Localized Na+/H+ exchanger 1 expression protects Ca2+-regulated adenylyl cyclases from changes in intracellular pH.

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  • Author(s): Willoughby D;Willoughby D; Masada N; Crossthwaite AJ; Ciruela A; Cooper DM
  • Source:
    The Journal of biological chemistry [J Biol Chem] 2005 Sep 02; Vol. 280 (35), pp. 30864-72. Date of Electronic Publication: 2005 Jul 07.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Print ISSN: 0021-9258 (Print) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Hydrogen-Ion Concentration*; Adenylyl Cyclases/*metabolism ; Calcium/*metabolism ; Isoenzymes/*metabolism ; Sodium-Hydrogen Exchangers/*metabolism; Adenylyl Cyclases/genetics ; Animals ; Caveolins/metabolism ; Cell Line ; Cyclic AMP/metabolism ; Humans ; Isoenzymes/genetics ; Membrane Microdomains/chemistry ; Membrane Microdomains/metabolism ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Rats ; Sodium-Hydrogen Exchangers/genetics
    • Abstract:
      The Ca2+-sensitive adenylyl cyclases (ACs) are exclusively regulated by capacitative Ca2+ entry (CCE) in nonexcitable cells. The present study investigates whether this Ca2+-dependent modulation of AC activity is further regulated by local pH changes that can arise beneath the plasma membrane as a consequence of cellular activity. Ca2+ stimulation of AC8 expressed in HEK 293 cells and inhibition of endogenous AC6 in C6-2B glioma cells exhibited clear sensitivity to modest pH changes in vitro. Acid pH (pH 7.14) reduced the Ca2+ sensitivity of both ACs, whereas alkaline pH (pH 7.85) enhanced the responsiveness of the enzymes to Ca2+, compared with controls (pH 7.50). Surprisingly, in the intact cell, the response of AC8 and AC6 to CCE was largely unperturbed by similar changes in intracellular pH (pH(i)), imposed using a weak acid (propionate) or weak base (trimethylamine). A range of hypotheses were tested to identify the mechanism(s) that could underlie this lack of pH effect in the intact cell. The pH sensitivity of CCE in HEK 293 cells is likely to dampen the effects of pH(i) on Ca2+-regulated ACs and may partly explain the discrepancy between in vitro and in vivo data. However, we have found that the Na+/H+ exchanger (NHE), NHE1, is functionally active in these cells, and like AC8 (and AC6) it resides in lipid rafts or caveolae, which may create cellular microdomains where pH(i) is tightly regulated. An abundance of NHE1 in these cellular subdomains may generate a privileged environment that protects the Ca2+-sensitive ACs and other caveolar proteins from local acid shifts.
    • Grant Information:
      GM32483 United States GM NIGMS NIH HHS; United Kingdom Wellcome Trust
    • Accession Number:
      0 (Caveolins)
      0 (Isoenzymes)
      0 (Protein Isoforms)
      0 (Sodium-Hydrogen Exchangers)
      0 (growth factor-activatable Na-H exchanger NHE-1)
      E0399OZS9N (Cyclic AMP)
      EC 4.6.1.1 (Adenylyl Cyclases)
      SY7Q814VUP (Calcium)
    • Publication Date:
      Date Created: 20050709 Date Completed: 20051025 Latest Revision: 20210209
    • Publication Date:
      20231215
    • Accession Number:
      10.1074/jbc.M414355200
    • Accession Number:
      16002403