Calmodulin increases the sensitivity of type 3 inositol-1,4, 5-trisphosphate receptors to Ca(2+) inhibition in human bronchial mucosal cells.
Inositol-1,4,5-trisphosphate (IP(3)) releases Ca(2+) from intracellular stores by binding to its receptor (IP(3)R), a multigene family of Ca(2+)-release channels consisting of IP(3)R1, IP(3)R2, and IP(3)R3. IP(3)R1 is stimulated by low cytoplasmic Ca(2+) concentrations and inhibited by high concentrations. Discrepant reports appeared about the effect of cytoplasmic Ca(2+) on IP(3)R3, showing either a bell-shaped dependence or only a stimulatory phase with no negative feedback by high Ca(2+) concentrations. We investigated how calmodulin interfered with the feedback of cytosolic Ca(2+) on the unidirectional IP(3)-induced Ca(2+) release in permeabilized 16HBE14o- bronchial mucosal cells, where IP(3)R3 represents 93% of the receptors at the mRNA level and 81% at the protein level. Calmodulin inhibited the Ca(2+) release induced by 1.5 microM IP(3) with an IC(50) value of 9 microM. This inhibition was absolutely dependent on the presence of cytosolic Ca(2+). Ca(2+) inhibited the IP(3)R with an IC(50) value of 0.92 microM Ca(2+) in the absence of calmodulin and with an IC(50) value of 0.15 microM Ca(2+) in its presence. It is concluded that: 1) IP(3)R3 can be inhibited by calmodulin, 2) IP(3)R3 is inhibited by high Ca(2+) concentrations, and 3) calmodulin shifts the inhibitory part of the Ca(2+)-response curve toward lower Ca(2+) concentrations.
Missiaen
L
L
Laboratorium voor Fysiologie, K.U.Leuven Campus Gasthuisberg O/N, Leuven, Belgium. Ludwig.Missiaen@med.kuleuven.ac.be
DeSmedt
H
H
Bultynck
G
G
Vanlingen
S
S
Desmet
P
P
Callewaert
G
G
Parys
J B
JB
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002147:Calmodulin / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010539:Permeability; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism
D015220:Calcium Channels; D002147:Calmodulin; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D002118:Calcium