The N-terminal domain of human hemokinin-1 influences functional selectivity property for tachykinin receptor neurokinin-1

• Published in: Biochemical pharmacology Vol. 81; no. 5; pp. 661 - 668
• Main Authors: Mou, Lingyun, Xing, Yanhong, Kong, Ziqing, Zhou, Ying, Chen, Zongyao, Wang, Rui
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.03.2011; Elsevier
• Subjects: adenylate cyclase; agonists; amino acids; Animals; Biological and medical sciences; calcium; Calcium - metabolism; CHO Cells; Cricetinae; Cricetulus; Endocytosis; ERK1/2; Functional selectivity; Hemokinin-1; Humans; inflammation; Intracellular Space - metabolism; Medical sciences; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Neurokinin-1 receptor; NF-kappa B - metabolism; NF-κB; pharmacology; Pharmacology. Drug treatments; Phosphorylation; Protein Structure, Tertiary; Receptors, Neurokinin-1 - agonists; Receptors, Neurokinin-1 - physiology; signal transduction; Structure-Activity Relationship; Tachykinins - chemistry; Tachykinins - pharmacology; Tachykinins - physiology; vasodilation; NF-κB; ERK1/2; Hemokinin-1; Neurokinin-1 receptor; cAMP; Functional selectivity; Human; NK1 Tachykinin receptor; Selectivity; Extracellular signal-regulated protein kinase 2; Extracellular signal-regulated protein kinase 1; Transcription factor NFκB; Tachykinin receptor; Hemokinin 1
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2010.12.007

Human hemokinin-1 (hHK-1) is a substance P-like tachykinin peptide preferentially expressed in non-neuronal tissues. It is involved in multiple physiological functions such as inflammation, hematopoietic cells development and vasodilatation via the interaction with tachykinin receptor neurokinin-1 (NK1). To further understand the intracellular signal transduction mechanism under such functional multiplicity, current study was focused on the differential activation of Gs and Gq pathways by hHK-1 and its C-terminal fragments, which is termed as functional selectivity. We demonstrated these hHK-1 and related peptide fragments can independently activate Gs and Gq pathways, showing a relative bias toward Gq over Gs pathway. The T1, K3 and Q6 of hHK-1 might play roles in the activation of adenylate cyclase mediated by Gs, while having negligible effect on Gq mediated intracellular calcium release. The stepwise truncation of N-terminal amino acid of hHK-1 caused gradual decrease in ERK1/2 phosphorylation level and NF-κB activity. However, it had little influence on the induction of NK1 receptor desensitization and internalization. Taken together these data support that hHK-1 and its C-terminal fragments are human NK1 receptor agonists with different functional selectivity properties and that such functional selectivity leads to differential activation of downstream signaling and receptor trafficking.