CIB1, a ubiquitously expressed Ca2+-binding protein ligand of the InsP3 receptor Ca2+ release channel.
A family of Ca(2+)-binding proteins (CaBPs) was shown to bind to the inositol 1,4,5-trisphosphate receptor (InsP(3)R) Ca(2+) release channel and gate it in the absence of InsP(3), establishing them as protein ligands (Yang, J., McBride, S., Mak, D.-O. D., Vardi, N., Palczewski, K., Haeseleer, F., and Foskett, J. K. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 7711-7716). However, the neuronally restricted expression of CaBP and its inhibition of InsP(3)R-mediated Ca(2+) signaling when overexpressed (Kasri, N. N., Holmes, A. M., Bultynck, G., Parys, J. B., Bootman, M. D., Rietdorf, K., Missiaen, L., McDonald, F., De Smedt, H., Conway, S. J., Holmes, A. B., Berridge, M. J., and Roderick, H. L. (2004) EMBO J. 23, 312-321; Haynes, L. P., Tepikin, A. V., and Burgoyne, R. D. (2004) J. Biol. Chem. 279, 547-555) have raised questions regarding the functional implications of this regulation. We have discovered the Ca(2+)-binding protein CIB1 (calmyrin) as a ubiquitously expressed ligand of the InsP(3)R. CIB1 binds to all mammalian InsP(3)R isoforms in a Ca(2+)-sensitive manner dependent on its two functional EF-hands and activates InsP(3)R channel gating in the absence of InsP(3). In contrast, overexpression of CIB1 or CaBP1 attenuated InsP(3)R-dependent Ca(2+) signaling, and in vitro pre-exposure to CIB1 reduced the number of channels available for subsequent stimulation by InsP(3). These results establish CIB1 as a ubiquitously expressed activating and inhibiting protein ligand of the InsP(3)R.
White
Carl
C
Departments of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Yang
Jun
J
Departments of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Monteiro
Mervyn J
MJ
University of Maryland Biotechnology Institute and Medical Biotechnology Center, University of Maryland, Baltimore, Maryland 21201.
Foskett
J Kevin
JK
Departments of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104; Departments of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104. Electronic address: foskett@mail.med.upenn.edu.
D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry*; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000502:physiology; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D006367:HeLa Cells; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007700:Kinetics; D008024:Ligands; D016716:PC12 Cells; D020033:Protein Isoforms; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry*; D014981:Xenopus
C109198:CIB1 protein, human; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D002118:Calcium