The I 1 ‐Imidazoline Receptor and Its Cellular Signaling Pathways a

Two primary questions are addressed. First, do I 1 ‐imidazoline binding sites fulfill all the essential criteria for identification as a true receptor? Second, what are the cellular signaling pathways coupled to this novel receptor? I 1 ‐imidazoline binding sites show specificity in binding assays, linkage to physiologic functions, appropriate anatomic, and cellular and subcellular localization. Most important, binding affinities correlate with functional drug responses. I 1 ‐imidazoline binding sites meet several additional criteria identified with functional receptors: they show physiologic regulation and endogenous ligands and, most crucially, are coupled to cellular signaling events. A series of studies have identified cellular events triggered by I 1 ‐imidazoline receptor occupancy. This receptor is not coupled to conventional pathways downstream of heterotrimeric G‐proteins, such as activation or inhibition of adenylyl or guanylyl cyclases, stimulation of inositol phospholipid hydrolysis, or induction of rapid calcium fluxes. The I 1 ‐imidazoline receptor is coupled to choline phospholipid hydrolysis, leading to the generation of diacylglyceride, arachidonic acid, and eicosanoids. Additional cellular responses include inhibition of Na + /H + exchange and induction of genes for catecholamine synthetic enzymes. The signaling pathways linked to the I 1 ‐imidazoline receptor are similar to those of the interleukin family, implying that I 1 ‐receptors may belong to the family of neurocytokine receptors.