Novel targets and techniques in imidazoline receptor research.

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 I1-imidazoline binding site (I1-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 I1-receptor. The signal transduction mechanisms of I1-receptors are similarly unclear, but much progress has been made. Evidence clearly indicates that ligands with high affinity for I1-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 I1-receptor. This suggests that there is no I1-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 I1-imidazoline "receptor" family and may represent the low affinity I1-receptor. I1-Receptor ligands can be shown to bind to, or block, the following members of the ligand-gated ion channel super family, the 5HT3, 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 I1-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 I1-receptor ligands and that searches for receptors based on this motif may reveal novel imidazoline "receptors."