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Science 1 November 1996:
Vol. 274. no. 5288, pp. 774 - 777
DOI: 10.1126/science.274.5288.774
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Reports

PIN: An Associated Protein Inhibitor of Neuronal Nitric Oxide Synthase

Samie R. Jaffrey and Solomon H. Snyder *

The neurotransmitter functions of nitric oxide are dependent on dynamic regulation of its biosynthetic enzyme, neuronal nitric oxide synthase (nNOS). By means of a yeast two-hybrid screen, a 10-kilodalton protein was identified that physically interacts with and inhibits the activity of nNOS. This inhibitor, designated PIN, appears to be one of the most conserved proteins in nature, showing 92 percent amino acid identity with the nematode and rat homologs. Binding of PIN destabilizes the nNOS dimer, a conformation necessary for activity. These results suggest that PIN may regulate numerous biological processes through its effects on nitric oxide synthase activity.

Departments of Neuroscience, Pharmacology and Molecular Sciences, and Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
*   To whom correspondence should be addressed.

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PNAS 96, 12150-12155
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Both the Neuronal and Inducible Isoforms Contribute to Upregulation of Retinal Nitric Oxide Synthase Activity by Brain-Derived Neurotrophic Factor.
N. Klocker, P. Kermer, M. Gleichmann, M. Weller, and M. Bahr (1999)
J. Neurosci. 19, 8517-8527
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Ischemic Cell Death in Brain Neurons.
P. Lipton (1999)
Physiol Rev 79, 1431-1568
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Tetrahydrobiopterin Inhibits Monomerization and Is Consumed during Catalysis in Neuronal NO Synthase.
A. Reif, L. G. Frohlich, P. Kotsonis, A. Frey, H. M. Bommel, D. A. Wink, W. Pfleiderer, and H. H. H. W. Schmidt (1999)
J. Biol. Chem. 274, 24921-24929
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Molecular control of nitric oxide synthases in the cardiovascular system.
A. Papapetropoulos, R. D. Rudic, and W. C Sessa (1999)
Cardiovasc Res 43, 509-520
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Signal transduction of eNOS activation.
I. Fleming and R. Busse (1999)
Cardiovasc Res 43, 532-541
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Drosophila roadblock and Chlamydomonas Lc7: A Conserved Family of Dynein-Associated Proteins Involved in Axonal Transport, Flagellar Motility, and Mitosis.
A. B. Bowman, R. S. Patel-King, S. E. Benashski, J. M. McCaffery, L. S.B. Goldstein, and S. M. King (1999)
J. Cell Biol. 146, 165-180
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Expression and Regulation of Protein Inhibitor of Neuronal Nitric Oxide Synthase in Ventilatory Muscles.
Y. Guo, M. T. Greenwood, B. J. Petrof, and S. N. A. Hussain (1999)
Am. J. Respir. Cell Mol. Biol. 20, 319-326
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Kalirin Inhibition of Inducible Nitric-oxide Synthase.
E. A. Ratovitski, M. R. Alam, R. A. Quick, A. McMillan, C. Bao, C. Kozlovsky, T. A. Hand, R. C. Johnson, R. E. Mains, B. A. Eipper, et al. (1999)
J. Biol. Chem. 274, 993-999
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Protein Inhibitor of Neuronal Nitric-oxide Synthase, PIN, Binds to a 17-Amino Acid Residue Fragment of the Enzyme.
J.-S. Fan, Q. Zhang, M. Li, H. Tochio, T. Yamazaki, M. Shimizu, and M. Zhang (1998)
J. Biol. Chem. 273, 33472-33481
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Regulation of nitric oxide production in response to skeletal muscle activation.
Y. Fujii, Y. Guo, and S. N. A. Hussain (1998)
J Appl Physiol 85, 2330-2336
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HMN-1180, a Small Molecule Inhibitor of Neuronal Nitric Oxide Synthase.
M. Nishio, Y. Watanabe, and H. Hidaka (1998)
J. Pharmacol. Exp. Ther. 287, 1063-1067
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The "8-kD" Cytoplasmic Dynein Light Chain Is Required for Nuclear Migration and for Dynein Heavy Chain Localization in Aspergillus nidulans.
S. M. Beckwith, C. H. Roghi, B. Liu, and N. Ronald Morris (1998)
J. Cell Biol. 143, 1239-1247
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1,25-Dihydroxyvitamin D3 Induces Nitric Oxide Synthase and Suppresses Growth of Mycobacterium tuberculosis in a Human Macrophage-Like Cell Line.
K. A. Rockett, R. Brookes, I. Udalova, V. Vidal, A. V. S. Hill, and D. Kwiatkowski (1998)
Infect. Immun. 66, 5314-5321
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Diaphragm Sarcolemmal Injury Is Induced by Sepsis and Alleviated by Nitric Oxide Synthase Inhibition.
M.-C. LIN, S. EBIHARA, Q. E. DWAIRI, S. N. A. HUSSAIN, L. YANG, S. B. GOTTFRIED, A. COMTOIS, and B. J. PETROF (1998)
Am. J. Respir. Crit. Care Med. 158, 1656-1663
   Abstract »    Full Text »    PDF »


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