Centrally administered hemokinin-1 (HK-1), a neurokinin NK1 receptor agonist, produces substance P-like behavioral effects in mice and gerbils.
Hemokinin-1 (HK-1) is a recently described mouse tachykinin peptide whose biological functions are not fully understood. To date, a unique receptor for HK-1 has not been identified. Recent studies suggest HK-1 may have a role in immunological functions, but there has been little characterization of HK-1's effects in the central nervous system (CNS). In the present studies, we confirm that HK-1 is an endogenous agonist at all of the known tachykinin receptors, and is selective for the NK1 receptor over the NK2 and NK3 subtypes. CHO cells transfected with the human NK1 receptor released intracellular calcium in response to HK-1. In addition, HK-1 competed with substance P (SP) for binding to mouse NK1 and human NK1 receptors. In vivo central administration of HK-1 to gerbils and mice induced foot-tapping and scratching behaviors, respectively, similar to those observed following central administration of SP or the NK1 receptor agonist, GR-73632. Furthermore, these behavioral effects were blocked by the selective NK1 receptor antagonist, MK-869. Finally, a comprehensive expression analysis of HK-1 demonstrated that HK-1 mRNA is much more broadly expressed than previously reported with expression observed in many brain regions. Together these data demonstrate that HK-1 is a functional agonist at NK1 receptors and suggest that HK-1 may function both centrally and peripherally.
Duffy
R A
RA
Schering-Plough Research Institute, Department of CNS Biological Research, 2051 Galloping Hill Road, Kenilworth, NJ 07033, USA. ruth.duffy@spcorp.com
Hedrick
J A
JA
Randolph
G
G
Morgan
C A
CA
Cohen-Williams
M E
ME
Vassileva
G
G
Lachowicz
J E
JE
Laverty
M
M
Maguire
M
M
Shan
L-S
LS
Gustafson
E
E
Varty
G B
GB
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005260:Female; D005849:Gerbillinae; D006801:Humans; D008297:Male; D051379:Mice; D064729:Neurokinin-1 Receptor Antagonists; D011498:Protein Precursors / Q000008:administration & dosage* / Q000096:biosynthesis; D018040:Receptors, Neurokinin-1 / Q000819:agonists* / Q000378:metabolism; D013373:Substance P / Q000096:biosynthesis / Q000494:pharmacology*; D015320:Tachykinins / Q000008:administration & dosage* / Q000096:biosynthesis
D064729:Neurokinin-1 Receptor Antagonists; D011498:Protein Precursors; D018040:Receptors, Neurokinin-1; C486037:TAC4 protein, human; C423233:Tac4 protein, mouse; D015320:Tachykinins; D013373:Substance P