rev Neurobiol. 2016; 128: 91-126
        • Alioua A.
        • Huggins J.P.
        • Rousseau E.
        PKG-I alpha phosphorylates the alpha-subunit and upregulates reconstituted GKCa channels from tracheal smooth muscle.
        Am J Physiol. 1995; 268: L1057-L1063
        • Jackson W.F.
        • Huebner J.M.
        • Rusch N.J.
        Enzymatic isolation and characterization of single vascular smooth muscle cells from cremasteric arterioles.
        Microcirculation. 1997; 4: 35-50
        • Suzuki Y.
        • Yamamura H.
        • Ohya S.
        • Imaizumi Y.
        Caveolin-1 facilitates the direct coupling between large conductance Ca2+-activated K+ (BKCa) and Cav1.2 Ca2+ channels and their clustering to regulate membrane excitability in vascular myocytes.
        J Biol Chem. 2013; 288: 36750-36761
        • Lu R.
        • Alioua A.
        • Kumar Y.
        • Eghbali M.
        • Stefani E.
        • Toro L.
        MaxiK channel partners: physiological impact.
        J Physiol. 2006; 570: 65-72
        • Schubert R.
        • Nelson M.T.
        Protein kinases: tuners of the BKCa channel in smooth muscle.
        Trends Pharmacol Sci. 2001; 22: 505-512
        • Al-Karagholi M.A.
        • Gram C.
        • Nielsen C.A.W.
        • Ashina M.
        Targeting BKCa channels in migraine: rationale and perspectives.
        CNS Drugs. 2020; 34: 325-335
        • Xu Z.
        • Wu Y.
        • Zhang Y.
        • Zhang H.
        • Shi L.
        Melatonin activates BKCa channels in cerebral artery myocytes via both direct and MT receptor/PKC-mediated pathway.
        Eur J Pharmacol. 2019; 842: 177-188
        • Schneider H.
        • Schubert K.M.
        • Blodow S.
        • Kreutz C.P.
        • Erdogmus S.
        • Wiedenmann M.
        • Qiu J.
        • Fey T.
        • Ruth P.
        • Lubomirov L.T.
        • Pfitzer G.
        • Mederos Y.S.M.
        • Hardie D.G.
        • Gudermann T.
        • Pohl U.
        AMPK dilates resistance arteries via activation of SERCA and BKCa channels in smooth muscle.
        Hypertension. 2015; 66: 108-116
        • Petkov G.V.
        Central role of the BK channel in urinary bladder smooth muscle physiology and pathophysiology.
        Am J Physiol Regul Integr Comp Physiol. 2014; 307: R571-R584
        • Ling S.
        • Sheng J.Z.
        • Braun A.P.
        The calcium-dependent activity of large-conductance, calcium-activated K+ channels is enhanced by Pyk2- and Hck-induced tyrosine phosphorylation.
        Am J Physiol Cell Physiol. 2004; 287: C698-C706
        • Zhou R.
        • Liu L.
        • Hu D.
        Involvement of BKCa alpha subunit tyrosine phosphorylation in vascular hyporesponsiveness of superior mesenteric artery following hemorrhagic shock in rats.
        Cardiovasc Res. 2005; 68: 327-335
        • Feng D.
        • Nan H.
        • Wang W.
        • Yan L.
        • Du P.
        • Zuo L.
        • Zhang K.
        • Zhao M.
        • Cui G.
        Expression and alteration of BKCa channels in the sphincter of Oddi's from rabbits with hypercholesterolemia.
        Channels (Austin). 2017; 11: 236-244
        • Greimers R.
        • Trebak M.
        • Moutschen M.
        • Jacobs N.
        • Boniver J.
        Improved four-color flow cytometry method using fluo-3 and triple immunofluorescence for analysis of intracellular calcium ion ([Ca2+]i) fluxes among mouse lymph node B- and T-lymphocyte subsets.
        Cytometry. 1996; 23: 205-217
        • Taguchi K.
        • Kaneko K.
        • Kubo T.
        Protein kinase C modulates Ca2+-activated K+ channels in cultured rat mesenteric artery smooth muscle cells.
        Biol Pharm Bull. 2000; 23: 1450-1454
        • Rozsa Z.
        • Pataricza J.
        • Nemeth J.
        • Papp J.G.
        Differential efficacy of vasodilators in hypercholesterolaemic rabbits.
        J Pharm Pharmacol. 1998; 50: 1035-1044
        • Wang F.
        • Yang Y.
        • Ji X.
        • Tao X.
        • Wang Y.
        • Wang C.
        Effects of paeoniflorin on the activity of muscle strips, intracellular calcium ion concentration and L-type voltage-sensitive calcium ion channels in the sphincter of Oddi of hypercholesterolemic rabbits.
        Mol Med Rep. 2019; 19: 5185-5194
        • Touyz R.M.
        • Alves-Lopes R.
        • Rios F.J.
        • Camargo L.L.
        • Anagnostopoulou A.
        • Arner A.
        • Montezano A.C.
        Vascular smooth muscle contraction in hypertension.
        Cardiovasc Res. 2018; 114: 529-539
        • Ghatta S.
        • Nimmagadda D.
        • Xu X.
        • O'Rourke S.T.
        Large-conductance, calcium-activated potassium channels: structural and functional implications.
        Pharmacol Ther. 2006; 110: 103-116
        • Mills R.D.
        • Mita M.
        • Walsh M.P.
        A role for the Ca(2+)-dependent tyrosine kinase Pyk2 in tonic depolarization-induced vascular smooth muscle contraction.
        J Muscle Res Cell Motil. 2015; 36: 479-489
        • Cheng J.
        • Mao L.
        • Wen J.
        • Li P.Y.
        • Wang N.
        • Tan X.Q.
        • Zhang X.D.
        • Zeng X.R.
        • Xu L.
        • Xia X.M.
        • Xia D.
        • He K.
        • Su S.
        • Yao H.
        • Yang Y.
        Different effects of hypertension and age on the function of large conductance calcium- and voltage-activated potassium channels in human mesentery artery smooth muscle cells.
        J Am Heart Assoc. 2016; 5: e003913
        • Shelton E.L.
        • Ector G.
        • Galindo C.L.
        • Hooper C.W.
        • Brown N.
        • Wilkerson I.
        • Pfaltzgraff E.R.
        • Paria B.C.
        • Cotton R.B.
        • Stoller J.Z.
        • Reese J.
        Transcriptional profiling reveals ductus arteriosus-specific genes that regulate vascular tone.
        Physiol Genomics. 2014; 46: 457-466
        • Du P.
        • Cui G.B.
        • Wang Y.R.
        • Zhang X.Y.
        • Ma K.J.
        • Wei J.G.
        Down regulated expression of the beta1 subunit of the big-conductance Ca2+ sensitive K+ channel in sphincter of Oddi cells from rabbits fed with a high cholesterol diet.
        Acta Biochim Biophys Sin (Shanghai). 2006; 38: 893-899
        • Shi L.
        • Liu B.
        • Zhang Y.
        • Xue Z.
        • Liu Y.
        • Chen Y.
        Exercise training reverses unparallel downregulation of MaxiK channel alpha- and beta1-subunit to enhance vascular function in aging mesenteric arteries.
        J Gerontol A Biol Sci Med Sci. 2014; 69: 1462-1473
        • Ling S.
        • Woronuk G.
        • Sy L.
        • Lev S.
        • Braun A.P.
        Enhanced activity of a large conductance, calcium-sensitive K+ channel in the presence of Src tyrosine kinase.
        J Biol Chem. 2000; 275: 30683-30689
        • Hirata A.
        • Igarashi M.
        • Yamaguchi H.
        • Suwabe A.
        • Daimon M.
        • Kato T.
        • Tominaga M.
        Nifedipine suppresses neointimal thickening by its inhibitory effect on vascular smooth muscle cell growth via a MEK-ERK pathway coupling with Pyk2.
        Br J Pharmacol. 2000; 131: 1521-1530
        • Liu Y.
        • Hou X.Y.
        • Zhang G.Y.
        • Xu T.L.
        L-type voltage-gated calcium channel attends regulation of tyrosine phosphorylation of NMDA receptor subunit 2A induced by transient brain ischemia.
        Brain Res. 2003; 972: 142-148
        • Hill M.A.
        • Potocnik S.J.
        • Martinez-Lemus L.A.
        • Meininger G.A.
        Delayed arteriolar relaxation after prolonged agonist exposure: functional remodeling involving tyrosine phosphorylation.
        Am J Physiol Heart Circ Physiol. 2003; 285: H849-H856
        • Wang Y.
        • Sun H.Y.
        • Liu Y.G.
        • Song Z.
        • She G.
        • Xiao G.S.
        • Wang Y.
        • Li G.R.
        • Deng X.L.
        Tyrphostin AG556 increases the activity of large conductance Ca(2+) -activated K(+) channels by inhibiting epidermal growth factor receptor tyrosine kinase.
        J Cell Mol Med. 2017; 21: 1826-1834
        • Bailey C.S.
        • Moldenhauer H.J.
        • Park S.M.
        • Keros S.
        • Meredith A.L.
        KCNMA1-linked channelopathy.
        J Gen Physiol. 2019; 151: 1173-1189
        • Matsuki K.
        • Kato D.
        • Takemoto M.
        • Suzuki Y.
        • Yamamura H.
        • Ohya S.
        • Takeshima H.
        • Imaizumi Y.
        Negative regulation of cellular Ca(2+) mobilization by ryanodine receptor type 3 in mouse mesenteric artery smooth muscle.
        Am J Physiol Cell Physiol. 2018; 315: C1-C9
        • Zhang L.X.
        • Li H.F.
        • Wang L.D.
        • Jin S.
        • Dou X.C.
        • Tian Z.F.
        • Ma Q.
        Resveratrol and genistein inhibition of rat isolated gastrointestinal contractions and related mechanisms.
        World J Gastroenterol. 2014; 20: 15335-15342
        • Ohta T.
        • Yasuda W.
        • Hasegawa A.
        • Ito S.
        • Nakazato Y.
        Effects of inhibitors for tyrosine kinase and non-selective cation channel on capacitative Ca(2+) entry in rat ileal smooth muscle.
        Eur J Pharmacol. 2000; 387: 211-220
        • Futatsugi A.
        • Nakamura T.
        • Yamada M.K.
        • Ebisui E.
        • Nakamura K.
        • Uchida K.
        • Kitaguchi T.
        • Takahashi-Iwanaga H.
        • Noda T.
        • Aruga J.
        • Mikoshiba K.
        IP3 receptor types 2 and 3 mediate exocrine secretion underlying energy metabolism.
        Science. 2005; 309: 2232-2234
        • Asakawa T.
        • Enomoto K.
        • Takano M.
        [Structure of adenylate cyclase and the coupling with the receptor-G protein system]. Japanese.
        Nihon Yakurigaku Zasshi. 1993; 101: 59-68
        • D'Agostino R.
        • Barberio L.
        • Gatto M.
        • Tropea T.
        • De Luca M.
        • Mandala M.
        Extra virgin olive oil phenols vasodilate rat mesenteric resistance artery via phospholipase C (PLC)-calcium microdomains-potassium channels (BKCa) signals.
        Biomolecules. 2021; 11: 137