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Review
, 133 (6), 755-80

Biological Significance of Agmatine, an Endogenous Ligand at Imidazoline Binding Sites

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Review

Biological Significance of Agmatine, an Endogenous Ligand at Imidazoline Binding Sites

W Raasch et al. Br J Pharmacol.

Figures

Figure 1
Figure 1
Imidazoline binding sites and their suggested functions. Agmatine binds with a moderate affinity (Ki values are taken from Li et al.) to α2-adrenoceptors as well as to I1 and I2 binding sites. Some authors (Chan, 1998; Molderings et al., 1998a; 1999a) attributed functions to binding sites (nonl1/non I2-binding sites) the affinity profile of which is consistent with neither the I1- nor the I2-binding sites.
Figure 2
Figure 2
Current working hypothesis depicting mechanisms regulating insulin secretion from pancreatic β-cells and proposed sites for interference by agmatine. ATP generated by glucose metabolism shuts down K+-channels, resulting in depolarization and subsequent influx of Ca2+ through voltage-activated Ca2+-channels. This influx of Ca2+ increases cytosolic Ca2+ concentration, which is accompanied by mobilization of Ca2+ from the endoplasmic reticulum (ER), an event triggering secretory granule translocation and exocytotic release of insulin. The respective binding of imidazolines (such as efaroxan) and sulphonylurea derivatives (such as glibenclamide) to I3-binding sites and the sulphonylurea receptor, also closes the K+-channels. Agmatine does not bind to I3-binding sites. However, agmatine may enhance insulin secretion via its metabolites, after it is taken up by specific transporters. Putrescine, spermidine are necessary for proinsulin biosynthesis, whereas spermine may exert a stimulatory or permissive role in RNA transcription and long-term insulin release. Polyamines are also probably involved in regulation of cytosolic Ca2+-concentration by blocking Ca2+-influx and its release from intracellular stores. Abbreviations: …▪quot; : stimulation; …•: inhibition.
Figure 3
Figure 3
Schematic representation of an agmatinergic synapse: L-arginine enters the nerve ending via a transporter and is decarboxylated by the mitochondrial arginine decarboxylase (ADC) to agmatine (AGM), which is stored in vesicles and metabolized to putrescine (PUT) by agmatinase (AGMase). Agmatine inhibits NO synthase (NOS) as well as monoamine oxidase (MAO) since it was demonstrated that I2-binding site (I2-BS) is a regulative binding site of MAO. After agmatine is released from the neuron it is subject for a specific uptake or it interacts with various pre- and postsynaptic receptors including the I1-binding site (I1-BS), α2 adrenoceptor (α2-R), NMDA, nicotinic cholineric (NIC), 5−HT3 (via the sigma-2 binding site) receptor. Furthermore, agmatine enters postsynaptic neurons via nicotinic and possibly NMDA ion channels. Whether such released agmatine represents a source for serum agmatine has not yet been determined. Peripheral effects of agmatine on blood pressure and cell growth are also a matter of debate. Released agmatine binds to presynaptic imidazoline binding sites and α2 adrenoceptors and in this way is involved in the regulation of catecholamines. Agmatine penetrates glial cells where it also modulates the expression and activity of iNOS.
Figure 4
Figure 4
Metabolism of L-arginine in the mammalian organism.
Figure 5
Figure 5
Influence of agmatine on cell growth: Control of cell growth can be attributed to two different pathways, namely a membrane receptor controlled pathway, and a pathway dependent on cellular polyamine content. Putrescine content is regulated by an active tranport mechanism as well as by arginine metabolism. Agmatine acts by stimulating an antizyme that inhibits both processes, so that a reduction in putrescine content occurs which contributes to an antiproliferative activity for agmatine. Agmatine also stimulates the spermidine/spermine acetyltransferase (SSAT), the key rate-limiting enzyme for polyamine intraconversion, and simultaneously inhibits S-adenosylmethionine decarboxylase (SAMDC), an enzyme which also has a modulating effect on intracellular polyamine content. Growth factors also stimulate membrane-located receptors. Following stimulation of protein kinase C (PKC) and MAP kinase (MAPK), expression of c-FOS and c-MYC occurs which eventually leads to DNA replication, cell proliferation and cell growth. Whether agmatine exerts an influence on this signal cascade has not yet been established.

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