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

Abstract

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.

• Authors: Lingyun Mou, Yanhong Xing, Ziqing Kong, Ying Zhou, Zongyao Chen, Rui Wang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 81 Issue 5 Pg. 661-8 (Mar 01 2011) ISSN: 1873-2968 [Electronic] England
• PMID: 21168392 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• NF-kappa B
• Receptors, Neurokinin-1
• Tachykinins
• hemokinin-1
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Calcium

Topics

• Animals
• CHO Cells
• Calcium (metabolism)
• Cricetinae
• Cricetulus
• Endocytosis
• Humans
• Intracellular Space (metabolism)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• NF-kappa B (metabolism)
• Phosphorylation
• Protein Structure, Tertiary
• Receptors, Neurokinin-1 (agonists, physiology)
• Structure-Activity Relationship
• Tachykinins (chemistry, pharmacology, physiology)