Interspecies polymorphisms confer constitutive activity to the Mastomys cholecystokinin-B/gastrin receptor.
The enteroendocrine hormone, gastrin, exerts trophic effects on the gastric mucosa through the CCK-B/gastrin receptor (CCK-BR). To varying degrees in different species, excess circulating gastrin leads to proliferation of enterochromaffin-like cells and to the development of gastric carcinoid tumors. The African rodent, Mastomys natalensis, is distinguished from other mammals by its propensity toward CCK-BR-mediated growth even in the absence of hypergastrinemia. Here, we report that the Mastomys CCK-BR, when expressed in COS-7 cells, differs from the respective human, canine, and rat receptor homologs by its ability to trigger ligand-independent (i.e., constitutive) inositol phosphate formation. To define the molecular basis of this observation, a series of Mastomys-human chimeric receptors was investigated. Functional characterization of these constructs revealed that a limited segment of the Mastomys CCK-BR, transmembrane domain VI through the C-terminal end, is sufficient to confer constitutive activity to the human protein. Mutagenesis studies within this CCK-BR region defined a combination of three Mastomys amino acids that, when introduced into the human receptor, together conferred a level of ligand-independent signaling comparable with the Mastomys CCK-BR. Complementing prior observations that single point mutations can lead to ligand-independent signaling, our findings suggest that multiple naturally occurring amino acid polymorphisms and/or mutations may together result in an enhanced basal level of receptor activity.
Schaffer
K
K
Division of Gastroenterology and GRASP Digestive Disease Center, Tupper Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
McBride
E W
EW
Beinborn
M
M
Kopin
A S
AS
D000818:Animals; D019556:COS Cells; D004285:Dogs; D006801:Humans; D009115:Muridae; D011110:Polymorphism, Genetic; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013045:Species Specificity
D011949:Receptors, Cholecystokinin; D011994:Recombinant Proteins