Noc2 is essential in normal regulation of exocytosis in endocrine and exocrine cells.
Rab3 is a subfamily of the small GTP-binding protein Rab family and plays an important role in exocytosis. Several potential effectors of Rab3, including rabphilin3 and Rims (Rim1 and Rim2), have been isolated and characterized. Noc2 was identified originally in endocrine pancreas as a molecule homologous to rabphilin3, but its role in exocytosis is unclear. To clarify the physiological function of Noc2 directly, we have generated Noc2 knockout (Noc2(-/-)) mice. Glucose intolerance with impaired insulin secretion was induced in vivo by acute stress in Noc2(-/-) mice, but not in wild-type (Noc2(+/+)) mice. Ca(2+)-triggered insulin secretion from pancreatic isles of Noc2(-/-) mice was markedly impaired, but was completely restored by treatment with pertussis toxin, which inhibits inhibitory G protein Gi/o signaling. In addition, the inhibitory effect of clonidine, an alpha(2)-adrenoreceptor agonist, on insulin secretion was significantly greater in Noc2(-/-) islets than in Noc2(+/+) islets. Impaired Ca(2+)-triggered insulin secretion was rescued by adenovirus gene transfer of wild-type Noc2 but not by that of mutant Noc2, which does not bind to Rab3. Accordingly, Noc2 positively regulates insulin secretion from endocrine pancreas by inhibiting Gi/o signaling, and the interaction of Noc2 and Rab3 is required for the effect. Interestingly, we also found a marked accumulation of secretory granules in various exocrine cells of Noc2(-/-) mice, especially in exocrine pancreas with no amylase response to stimuli. Thus, Noc2, a critical effector of Rab3, is essential in normal regulation of exocytosis in both endocrine and exocrine cells.
Matsumoto
Masanari
M
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Miki
Takashi
T
Shibasaki
Tadao
T
Kawaguchi
Miho
M
Shinozaki
Hidehiro
H
Nio
Junko
J
Saraya
Atsunori
A
Koseki
Haruhiko
H
Miyazaki
Masaru
M
Iwanaga
Toshihiko
T
Seino
Susumu
S
D048868:Adaptor Proteins, Signal Transducing; D000681:Amylases / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D046508:Culture Techniques; D005088:Exocrine Glands / Q000166:cytology / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism; D037342:Pertussis Toxin / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020692:rab3 GTP-Binding Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; C484660:Rph3al protein, mouse; D037342:Pertussis Toxin; D000681:Amylases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020692:rab3 GTP-Binding Proteins