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Originally published In Press as doi:10.1074/jbc.M202928200 on July 16, 2002

J. Biol. Chem., Vol. 277, Issue 38, 35061-35070, September 20, 2002
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Inhibition of the Inositol Trisphosphate Receptor of Mouse Eggs and A7r5 Cells by KN-93 via a Mechanism Unrelated to Ca2+/Calmodulin-dependent Protein Kinase II Antagonism*

Jeremy T. SmythDagger , Allison L. Abbott§, Bora LeeDagger , Ilse Sienaert||, Nael Nadif Kasri||, Humbert De Smedt||, Tom Ducibella§**, Ludwig Missiaen||, Jan B. Parys||Dagger Dagger , and Rafael A. FissoreDagger §§

From the Dagger  Molecular and Cellular Biology Program and Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts 01003, the § Department of Anatomy and Cellular Biology, Sackler School of Biomedical Sciences, the ** Department of Obstetrics and Gynecology, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111, and || Laboratorium voor Fysiologie, Katholieke Universiteit Leuven, Campus Gasthuisberg O/N, Herestraat 49, B-3000 Leuven, Belgium

KN-93, a Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor, concentration-dependently and reversibly inhibited inositol 1,4,5-trisphosphate receptor (IP3R)-mediated [Ca2+]i signaling in mouse eggs and permeabilized A7r5 smooth muscle cells, two cell types predominantly expressing type-1 IP3R (IP3R-1). KN-92, an inactive analog, was ineffective. The inhibitory action of KN-93 on Ca2+ signaling depended neither on effects on IP3 metabolism nor on the filling grade of Ca2+ stores, suggesting a direct action on the IP3R. Inhibition was independent of CaMKII, since in identical conditions other CaMKII inhibitors (KN-62, peptide 281-309, and autocamtide-related inhibitory peptide) were ineffective and since CaMKII activation was precluded in permeabilized cells. Moreover, KN-93 was most effective in the absence of Ca2+. Analysis of Ca2+ release in A7r5 cells at varying [IP3], of IP3R-1 degradation in eggs, and of [3H]IP3 binding in Sf9 microsomes all indicated that KN-93 did not affect IP3 binding. Comparison of the inhibition of Ca2+ release and of [3H]IP3 binding by KN-93 and calmodulin (CaM), either separately or combined, was compatible with a specific interaction of KN-93 with a CaM-binding site on IP3R-1. This was also consistent with the much smaller effect of KN-93 in permeabilized 16HBE14o- cells that predominantly express type 3 IP3R, which lacks the high affinity CaM-binding site. These findings indicate that KN-93 inhibits IP3R-1 directly and may therefore be a useful tool in the study of IP3R functional regulation.

* This work was supported in part by a Lotta M. Crabtree Fellowship in Agriculture (to J. T. S.), a Lalor Foundation Grant (to A. L. A.), National Institutes of Health Grant HD-24191 (to T. D.), the Program on Interuniversity Poles of Attraction (to J. B. P., H. D. S., and L. M.), Concerted Actions of the K.U. Leuven Grant 99/08 (to L. M., H. D. S., and J. B. P.), and United States Department of Agriculture Grant 99-2371 (to R. A. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Genetics, Dartmouth College, Hanover, NH 03755.

Dagger Dagger To whom correspondence may be addressed: Dept. of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003. Tel.: 413-545-5548; Fax: 413-545-6326; E-mail: rfissore@vasci.umass.edu.

§§ To whom correspondence may be addressed: Laboratorium voor Fysiologie, Katholieke Universiteit Leuven, Campus Gasthuisberg O/N, B-3000 Leuven, Belgium. Tel.: 32-16-345736; Fax: 32-16-345991; E-mail: jan.parys@med.kuleuven.ac.be.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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