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 Gi͞o signaling. In addition, the inhibitory effect of clonidine, an ␣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 Gi͞o 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.

We have previously shown that cAMP-binding protein cAMP-guanidine nucleotide exchange factor II (GEFII) (or Epac2) interacting with Rim2 is involved in cAMPdependent, protein kinase A-independent exocytosis in pancreatic ␤-cells. The action of the cAMP-GEFII⅐Rim2 complex requires both intracellular cAMP and Ca 2؉ . Although Rim2 has C 2 domains, its role as a Ca 2؉ sensor has remained unclear. In the present investigation, we have discovered that Piccolo, a CAZ (cytoskeletal matrix associated with the active zone) protein in neurons that is structurally related to Rim2, also binds to cAMP-GE-FII and that it forms both homodimer and heterodimer with Rim2 in a Ca 2؉ -dependent manner, whereas Rim2 alone does not form the homodimer. The association of Piccolo⅐Rim2 heterodimerization is stronger than Piccolo⅐Piccolo homodimerization. Treatment of pancreatic islets with antisense oligodeoxynucleotides against Piccolo inhibits insulin secretion induced by cAMP analog 8-bromo-cyclic AMP plus high glucose stimulation. These results suggest that Piccolo serves as a Ca 2؉ sensor in exocytosis in pancreatic ␤-cells and that the formation of a cAMP-GEFII⅐Rim2⅐Piccolo complex is important in cAMP-induced insulin secretion. In addition, this study suggests that CAZ proteins similar to those in neurons are also function in pancreatic ␤-cells.

Numerical predictions are compared with the experiments of swirling turbulent flows in a pipe where the swirl is driven by the pipe wall rotating around the pipe axis. The laminarization phenomena, that is, the deformation of the axial velocity profile into a shape similar to the laminar one and the decrease of the friction factor, caused by the pipe rotation can be predicted by the calculations applying the stress equation turbulence model. However, calculations applying two types of the k-ε two-equation models with and without the modification by the Richardson number, cannot predict the laminarization phenomena and the characteristic behaviors due to the swirl. The interpretations of the laminarization phenomena and the applicability of the turbulence models are presented.