Kalirin Inhibition of Inducible Nitric-oxide Synthase*
- Edward A. Ratovitski‡,
- M. Rashidul Alam§,
- Richard A. Quick‡,
- Audrey McMillan‡,
- Clare Bao‡,
- Chaim Kozlovsky‡,
- Tracey A. Hand§,
- Richard C. Johnson§,
- Richard E. Mains§,
- Betty A. Eipper§ and
- Charles J. Lowenstein‡¶*
- From the Division of Cardiology, ‡Department of Medicine, and §Department of Neurosciences, School of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Abstract
Nitric oxide (NO) acts as a neurotransmitter. However, excess NO produced from neuronal NO synthase (nNOS) or inducible NOS (iNOS) during inflammation of the central nervous system can be neurotoxic, disrupting neurotransmitter and hormone production and killing neurons. A screen of a hippocampal cDNA library showed that a unique region of the iNOS protein interacts with Kalirin, previously identified as an interactor with a secretory granule peptide biosynthetic enzyme. Kalirin associates with iNOS in vitroand in vivo and inhibits iNOS activity by preventing the formation of iNOS homodimers. Expression of exogenous Kalirin in pituitary cells dramatically reduces iNOS inhibition of ACTH secretion. Thus Kalirin may play a neuroprotective role during inflammation of the central nervous system by inhibiting iNOS activity.
Footnotes
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↵* This work was supported in part by American Heart Association-Maryland Affiliate (to E. A. R.), National Institutes of Health Grants R01 DK32948 (to R. E. M.), DA00266 (to B. A. E.), P50 HL52315 (to C. J. L.), and R01 HL5361 (to C. J. L.), the Ciccarone Center for the Prevention of Heart Disease (to C. J. L.), the Cora and John H. Davis Foundation (to E. A. R. and C. J. L.), and the Bernard Bernard Foundation (to C. J. L.).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.
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↵¶ To whom correspondence and reprint requests should be addressed: Division of Cardiology, Dept. of Medicine, Johns Hopkins University School of Medicine, 950 Ross Bldg., 720 Rutland Ave., Baltimore, MD 21205. Tel.: 410-955-1530; Fax: 410-614-5129; E-mail:clowenst{at}welchlink.welch.jhu.edu.
- Abbreviations:
- NO
-
nitric oxide
- NOS
-
nitric-oxide synthase
- nNOS
-
NO synthase
- iNOS
-
inducible NOS
- PAM
-
peptidylglycine α-amidating monooxygenase
- ACTH
-
adrenocorticotropic hormone
- CRH
-
corticotropin-releasing hormone
- LPS
-
lipopolysaccharide
- IFN-γ
-
interferon-gamma
- NAME
-
nitro-arginine methyl ester
- ONGP
-
o-nitrophenyl-β-d-galactopyranoside
- PAGE
-
polyacrylamide gel electrophoresis
- PMSF
-
phenylmethylsulfonyl fluoride
- GST
-
glutathione S-transferase
- NMDA
-
N-methyl-d-aspartate.
-
- Received June 18, 1998.
- Revision received October 6, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
