HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 106/1/12    most recent 90702.2008v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sharma, S. D. Articles by Kumar, G. K. Search for Related Content PubMed PubMed Citation Articles by Sharma, S. D. Articles by Kumar, G. K.

Intermittent hypoxia activates peptidylglycine -amidating monooxygenase in rat brain stem via reactive oxygen species-mediated proteolytic processing

Center for Systems Biology, Department of Medicine, Section of Emergency Medicine, University of Chicago, Chicago, Illinois

Submitted 29 May 2008 ; accepted in final form 22 September 2008

Intermittent hypoxia (IH) associated with sleep apneas leads to cardiorespiratory abnormalities that may involve altered neuropeptide signaling. The effects of IH on neuropeptide synthesis have not been investigated. Peptidylglycine -amidating monooxygenase (PAM; EC 1.14.17.3 [EC] ) catalyzes the -amidation of neuropeptides, which confers biological activity to a large number of neuropeptides. PAM consists of O₂-sensitive peptidylglycine -hydroxylating monooxygenase (PHM) and peptidyl--hydroxyglycine -amidating lyase (PAL) activities. Here, we examined whether IH alters neuropeptide synthesis by affecting PAM activity and, if so, by what mechanisms. Experiments were performed on the brain stem of adult male rats exposed to IH (5% O₂ for 15 s followed by 21% O₂ for 5 min; 8 h/day for up to 10 days) or continuous hypoxia (0.4 atm for 10 days). Analysis of brain stem extracts showed that IH, but not continuous hypoxia, increased PHM, but not PAL, activity of PAM and that the increase of PHM activity was associated with a concomitant elevation in the levels of -amidated forms of substance P and neuropeptide Y. IH increased the relative abundance of 42- and 35-kDa forms of PHM (1.6- and 2.7-fold, respectively), suggesting enhanced proteolytic processing of PHM, which appears to be mediated by an IH-induced increase of endoprotease activity. Kinetic analysis showed that IH increases V_max but has no effect on K_m. IH increased generation of reactive oxygen species in the brain stem, and systemic administration of antioxidant prevented IH-evoked increases of PHM activity, proteolytic processing of PHM, endoprotease activity, and elevations in substance P and neuropeptide Y amide levels. Taken together, these results demonstrate that IH activates PHM in rat brain stem via reactive oxygen species-dependent posttranslational proteolytic processing and further suggest that PAM activation may contribute to IH-mediated peptidergic neurotransmission in rat brain stem.

peptidylglycine -hydroxylating monooxygenase; posttranslational proteolytic processing; oxidative stress; -amidated peptides

This article has been cited by other articles:

				S. Veasey Peptide amidation: a push me, don't pull you for the morbidities in sleep apnea J Appl Physiol, January 1, 2009; 106(1): 3 - 4. [Full Text] [PDF]