Neural roles for heme oxygenase: Contrasts to nitric oxide synthase

Abstract

The heme oxygenase (HO) and nitric oxide (NO) synthase (NOS) systems display notable similarities as well as differences. HO and NOS are both oxidative enzymes using NADPH as an electron donor. The constitutive forms of the enzyme are differentially activated, with calcium entry stimulating NOS by binding to calmodulin, whereas calcium entry activates protein kinase C to phosphorylate and activate HO2. Although both NO and carbon monoxide (CO) stimulate soluble guanylyl cyclase to form cGMP, NO also S-nitrosylates selected protein targets. Both involve constitutive and inducible biosynthetic enzymes. However, functions of the inducible forms are virtual opposites. Macrophage-inducible NOS generates NO to kill other cells, whereas HO1 generates bilirubin to exert antioxidant cytoprotective effects and also provides cytoprotection by facilitating iron extrusion from cells. The neuronal form of HO, HO2, is also cytoprotective. Normally, neural NO in the brain seems to exert some sort of behavioral inhibition. However, excess release of NO in response to glutamate's Nmethyl-D-aspartate receptor activation leads to stroke damage. On the other hand, massive neuronal firing during a stroke presumably activates HO2, leading to neuroprotective actions of bilirubin. Loss of this neuroprotection after HO inhibition by mutant forms of amyloid precursor protein may mediate neurotoxicity in Familial Alzheimer's Disease. NO and CO both appear to be neurotransmitters in the brain and peripheral autonomic nervous system. They also are physiologic endothelial-derived relaxing factors for blood vessels. In the gastrointestinal pathway, NO and CO appear to function as coneurotransmitters, both stimulating soluble guanylyl cyclase to cause smooth muscle relaxation.

Contributions of astrocytes and CO to pial arteriolar dilation to glutamate in newborn pigs

“…Release of glutamate from presynaptic neurons increases blood flow to match the increased metabolic demands of stimulated neurons (37). Neuronal activation in response to excitatory neurotransmitters may affect brain vessels via neurally derived vasorelaxant factors, including NO (11,39,51) and CO (2). Glutamate and selective NMDA-and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor agonists increase CO production by piglet cerebral microvessels (29,43) and astrocytes (52).…”

“…Of note, others have failed to detect glutamate receptor-mediated responses at all in isolated cerebral arteries (50). The smaller or absent dilatory response to glutamate in vitro compared with the in vivo response, coupled with similar dilator responses to isoproterenol in vitro and in vivo (2,14,53), suggests that cells underrepresented in the isolated arteriole contribute to the dilation in response to glutamate in vivo. The present data suggest that astrocytes, although immunodetectable on our isolated pial arterioles, could be the underrepresented cell type when the arteriole is removed from the intact brain.…”

Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases

“…Traditionally, bilirubin was viewed as a neurotoxin and of clinical significance only in relation to neonatal jaundice. Now, bilirubin is seen as a potent antioxidant that is able to protect neurons against free radical damage [10,[157][158][159][160][161].…”

Crystal Structures of the NO- and CO-bound Heme Oxygenase from Neisseriae meningitidis

“…In contrast, HO-2 is a constitutively expressed 36-kDa protein existing primarily in the testes and in some regions of the brain (4). This finding has led to the proposal that one role of HO-2 is the production of carbon monoxide, which is controversially thought to act as a neuronal messenger by stimulating guanylate cyclase activity (5)(6)(7)(8)(9)(10).…”