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...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2004-09, Vol.101 (37), p.13677-13682
Hauptverfasser: Prell, George D., Martinelli, Giorgio P., Holstein, Gay R., Matulić-Adamić, Jasenka, Watanabe, Kyoichi A., Susan L. F. Chan, Morgan, Noel G., Haxhiu, Musa A., Ernsberger, Paul, Black, James W.
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container_issue 37
container_start_page 13677
container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 101
creator Prell, George D.
Martinelli, Giorgio P.
Holstein, Gay R.
Matulić-Adamić, Jasenka
Watanabe, Kyoichi A.
Susan L. F. Chan
Morgan, Noel G.
Haxhiu, Musa A.
Ernsberger, Paul
Black, James W.
description 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 Ca2+-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.
doi_str_mv 10.1073/pnas.0404846101
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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 Ca2+-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. 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F. Chan</creatorcontrib><creatorcontrib>Morgan, Noel G.</creatorcontrib><creatorcontrib>Haxhiu, Musa A.</creatorcontrib><creatorcontrib>Ernsberger, Paul</creatorcontrib><creatorcontrib>Black, James W.</creatorcontrib><title>Imidazoleacetic Acid-Ribotide: An Endogenous Ligand That Stimulates Imidazol(in)e Receptors</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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. 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Chan</au><au>Morgan, Noel G.</au><au>Haxhiu, Musa A.</au><au>Ernsberger, Paul</au><au>Black, James W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Imidazoleacetic Acid-Ribotide: An Endogenous Ligand That Stimulates Imidazol(in)e Receptors</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2004-09-14</date><risdate>2004</risdate><volume>101</volume><issue>37</issue><spage>13677</spage><epage>13682</epage><pages>13677-13682</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><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 Ca2+-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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>15365189</pmid><doi>10.1073/pnas.0404846101</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record>
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subjects Adrenal Medulla - metabolism
Agonists
Animals
Antibodies - immunology
Antibody Specificity
Arachidonic Acid - metabolism
Biological Sciences
Brain Stem - cytology
Calcium - metabolism
Central nervous system
Enzyme-Linked Immunosorbent Assay
Humans
Hypertension - chemically induced
Imidazoles - chemistry
Imidazoles - immunology
Imidazoles - pharmacology
Imidazoline Receptors
Insulin
Insulin - metabolism
Insulin antibodies
Insulin Secretion
Islets of Langerhans - metabolism
Isomerism
Isomers
Ligands
Molecular Structure
Neurons
Neurons - metabolism
PC12 Cells
Rats
Receptors
Receptors, Drug - agonists
Receptors, Drug - metabolism
Ribosemonophosphates - chemistry
Ribosemonophosphates - immunology
Ribosemonophosphates - pharmacology
Vehicles
title Imidazoleacetic Acid-Ribotide: An Endogenous Ligand That Stimulates Imidazol(in)e Receptors
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