Calcium/calmodulin regulates signaling at the α 1A adrenoceptor.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: 2005- : Amsterdam : Elsevier Science
      Original Publication: Amsterdam, North Holland Pub. Co.
    • Subject Terms:
      Calcium/*metabolism ; Calmodulin/*metabolism ; Receptors, Adrenergic, alpha-1/*metabolism ; Signal Transduction/*physiology; Amino Acid Sequence ; Calcium/pharmacology ; Calmodulin/pharmacology ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Protein Binding/physiology ; Receptors, Adrenergic, alpha-1/genetics ; Signal Transduction/drug effects
    • Abstract:
      Cardiovascular functions are mediated by multiple 7-pass transmembrane receptors whose activation promotes contraction or relaxation of the tissues. The α 1 adrenoceptor type 1A plays important roles in the control of vascular tone and myocardial contractility via Ca 2+ -dependent actions. Here, using novel FRET-based biosensors, we identified a novel Ca 2+ -dependent interaction between calmodulin (CaM) and the human α 1A adrenoceptor at the juxtamembranous region of its 4th submembrane domain (SMD4 JM , a.a. 333-361). SMD4 JM houses the known nuclear localization signal of α 1A adrenoceptor (NLS, a.a. 334-349). We found that NLS itself also interacts with CaM, but with lower affinity and Ca 2+ sensitivity, indicating that full interaction between CaM and α 1A receptor in this region requires segment a.a. 333-361. Combined K353Q/L356A substitutions in the non-NLS segment of SMD4 JM cause a 3.5-fold reduction in the affinity of CaM-SMD4 JM interaction. Overexpression of wild-type α 1A adrenoceptor in cells enhances phosphorylation of the extracellular signal-regulated kinases 1/2 (ERK1/2) stimulated by A61603, while overexpression of the K353Q/L356A α 1A receptor mutant significantly reduces this signal. Norepinephrine stimulates intracellular Ca 2+ signals that are higher in cells overexpressing wild-type receptor but lower in cells overexpressing the K353Q/L356A receptor compared to non-transfected cells in the same microscopic environments. These data support a novel and important role for Ca 2+ -dependent CaM interaction at SMD4 JM in α 1A adrenoceptor-mediated signaling.
      (Copyright © 2019 Elsevier B.V. All rights reserved.)
    • References:
      J Biol Chem. 1999 Jul 30;274(31):22081-8. (PMID: 10419536)
      FEBS Lett. 1999 Jul 23;455(3):367-71. (PMID: 10437806)
      Science. 1999 Nov 5;286(5442):1180-4. (PMID: 10550060)
      Nature. 1999 Dec 23-30;402(6764):884-8. (PMID: 10622253)
      J Pharmacol Exp Ther. 2002 Jul;302(1):58-65. (PMID: 12065700)
      J Biol Chem. 2003 Jul 4;278(27):24247-50. (PMID: 12738782)
      Br J Pharmacol. 1992 Sep;107(1):185-8. (PMID: 1330160)
      J Biol Chem. 2004 Apr 23;279(17):17027-37. (PMID: 14752100)
      Cell Calcium. 2004 May;35(5):415-25. (PMID: 15003851)
      Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):5969-74. (PMID: 15840729)
      Cell Calcium. 2005 Jun;37(6):541-53. (PMID: 15862345)
      Cell Calcium. 2007 Apr;41(4):353-64. (PMID: 16999996)
      Biochemistry. 2007 Nov 20;46(46):13415-24. (PMID: 17958378)
      Cardiovasc Res. 2008 Feb 1;77(3):452-62. (PMID: 18032391)
      Mol Biol Cell. 2008 Nov;19(11):4640-50. (PMID: 18768750)
      J Biol Chem. 2008 Nov 14;283(46):31531-40. (PMID: 18790737)
      Circ Heart Fail. 2009 Nov;2(6):654-63. (PMID: 19919991)
      Cell Signal. 2012 Mar;24(3):794-802. (PMID: 22120526)
      PLoS One. 2013 Jun 05;8(6):e65266. (PMID: 23755207)
      PLoS One. 2013 Aug 22;8(8):e72430. (PMID: 23991110)
      PLoS One. 2014 Feb 21;9(2):e89669. (PMID: 24586950)
      Circulation. 2014 Jul 15;130(3):244-55. (PMID: 24928680)
      J Biol Chem. 2015 May 22;290(21):13293-307. (PMID: 25847233)
      Am J Physiol Heart Circ Physiol. 2015 Sep;309(5):H888-96. (PMID: 26116709)
      PLoS One. 2015 Nov 16;10(11):e0142787. (PMID: 26571308)
      J Biol Chem. 2016 May 13;291(20):10805-23. (PMID: 26987903)
      Pharmacol Rev. 1988 Jun;40(2):87-119. (PMID: 2853370)
      Biochem J. 2017 Oct 23;474(21):3627-3642. (PMID: 28935720)
      Biochem Pharmacol. 2018 Jun;152:187-200. (PMID: 29605626)
      J Biochem. 1982 Oct;92(4):1041-8. (PMID: 7174634)
      J Pharmacol Exp Ther. 1995 Jul;274(1):97-103. (PMID: 7616455)
      J Biol Chem. 1995 Sep 15;270(37):21532-8. (PMID: 7665565)
      EMBO J. 1997 Apr 1;16(7):1575-81. (PMID: 9130702)
      J Biol Chem. 1997 Aug 8;272(32):20291-8. (PMID: 9242710)
      J Cardiovasc Pharmacol. 1998 Jul;32(1):117-22. (PMID: 9676730)
    • Grant Information:
      R15 HL112184 United States HL NHLBI NIH HHS
    • Contributed Indexing:
      Keywords: Calcium; Calmodulin; Phosphorylation; Submembrane domain; α(1A) adrenoceptor
    • Accession Number:
      0 (Calmodulin)
      0 (Receptors, Adrenergic, alpha-1)
      SY7Q814VUP (Calcium)
    • Publication Date:
      Date Created: 20190129 Date Completed: 20190606 Latest Revision: 20200405
    • Publication Date:
      20221213
    • Accession Number:
      PMC6409194
    • Accession Number:
      10.1016/j.ejphar.2019.01.042
    • Accession Number:
      30690001