ABSTRACT: Two primary questions are addressed. First, do I1-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? I1-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. I1-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 I1-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 I1-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 I1-imidazoline receptor are similar to those of the interleukin family, implying that I1-receptors may belong to the family of neurocytokine receptors.