Imidazoline Receptors and Their Endogenous Ligands

Abstract

Imidazoline (I) receptors constitute a family of nonadrenergic high-affinity binding sites for clonidine, idazoxan, and allied drugs. One major subclass, the I1 receptors, whose subcellular distribution and signal transduction mechanisms are uncertain, partly mediates the central hypotensive actions of clonidine-like drugs. The I2 receptors, another subclass, are mitochondrial, not G protein coupled, and have diversified functions. Several endogenous ligands for I receptors, collectively termed clonidine-displacing substances (CDSs), have been detected in tissues and serum, but the structure of only one, agmatine (decarboxylated arginine), is known. Agmatine, widely distributed and bioactive, binds, like clonidine, to alpha 2-adrenergic and I receptors of all subclasses. The presence of agmatine and its biosynthetic enzyme in synaptosomes and specific neuronal pathways as well as serum suggests that it may be a novel neurotransmitter/hormone. Another CDS that binds to I receptors and to antibodies to imidazoline drugs has been detected, but its structure is unknown.

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

“…I 2 Rs are binding sites on monoamine oxidases and possibly other proteins (33). The initial suggestion that IAA-ribotide may be an I-R ligand came from our observation that it had physicochemical properties m similar to those of an unidentified endogenous substance(s) reported to act at I 1 Rs and I 3 Rs (25,26,(34)(35)(36)(37)(38). This substance(s), extracted from mammalian tissue, was proposed as a putative I-R ligand and called clonidine-displacing substance (CDS), on the basis of its ability to displace the imidazoline drug clonidine (or its congeners) from I-R-specific sites.…”

“…We then pursued the hypothesis that endogenous IAA-ribotide may interact with ''imidazoline-Rs'' (I-Rs), formerly the ''imidazole-Rs'' postulated by Karppanen and coworkers (4,22,23). [The concept of I-Rs arose from the fact that some effects of imidazoline-like ␣-adrenergic receptor (␣-R) ligands (e.g., clonidine) are blocked by imidazoles and imidazolines and are incompletely mimicked or blocked by drugs lacking similar structures, such as the catecholamines (4,(24)(25)(26).] Three I-R subclasses are known.…”

“…Three I-R subclasses are known. I 1 Rs and I 3 Rs regulate processes, such as sympathetic outflow and blood pressure by the rostroventrolateral medulla (RVLM), and the release of arachidonic acid (AA) from PC12 cells and of insulin from pancreatic islets (25)(26)(27)(28)(29). I 1 Rs have been characAbbreviations: IAA, imidazole-4-acetic acid; IAA-RP, IAA-ribotide; IAA-R, IAA-riboside; I-5-AA-RP, imidazole-5-acetic acid-ribotide; RVLM, rostroventrolateral medulla; CDS, clonidine-displacing substance; I-R, imidazol(in)e receptor; AA, arachidonic acid; ␣2R, ␣2-receptor; alk-Pase, alkaline phosphatase; MAP, mean arterial pressure; HR, heart rate; SH, spontaneously hypertensive.…”

“…This substance(s), extracted from mammalian tissue, was proposed as a putative I-R ligand and called clonidine-displacing substance (CDS), on the basis of its ability to displace the imidazoline drug clonidine (or its congeners) from I-R-specific sites. Some CDSs may contain a group of substances rather than a single entity, but, thus far, only one, agmatine, has been identified in one preparation (25,26). However, agmatine binds mainly to I 2 sites (where its role is unknown), has actions unrelated to I-Rs (39), and lacks significant activity at I 1 Rs and I 3 Rs (25,26).…”

“…Some CDSs may contain a group of substances rather than a single entity, but, thus far, only one, agmatine, has been identified in one preparation (25,26). However, agmatine binds mainly to I 2 sites (where its role is unknown), has actions unrelated to I-Rs (39), and lacks significant activity at I 1 Rs and I 3 Rs (25,26). Here, we demonstrate that I-4-AA-RP is the endogenous ribotide isomer (Fig.…”