DIFFERENTIAL ACTIVATION OF INTRACELLULAR EFFECTOR BY 2 ISOFORMS OF HUMAN NEUROKININ-1 RECEPTOR

Two isoforms of the human neurokinin-1 receptor were cloned and charac terized in heterologous expression systems of mammalian cell culture a nd Xenopus oocytes. The two isoforms differ only in the length of the encoded polypeptide. The peptide-binding properties of the long form o f human neurokinin-1 receptor are consistent with those of the native neurokinin-1 receptor of mammalian tissues, where substance P is the m ost potent agonist. Peptide agonists elicit an oscillating current in Xenopus oocytes expressing the long form. In contrast, the short form of human neurokinin-1 receptor expressed in COS cells binds substance P with an apparent affinity at least 10-fold lower than that of the lo ng form, and it elicits the electrophysiological response only weakly in Xenopus oocytes. These data suggest that the short form couples to a different effector system. Sequence analysis suggested that the two isoforms may arise from alternative pre-mRNA splicing. These results i ndicate that multiple forms of the human neurokinin-1 receptor exist a nd the differential activation of intracellular effector may be involv ed in generating the complex biological effects of substance P.