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 domain of the peptide. A C-terminal SP fragment (SP(6-11)) and analog (septide) and neurokinin A (NKA; a related tachykinin with a divergent N-terminal amino acid sequence) were found to be full neurokinin-1 receptor (NK-1R) agonists, 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-1R whereas SP(6-11), septide, and NKA(only)caused 74 +/- 3.5, 50.6 +/- 8, and 71.5 +/- 4.4% maximal desensitization, respectively (mean +/- SEM; P < 0.001 vs SP). When a series of SP C-terminal fragment peptides were tested for their NK-1R desensitizing activity, it was found that SP(5-11)and SP(6-11)caused significantly less maximal NK-1R desensitization than SP. SP N-terminal fragment peptides had no effect on the ability of SP(6-11)to compete with(3)H-SP binding, generate an IP(3)response, or cause NK-1R desensitization when tested with or without SP(6-11). SP, SP(6-11), septide, and NKA all maximally stimulated 8-9-fold increases in NK-1R phosphorylation. When attached to the C-terminal domain of SP responsible for NK-1R binding and agonism, the N-terminus of SP is responsible for 25-50% of homologous desensitization and this may occur via a mechanism other than NK-1R phosphorylation.
Vigna
S R
SR
Departments of Cell Biology and Medicine, Duke University Medical Center, Durham VA Medical Center, NC 27710, USA. srv@duke.edu
D000818:Animals; D002461:Cell Line, Transformed; D015544:Inositol 1,4,5-Trisphosphate / Q000032:analysis; D007668:Kidney / Q000166:cytology; D015288:Neurokinin A / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology; D013373:Substance P / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D014162:Transfection
D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D013373:Substance P; C031661:substance P (5-11); C038417:substance P (3-11); C032682:substance P (4-11); C078436:Substance P (1-6); C036877:substance P (1-7); D015544:Inositol 1,4,5-Trisphosphate; D015288:Neurokinin A