title: 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.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Medicine, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, PR China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Mou
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Xing
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Kong
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Zongyao
authors.initials: Z
authors.lastname: Chen
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004705:Endocytosis; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000502:physiology*; D013329:Structure-Activity Relationship; D015320:Tachykinins / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; C507968:hemokinin-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium