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

George D. Prell, Giorgio P. Martinelli, Gay R. Holstein, Jasenka Matulić-Adamić, Kyoichi A. Watanabe, Susan L.F. Chan, Noel G. Morgan, Musa A. Haxhiu, Paul Ernsberger

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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.

Original languageEnglish
Pages (from-to)13677-13682
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number37
DOIs
StatePublished - 14 Sep 2004

Keywords

  • Anti-IAA-RP antibodies
  • Clonidine-displacing substance (CDS)
  • Histamine
  • Hypertension
  • Pancreatic beta cells

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