The N-terminal domain of substance P is required for complete homologous desensitization but not phosphorylation of the rat neurokinin-1 receptor

The agonist activity of substance P (SP) is a function of the C-terminal do main of the peptide. A C-terminal SP fragment (SP6-11) and analog (septide) and neurokinin A (NKA; a related tachykinin with a divergent N-terminal am ino acid sequence) were found to be full neurokinin-l receptor (NK-1R) agon ists, but were not able to desensitize the receptor maximally as much as SP . Substance P caused 95.6 +/- 0.9% maximal desensitization of the NK-IR whe reas SP6-11, septide, and NKA (only) caused 74 +/- 3.5, 50.6 +/- 8, and 71. 5 +/- 4.4% maximal desensitization, respectively (mean +/- SEM; P < 0.001 v s SP). When a series of SP C-terminal fragment peptides were tested for the ir NK-1R desensitizing activity, it was found that SP5-11 and SP6-11 caused significantly less maximal NK-1R desensitization than SP. SP N-terminal fr agment peptides had no effect on the ability of SP6-11 to compete with H-3- SP binding, generate an IP3 response, or cause NK-1R desensitization when t ested with or without SP6-11 SP, SP6-11, septide, and NKA ail maximally sti mulated 8-9-fold increases in NK-IR phosphorylation. When attached to the C -terminal domain of SP responsible for NK-IR binding and agonism, the N-ter minus of SP is responsible for 25-50% of homologous desensitization and thi s may occur via a mechanism other than NK-IR phosphorylation. (C) 2001 Harc ourt Publishers Ltd.