A SUBSTANCE-P (NEUROKININ-1) RECEPTOR MUTANT CARBOXYL-TERMINALLY TRUNCATED TO RESEMBLE A NATURALLY-OCCURRING RECEPTOR ISOFORM DISPLAYS ENHANCED RESPONSIVENESS AND RESISTANCE TO DESENSITIZATION

Two isoforms of the substance P (SP) receptor, differing in the length of the cytoplasmic carboxylterminus by approximate to 8 kDa, have bee n detected previously in rat salivary glands and other tissues, The bi nding and functional properties of these two isoforms have been Invest igated using full-length (407 amino acids) and carboxyl-terminally tru ncated (324 amino acids) rat SP receptors transfected stably into Chin ese hamster ovary cells, Both the full-length and the truncated recept or bound radiolabeled SP with a similar K-d (approximate to 0.1 nM), T he average number of high affinity SP binding sites per cell was 1.0 x 10(5) and 0.3 x 10(5) for the full-length and the truncated SP recept or, respectively, In both cell lines, SP induced a rapid but transient Increase in cytosolic calcium concentration ([Ca2+](i)), which consis ted of the release of Ca2+ from intracellular stores and the influx of extracellular Ca2+, Both components are dependent on phospholipase C activation. Although the full-length and the truncated receptor utiliz e the same calcium pathways, they differ in their EC50 values (0.28 nM for the full-length; 0.07 nM for the truncated), These differences in responsiveness may be related to the observed differences in receptor desensitization. The truncated receptor, in contrast to the full-leng th receptor, does not undergo rapid and long-lasting desensitization. Cells possessing the short isoform of the SP receptor would thus be ex pected to exhibit a prolonged responsiveness.