Calmodulin Increases the Sensitivity of Type 3 Inositol-1,4,5-trisphosphate Receptors to Ca2+ Inhibition in Human Bronchial Mucosal Cells

  1. Ludwig Missiaen,
  2. Humbert DeSmedt,
  3. Geert Bultynck,
  4. Sara Vanlingen,
  5. Patrick Desmet,
  6. Geert Callewaert and
  7. Jan B. Parys
  1. Laboratorium voor Fysiologie, K.U.Leuven Campus Gasthuisberg O/N, Leuven, Belgium

    Abstract

    Inositol-1,4,5-trisphosphate (IP3) releases Ca2+ from intracellular stores by binding to its receptor (IP3R), a multigene family of Ca2+-release channels consisting of IP3R1, IP3R2, and IP3R3. IP3R1 is stimulated by low cytoplasmic Ca2+ concentrations and inhibited by high concentrations. Discrepant reports appeared about the effect of cytoplasmic Ca2+ on IP3R3, showing either a bell-shaped dependence or only a stimulatory phase with no negative feedback by high Ca2+ concentrations. We investigated how calmodulin interfered with the feedback of cytosolic Ca2+ on the unidirectional IP3-induced Ca2+ release in permeabilized 16HBE14o- bronchial mucosal cells, where IP3R3 represents 93% of the receptors at the mRNA level and 81% at the protein level. Calmodulin inhibited the Ca2+ release induced by 1.5 μM IP3 with an IC50 value of 9 μM. This inhibition was absolutely dependent on the presence of cytosolic Ca2+. Ca2+ inhibited the IP3R with an IC50 value of 0.92 μM Ca2+ in the absence of calmodulin and with an IC50 value of 0.15 μM Ca2+ in its presence. It is concluded that: 1) IP3R3 can be inhibited by calmodulin, 2) IP3R3 is inhibited by high Ca2+ concentrations, and 3) calmodulin shifts the inhibitory part of the Ca2+-response curve toward lower Ca2+ concentrations.

    Footnotes

    • Send reprint requests to: Dr. Ludwig Missiaen, Laboratorium voor Fysiologie, K.U.Leuven Campus Gasthuisberg O/N, Herestraat 49, B-3000 Leuven, Belgium. E-mail: Ludwig.Missiaen{at}med.kuleuven.ac.be

    • This work was supported by the Interuniversity Poles of Attraction Program, Belgian State, Prime Minister's Office, Federal Office for Scientific, Technical and Cultural Affairs IUAP P4/23 and by European Commission Grant BMH4-CT96-0656.

    • Abbreviations:
      IP3
      inositol-1,4,5-trisphosphate
      IP3R
      inositol-1,4,5-trisphosphate receptor
      BAPTA
      1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
      • Received July 12, 1999.
      • Accepted December 10, 1999.
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    1. Molecular Pharmacology March 1, 2000 vol. 57 no. 3 564-567
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