Identification, localization and receptor characterization of novel mammalian substance P-like peptides.
Hemokinin-1 (HK-1) is a novel substance P (SP)-like peptide that is encoded by the preprotachykinin C (PPT-C) gene recently identified in mouse B cells and shown to be a potentially important regulator of B cell development (Nat. Immunol. 1 (2000) 392). We have now isolated and characterized the human and rat orthologs of PPT-C and examined activities of human and mouse HK-1 on the three tachykinin receptors, neurokinin-1-3 (NK1-3). The rat PPT-C polypeptide is highly homologous to mouse PPT-C and contains the same processing sites to generate predicted HK-1. The human PPT-C polypeptide is also homologous to mouse PPT-C, however, it contains two potential monobasic cleavage sites rather than a single dibasic cleavage site at the amino-terminal end of the predicted HK-1 peptide. Thus, human PPT-C has the potential to generate full length predicted HK-1 as well as a truncated version (HK-1(4-11)). Polymerase chain reaction analysis revealed that both human and mouse PPT-C were expressed in a variety of tissues with strong signals detected in the skin of both species and in the mouse brain. Binding and functional analysis indicated that human and mouse HK-1 peptides were nearly identical to SP in their overall activity profile on the three NK receptors with the most potent affinity for the NK1 receptor. The results indicate that PPT-C encodes another high affinity ligand of the NK1 receptor which may play an important role in mediating some of the physiological roles previously assigned to the NK1 receptor.
Kurtz
Marc M
MM
Department of Immunology/Rheumatology, Merck Research Laboratories, Rahway, NJ 07065, USA.
Wang
Ruiping
R
Clements
Michelle K
MK
Cascieri
Margaret A
MA
Austin
Christopher P
CP
Cunningham
Barry R
BR
Chicchi
Gary G
GG
Liu
Qingyun
Q
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D030541:Databases, Genetic; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000378:metabolism; D018039:Receptors, Tachykinin / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015320:Tachykinins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology
D010446:Peptide Fragments; D011498:Protein Precursors; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; C486037:TAC4 protein, human; C423233:Tac4 protein, mouse; D015320:Tachykinins