Prototypic G protein-coupled receptor for the intestinotrophic factor glucagon-like peptide 2.
Glucagon-like peptide 2 (GLP-2) is a 33-aa proglucagon-derived peptide produced by intestinal enteroendocrine cells. GLP-2 stimulates intestinal growth and up-regulates villus height in the small intestine, concomitant with increased crypt cell proliferation and decreased enterocyte apoptosis. Moreover, GLP-2 prevents intestinal hypoplasia resulting from total parenteral nutrition. However, the mechanism underlying these actions has remained unclear. Here we report the cloning and characterization of cDNAs encoding rat and human GLP-2 receptors (GLP-2R), a G protein-coupled receptor superfamily member expressed in the gut and closely related to the glucagon and GLP-1 receptors. The human GLP-2R gene maps to chromosome 17p13.3. Cells expressing the GLP-2R responded to GLP-2, but not GLP-1 or related peptides, with increased cAMP production (EC50 = 0.58 nM) and displayed saturable high-affinity radioligand binding (Kd = 0.57 nM), which could be displaced by synthetic rat GLP-2 (Ki = 0.06 nM). GLP-2 analogs that activated GLP-2R signal transduction in vitro displayed intestinotrophic activity in vivo. These results strongly suggest that GLP-2, like glucagon and GLP-1, exerts its actions through a distinct and specific novel receptor expressed in its principal target tissue, the gastrointestinal tract.
Munroe
D G
DG
Allelix Biopharmaceuticals Inc., 6850 Goreway Drive, Mississauga, Ontario L4V 1V7, Canada. dmunroe@allelix.com
Gupta
A K
AK
Kooshesh
F
F
Vyas
T B
TB
Rizkalla
G
G
Wang
H
H
Demchyshyn
L
L
Yang
Z J
ZJ
Kamboj
R K
RK
Chen
H
H
McCallum
K
K
Sumner-Smith
M
M
Drucker
D J
DJ
Crivici
A
A
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015723:Gene Library; D052216:Glucagon-Like Peptide 1; D053767:Glucagon-Like Peptide 2; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D018027:Receptors, Glucagon / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014162:Transfection