Unique roles of G protein-coupled histamine H2 and gastrin receptors in growth and differentiation of gastric mucosa.
Disruption of histamine H2 receptor and gastrin receptor had different effects growth of gastric mucosa: hypertrophy and atrophy, respectively. To clarify the roles of gastrin and histamine H2 receptors in gastric mucosa, mice deficient in both (double-null mice) were generated and analyzed. Double-null mice exhibited atrophy of gastric mucosae, marked hypergastrinemia and higher gastric pH than gastrin receptor-null mice, which were unresponsive even to carbachol. Comparison of gastric mucosae from 10-week-old wild-type, histamine H2 receptor-null, gastrin receptor-null and double-null mice revealed unique roles of these receptors in gastric mucosal homeostasis. While small parietal cells and increases in the number and mucin contents of mucous neck cells were secondary to impaired acid production, the histamine H2 receptor was responsible for chief cell maturation in terms of pepsinogen expression and type III mucin. In double-null and gastrin receptor-null mice, despite gastric mucosal atrophy, surface mucous cells were significantly increased, in contrast to gastrin-null mice. Thus, it is conceivable that gastrin-gene product(s) other than gastrin-17, in the stimulated state, may exert proliferative actions on surface mucous cells independently of the histamine H2 receptor. These findings provide evidence that different G-protein coupled-receptors affect differentiation into different cell lineages derived from common stem cells in gastric mucosa.
Fukushima
Yasushi
Y
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. fksm@mth.biglobe.ne.jp
Matsui
Toshimitsu
T
Saitoh
Toshihito
T
Ichinose
Masao
M
Tateishi
Keisuke
K
Shindo
Takayuki
T
Fujishiro
Midori
M
Sakoda
Hideyuki
H
Shojima
Nobuhiro
N
Kushiyama
Akifumi
A
Fukuda
Satoru
S
Anai
Motonobu
M
Ono
Hiraku
H
Oka
Masashi
M
Shimizu
Yasuhito
Y
Kurihara
Hiroki
H
Nagai
Ryozo
R
Ishikawa
Takashi
T
Asano
Tomoichiro
T
Omata
Masao
M
D000818:Animals; D001284:Atrophy; D002217:Carbachol / Q000008:administration & dosage; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D019070:Cell Lineage / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005745:Gastric Acidity Determination; D005753:Gastric Mucosa / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology; D005755:Gastrins / Q000008:administration & dosage; D006632:Histamine / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043887:Receptor, Cholecystokinin B / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011970:Receptors, Histamine H2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D005755:Gastrins; D043887:Receptor, Cholecystokinin B; D011970:Receptors, Histamine H2; C013550:gastrin 17; D006632:Histamine; D002217:Carbachol