Imidazoleacetic acid-ribotide: An endogenous ligand that stimulates imidazol(in)e receptors

Abstract

We identified the previously unknown structures of ribosylated imidazoleacetic acids in rat, bovine, and human tissues to be imidazole-4-acetic acid-ribotide (IAA-RP) and its metabolite, imidazole-4-acetic acid-riboside. We also found that IAA-RP has physicochemical properties similar to those of an unidentified substance(s) extracted from mammalian tissues that interacts with imidazol(in)e receptors (I-Rs). [''Imidazoline,'' by consensus (International Union of Pharmacology), includes imidazole, imidazoline, and related compounds. We demonstrate that the imidazole IAA-RP acts at I-Rs, and because few (if any) imidazolines exist in vivo, we have adopted the term ''imidazol(in)e-Rs.''] The latter regulate multiple functions in the CNS and periphery. We now show that IAA-RP (i) is present in brain and tissue extracts that exhibit I-R activity; (ii) is present in neurons of brainstem areas, including the rostroventrolateral medulla, a region where drugs active at I-Rs are known to modulate blood pressure; (iii) is present within synaptosome-enriched fractions of brain where its release is Ca 2؉ -dependent, consistent with transmitter function; (iv) produces I-R-linked effects in vitro (e.g., arachidonic acid and insulin release) that are blocked by relevant antagonists; and (v) produces hypertension when microinjected into the rostroventrolateral medulla. Our data also suggest that IAA-RP may interact with a novel imidazol(in)e-like receptor at this site. We propose that IAA-RP is a neuroregulator acting via I-Rs.clonidine-displacing substance (CDS) ͉ hypertension ͉ pancreatic beta cells ͉ anti-IAA-RP antibodies ͉ histamine

Distribution and cellular localization of imidazoleacetic acid-ribotide, an endogenous ligand at imidazol(in)e and adrenergic receptors, in rat brain

“…IAA-RP derives from the ribosylation of IAA (Crowley, 1964) via a rare (possibly unique) mechanism in mammals in which ATP is used as an energy source rather than as a substrate. IAA-RP exhibits depolarization-induced, calcium-dependent release from the synaptosome-and vesicleenriched P 2 fraction of rat brain (Prell et al, 2004), a property consistent with synaptic function. It exhibits a rapid turnover rate and is dephosphorylated by multiple phosphatases and ecto-5′-nucleotidases to produce its terminal metabolite imidazoleacetic acid-riboside (IAA-R) (Karjala, 1955;Tabor and Hayaishi, 1955;Prell et al, 2004).…”

“…IAA-RP exhibits depolarization-induced, calcium-dependent release from the synaptosome-and vesicleenriched P 2 fraction of rat brain (Prell et al, 2004), a property consistent with synaptic function. It exhibits a rapid turnover rate and is dephosphorylated by multiple phosphatases and ecto-5′-nucleotidases to produce its terminal metabolite imidazoleacetic acid-riboside (IAA-R) (Karjala, 1955;Tabor and Hayaishi, 1955;Prell et al, 2004). In brain and other tissues, IAA-RP displays low and high affinity binding to α 2 -adrenergic receptors (α 2 ARs) and imidazol(in)e binding sites (IRs), respectively (for an explanation of the inidazol(in)e nomenclature, see (Prell et al, 2004)).…”

“…We recently reported that the I-4 isomer of imidazoleacetic acid-ribotide (IAA-RP) is a putative neurotransmitter or neuromodulator in mammalian brain (Prell et al, 2004). In brain, IAA-RP is synthesized primarily through a pathway that is initiated by the transamination of histidine and that leads to the production of imidazoleacetic acid (IAA).…”

“…It exhibits a rapid turnover rate and is dephosphorylated by multiple phosphatases and ecto-5′-nucleotidases to produce its terminal metabolite imidazoleacetic acid-riboside (IAA-R) (Karjala, 1955;Tabor and Hayaishi, 1955;Prell et al, 2004). In brain and other tissues, IAA-RP displays low and high affinity binding to α 2 -adrenergic receptors (α 2 ARs) and imidazol(in)e binding sites (IRs), respectively (for an explanation of the inidazol(in)e nomenclature, see (Prell et al, 2004)). While the roles of α 2 ARs in nervous system functions such as blood pressure control have been examined for decades (Reis, 1996;Head, 1999;Chan et al, 2005), studies of IR-related activity are relatively recent (Head and Mayorov, 2006).…”

“…I 3 Rs were originally identified in pancreatic beta cells and have been shown to mediate insulin secretion (Morgan, 1999). In addition an I 3 -like binding site that appears to modulate blood pressure has been proposed (Prell et al, 2004).…”