The agmatine-degrading enzyme agmatinase: a key to agmatine signaling in rat and human brain?

Abstract

Agmatinase, an ureohydrolase belonging to the arginase family, is widely expressed in mammalian tissues including the brain. Here, it may serve two different functions, the inactivation of the arginine derivative agmatine, a putative neurotransmitter, and the formation of the diamine putrescine. In order to identify the cellular sources of agmatinase expression in the brain, we generated a polyclonal monospecific antibody against recombinant rat agmatinase. With immunocytochemistry, selected areas of rat and human brain were screened. Clearly, in both species agmatinase-like immunoreactivity was predominantly detected in distinct populations of neurons, especially cortical interneurons. Also, principal neurons in limbic regions like the habenula and in the cerebellum robustly expressed agmatinase protein. When comparing the overall agmatinase expression with immunocytochemical data available for agmatine and polyamine biosynthetic enzymes, the observed pattern may argue in favor of an agmatine inactivating function rather than fueling the alternative pathway of polyamine synthesis. The putative neurotransmitter agmatine is seemingly involved with mental disorders. Therefore, agmatinase may be similarly important for pathogenesis. The normal expression profile of the protein as described here may therefore be altered under pathological conditions.

Synaptic localisation of agmatinase in rat cerebral cortex revealed by virtual pre-embedding

“…As agmatine persists in the brain with a half-life of approximately 12 h (Roberts et al 2005), neuromodulatory effects could be effectively terminated by the action of Agm. We therefore postulated that the fine structural localisation of the enzyme may not only further support a synaptic role for agmatine (Bernstein et al 2011), but also may help to identify brain circuits involved with agmatine neurotransmitter/neuromodulatory action. The data presented here demonstrating the expression of Agm in preand postsynaptic compartments of the rat cerebral cortex indeed support the proposed role for Agm as a local inactivator of the neurotransmitter/neuromodulator agmatine.…”

“…The generation, purification and characterisation of the monospecific antibody against agmatinase have been described previously (Bernstein et al 2011). …”

“…Agmatinase (Agm), an arginase family enzyme converting agmatine to putrescine, is widely expressed in the mammalian brain (Bernstein et al 2011). It is not known, however, whether putrescine derived from agmatine degradation is used to also fuel an ornithine decarboxylaseindependent polyamine synthesis (Gilad et al 1996).…”

“…The ultrastructural localisation of Agm may therefore provide further evidence for a synaptic role for agmatine and help to identify synapse populations as potential targets for pharmacological intervention. So far, the cellular expression patterns of Agm in rat and healthy human brain (Bernstein et al 2011), as well as in human brains of individuals suffering from mood disorders (Bernstein et al 2012), have been described. In the rat, besides neuronal cell bodies, a diffuse Agm labelling was observed in several neuropil areas, including the cerebral cortex.…”

Redox dynamics of manganese as a mitochondrial life-death switch

“…Examples of these enzymes include galactosyltransferase [16], agmatinase [17], arginase [18], glutamine synthetase [19], pyruvate carboxylase [20, 21] and SOD2 [22, 23], as well as several kinases, hydrolases, transferases, and decarboxylases [24]. Some of these enzymes, such as manganese-containing SOD2, require a specific oxidation state in the binding pocket to perform its enzymatic reaction.…”