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Novel Targets and Techniques in Imidazoline Receptor Research a
Author(s) -
MUSGRAVE IAN F.,
HUGHES RICHARD A.
Publication year - 1999
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1999.tb09375.x
Subject(s) - imidazoline receptor , receptor , signal transduction , phospholipase c , ligand gated ion channel , chemistry , microbiology and biotechnology , ion channel , biophysics , biochemistry , biology , endocrinology
Imidazoline binding sites are now generally accepted as being receptors. Despite this acceptance, the molecular structure and signal transduction mechanisms of these receptors are still poorly understood. The I 1 ‐imidazoline binding site (I 1 ‐receptor) is localized to the plasma membrane, but it is not clear if this represents a conventional receptor. It is also not clear if there are multiple forms of the I 1 ‐receptor. The signal transduction mechanisms of I 1 ‐receptors are similarly unclear, but much progress has been made. Evidence clearly indicates that ligands with high affinity for I 1 ‐receptors stimulate a novel signal transduction pathway, phosphatidylcholine‐selective phospholipase C, in the rat adrenal medullary tumor cell line PC‐12. However, this may not be the case in all cell types as microphysiometry, a novel technique for determining cellular activation, could not detect receptor activation in cultured bovine adrenal medullary cells exposed to a number of imidazolines considered to be agonists at the I 1 ‐receptor. This suggests that there is no I 1 ‐receptor mediated stimulation of phosphatidylcholine‐specific phospholipase C in these cells. By contrast, nicotine‐stimulated increases in ion entry were blocked by clonidine. Ion channels have been suggested as another possible I 1 ‐imidazoline “receptor” family and may represent the low affinity I 1 ‐receptor. I 1 ‐Receptor ligands can be shown to bind to, or block, the following members of the ligand‐gated ion channel super family, the 5HT 3 , K + ATP , NMDA, and nicotinic acetylcholine receptors. The site of action appears to be the phencyclidine binding site in these channels, but other possibilities cannot be excluded. Molecular modeling suggests that I 1 ‐receptor selective ligands share a common three‐dimensional structure with phencyclidine, providing a basis for these actions. This suggests that a phencyclidine‐binding site motif may represent a novel site of action for I 1 ‐receptor ligands and that searches for receptors based on this motif may reveal novel imidazoline “receptors.”