TY - JOUR T1 - Calmodulin Increases the Sensitivity of Type 3 Inositol-1,4,5-trisphosphate Receptors to Ca<sup>2+</sup> Inhibition in Human Bronchial Mucosal Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 564 LP - 567 DO - 10.1124/mol.57.3.564 VL - 57 IS - 3 AU - Ludwig Missiaen AU - Humbert DeSmedt AU - Geert Bultynck AU - Sara Vanlingen AU - Patrick Desmet AU - Geert Callewaert AU - Jan B. Parys Y1 - 2000/03/01 UR - http://molpharm.aspetjournals.org/content/57/3/564.abstract N2 - 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. ER -