RT Journal Article SR Electronic T1 Calmodulin Increases the Sensitivity of Type 3 Inositol-1,4,5-trisphosphate Receptors to Ca2+ Inhibition in Human Bronchial Mucosal Cells JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 564 OP 567 DO 10.1124/mol.57.3.564 VO 57 IS 3 A1 Missiaen, Ludwig A1 DeSmedt, Humbert A1 Bultynck, Geert A1 Vanlingen, Sara A1 Desmet, Patrick A1 Callewaert, Geert A1 Parys, Jan B. YR 2000 UL http://molpharm.aspetjournals.org/content/57/3/564.abstract AB 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.