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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 37 Pg. 13677-82 (Sep 14 2004) ISSN: 0027-8424 [Print] United States
• PMID: 15365189 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies
• Imidazoles
• Imidazoline Receptors
• Insulin
• Ligands
• Receptors, Drug
• Ribosemonophosphates
• imidazoleacetic acid ribotide
• Arachidonic Acid
• Calcium

Topics

• Adrenal Medulla (metabolism)
• Animals
• Antibodies (immunology)
• Antibody Specificity
• Arachidonic Acid (metabolism)
• Brain Stem (cytology)
• Calcium (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Humans
• Hypertension (chemically induced)
• Imidazoles (chemistry, immunology, pharmacology)
• Imidazoline Receptors
• Insulin (metabolism)
• Insulin Secretion
• Islets of Langerhans (metabolism)
• Isomerism
• Ligands
• Molecular Structure
• Neurons (metabolism)
• PC12 Cells
• Rats
• Receptors, Drug (agonists, metabolism)
• Ribosemonophosphates (chemistry, immunology, pharmacology)