Attenuation of agonist-induced desensitization of the rat substance P receptor by progressive truncation of the C-terminus.

We have investigated the C-terminal tail of the rat substance P receptor (SPR) as a domain essential for agonist-induced desensitization. Four progressively shorter mutants, using premature termination in the C-terminus, were constructed and compared with the unaltered SPR using ectopic expression of wild-type and mutant receptors in Xenopus oocytes. These mutants were designated D16, D47, D70 and D96 with 16, 47, 70 and 96 amino acids residues deleted from the tail, respectively. Wild type SPR, D16 and D47 exhibited normal current responses when challenged with substance P, but D70 and D96 had reduced maximal current responses (70% and 5% of wild type SPR, respectively). D70, however, exhibited substantial resistance to substance P-induced desensitization in that 55%, versus 8% for wild type SPR, of the peak current of the first response was preserved on second challenge with substance P. Therefore, a domain from residues 338 to 360 of the rat SPR, though not necessary for the functional activity of the receptor, plays an essential role in agonist-induced desensitization.