[d-Arg1,d-Phe5,d-Trp7,9,Leu11]Substance P Acts as a Biased Agonist toward Neuropeptide and Chemokine Receptors

• Published in: The Journal of biological chemistry Vol. 273; no. 5; pp. 3097 - 3104
• Main Authors: Jarpe, M B, Knall, C, Mitchell, F M, Buhl, A M, Duzic, E, Johnson, G L
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 30.01.1998
• Subjects: 3T3 Cells; Animals; Antigens, CD - drug effects; Calcium - metabolism; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Humans; JNK Mitogen-Activated Protein Kinases; Mice; Mitogen-Activated Protein Kinases; Neutrophils - metabolism; Rats; Receptors, Bombesin - metabolism; Receptors, Chemokine - agonists; Receptors, Interleukin - drug effects; Receptors, Interleukin-8A; Receptors, Neuropeptide - agonists; Signal Transduction - drug effects; Substance P - analogs & derivatives; Substance P - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.5.3097

Substance P derivatives are potential therapeutic compounds for the treatment of small cell lung cancer and can cause apoptosis in small cell lung cancer cells in culture. These peptides act as broad spectrum neuropeptide antagonists, blocking calcium mobilization induced by gastrin-releasing peptide, bradykinin, cholecystokinin, and other neuropeptides. We show that [ d -Arg 1 , d -Phe 5 , d -Trp 7,9 ,Leu 11 ]substance P has unique agonist activities in addition to this described antagonist function. At doses that block calcium mobilization by neuropeptides, this peptide causes activation of c-Jun N-terminal kinase and cytoskeletal changes in Swiss 3T3 fibroblasts and stimulates migration and calcium flux in human neutrophils. Activation of c-Jun N-terminal kinase is dependent on the expression of the gastrin-releasing peptide receptor in rat 1A fibroblasts, demonstrating that the responses to the peptide are receptor-mediated. We hypothesize that [ d -Arg 1 , d -Phe 5 , d -Trp 7,9 ,Leu 11 ]substance P acts as a biased agonist on neuropeptide and related receptors, activating certain guanine nucleotide-binding proteins through the receptor, but not others.