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Heme oxygenase-2 is activated by calcium-calmodulin
Darren Boehning1, Leela Sedaghat, Thomas W Sedlak
1Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
The Journal of Biological Chemistry
|June 4, 2004
Summary
Calcium-calmodulin rapidly activates heme oxygenase-2 (HO2), an enzyme crucial for neurotransmission. This discovery reveals a molecular mechanism for how neuronal activity modulates CO production, impacting brain function.
Area of Science:
- Neuroscience
- Biochemistry
- Enzymology
Background:
- Heme oxygenase enzymes (HO1 and HO2) metabolize heme, producing carbon monoxide (CO).
- Carbon monoxide derived from HO2 is implicated as a neurotransmitter/neuromodulator in neurons.
- A molecular mechanism for HO2 activation during neuronal activity remains elusive.
Purpose of the Study:
- To identify molecular regulators of heme oxygenase-2 (HO2) activity.
- To elucidate the mechanism of rapid HO2 activation in response to neuronal signaling.
Main Methods:
- Yeast two-hybrid screening to identify HO2 interacting proteins.
- In vitro binding assays and enzyme activity measurements.
- Studies in primary cortical neuron cultures to assess endogenous HO2 activity.
Main Results:
- Calmodulin was identified as a binding partner for HO2.
- Calmodulin binds HO2 in a calcium-dependent manner, increasing its catalytic activity threefold.
- Mutations in the calmodulin-binding motif abolish calcium-dependent activation.
- Calcium-mobilizing agents stimulate endogenous HO2 activity in neurons.
Conclusions:
- Calcium-calmodulin acts as a direct regulator of HO2 activity.
- This interaction provides a mechanism for rapid, calcium-dependent HO2 activation during neuronal activity.
- Findings elucidate a novel signaling pathway influencing CO levels in the brain.