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Mechanism of activation of peptidylglycine alpha‐amidating monooxygenase by intermittent hypoxia
Author(s) -
Sharma Suresh D,
Khan Shakil A,
Prabhakar Nanduri R,
Kumar Ganesh K
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a789
Subject(s) - chemistry , aconitase , reactive oxygen species , superoxide , biochemistry , superoxide dismutase , mitochondrion , oxidative stress , microbiology and biotechnology , enzyme , biology
Peptidylglycine α‐amidating monooxygenase (PAM) catalyzes the oxidative cleavage and amidation of carboxy terminal glycine of inactive peptide precursor resulting in the formation of bioactive neuropeptides. Previously, we showed that intermittent hypoxia (IH) increases PAM activity in the rat brainstem. In this study, we examined whether reactive oxygen species (ROS) contributes to IH‐mediated increase in PAM activity. Experiments were performed with rats exposed to 10d of IH in the absence and presence of superoxide dismutase (SOD) mimetic, a scavenger of superoxide anion. IH increased PAM activity in the brainstem by ~2.7 fold and decreased aconitase activity, which is an index of increased ROS generation. Furthermore, IH facilitates the formation of truncated, more active form of PAM. IH also showed a similar increase in PAM activity and a concomitant elevation in protease activity in PC12 cell cultures. SOD mimetic either attenuated or abolished IH‐induced increases in PAM and protease activities, inhibition of aconitase activity and proteolytic processing of PAM in rat brainstem and PC12 cells. Treatment of control PC12 cells with rotenone (5 μM), an inhibitor of mitochondrial complex I, increased PAM activity similar to the level seen in IH cells, markedly inhibited aconitase activity and SOD mimetic prevented these effects. These findings suggest that IH‐induced increase in PAM activity involves activation of ROS‐mediated signaling pathway and that ROS, originating from mitochondria, may in part contribute to proteolytic processing and activation of PAM (supported by NIH HL‐25830).