Imidazoleacetic acid-ribotide: an endogenous ligand that stimulates imidazol(in)e receptors.
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.
Prell
George D
GD
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA. george.prell@mssm.edu
Martinelli
Giorgio P
GP
Holstein
Gay R
GR
Matulić-Adamić
Jasenka
J
Watanabe
Kyoichi A
KA
Chan
Susan L F
SL
Morgan
Noel G
NG
Haxhiu
Musa A
MA
Ernsberger
Paul
P
D000313:Adrenal Medulla / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology; D000918:Antibody Specificity; D016718:Arachidonic Acid / Q000378:metabolism; D001933:Brain Stem / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007093:Imidazoles / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D054755:Imidazoline Receptors; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D007536:Isomerism; D008024:Ligands; D015394:Molecular Structure; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D011955:Receptors, Drug / Q000819:agonists* / Q000378:metabolism; D012267:Ribosemonophosphates / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*
D000906:Antibodies; D007093:Imidazoles; D054755:Imidazoline Receptors; D007328:Insulin; D008024:Ligands; D011955:Receptors, Drug; D012267:Ribosemonophosphates; C094728:imidazoleacetic acid ribotide; D016718:Arachidonic Acid; D002118:Calcium