Functional selectivity of NK1 receptor signaling: peptide agonists can preferentially produce receptor activation or...

A cascade of events follows binding of an agonist ligand to the tachykinin NK(1) receptor. These events include activation of multiple signal transduction pathways as well as cellular modulation of receptor function by the process of desensitization. This study examines the differences in the abilities of naturally occurring peptide agonist ligands of the tachykinin NK(1) receptor to preferentially direct signaling through the receptor to produce signal activation versus receptor desensitization. The differential effects of tachykinin peptides with respect to ligand competition binding, receptor-G protein coupling, intracellular Ca(2+) elevations, and receptor desensitization have been measured. In relation to its potency in competition binding studies, substance P produces desensitization at lower concentrations, whereas higher concentrations are required to elicit a Ca(2+) response. In contrast to this, a related peptide, ranatachykinin C, is more effective at activating a Ca(2+) response relative to its ability to produce desensitization. This difference in functional selectivity is conserved for an amphibian and two mammalian ortholog tachykinin receptors. The present study demonstrates that peptide agonist ligands of NK(1) receptors can preferentially produce signal activation or desensitization.