Identification of a human gastrointestinal tract and immune system receptor for the peptide neuromedin U.
Neuromedin U (NmU) is a 25 amino acid peptide prominently expressed in the upper gastrointestinal (GI) tract and central nervous system. It is highly conserved throughout evolution and induces smooth muscle contraction in a variety of species. Our understanding of NmU biology has been limited because the identity of its receptor was unknown. Here we demonstrate that GPR66/FM-3 is specifically stimulated by NmU, causing the mobilization of intracellular calcium. This response was dose-dependent (EC(50) = 10 nM) and specific in that none of over 1000 ligands tested, including other neuromedins (NmB, C, L, K, N), induced a calcium flux in GPR66/FM-3-transfected cells. The GPR66/FM-3 mRNA is prominently expressed in the upper GI tract of humans, as is the mRNA for NmU, consistent with role for this receptor-ligand pair in regulating the function of this organ system. In addition, we show that whereas neuromedin U is expressed by monocytes and dendritic cells, GPR66/FM-3 is expressed by T cells and NK cells. These data suggest a previously unrecognized role for NmU as an immunoregulatory molecule.
Hedrick
J A
JA
Human Genome Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033-1300, USA. joseph.hedrick@spcorp.com
Morse
K
K
Shan
L
L
Qiao
X
X
Pang
L
L
Wang
S
S
Laz
T
T
Gustafson
E L
EL
Bayne
M
M
Monsma
F J
FJ
D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004064:Digestive System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism*; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D017981:Receptors, Neurotransmitter; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000378:metabolism*; D014162:Transfection
D008565:Membrane Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017981:Receptors, Neurotransmitter; C082444:neuromedin U receptor; C056900:neuromedin U; D002118:Calcium