Ca2+/calmodulin-dependent protein kinase II (CaM kinase II)
may play a key role in Ca2+-induced insulin secretion. We
have previously reported that treatment of insulinoma MIN6 cells with
...secretagogues activated CaM kinase II and increased the phosphorylation
of synapsin I, followed by insulin secretion. Here, we identified
isoforms of CaM kinase II in MIN6 cells and rat islets. Immunoblot
analysis suggested that the major isoforms of CaM kinase II were β′e
and δ2 at the protein level in MIN6 cells. Only the β′e isoform was
detected in rat islets by both RT-PCR and immunoblot analysis. We
transiently overexpressed β′e and δ2 isoforms in MIN6 cells and
confirmed that treatment of cells with tolbutamide and glucose
activated the isoforms. Immunoblot analysis with an antibody against
synapsin I phosphorylated by CaM kinase II demonstrated that treatment
with tolbutamide and glucose rapidly increased phosphorylation of
synapsin I and that phosphorylation was potentiated by overexpression
of the isoforms. The secretagogue-induced insulin secretion was
potentiated by overexpression of the isoforms. Our results further
support our conclusion that activation of CaM kinase II and the
concomitant phosphorylation of synapsin I contribute to insulin
secretion from pancreatic β-cells.
Abstract The finding of nuclear translocation of cathepsin L and its ability to process the CDP/Cux transcription factor uncovers an important role of cathepsin L in control of cell cycle ...progression. As the expression of certain cell cycle regulators is associated with nigral neuronal death, the present study was sought to investigate if nuclear translocation of cathepsin L and expression of certain cyclins were induced in DA neurons by 6-hydroxydopamine (6-OHDA). The neuroprotective effects of the cell cycle inhibitor olomoucine against 6-OHDA-induced death of nigral neurons were examined. Using immunocytochemistry and real-time PCR we demonstrated that cyclin D1, cyclin B1 and proliferating cell nuclear antigen (PCNA) were aberrantly expressed in some dopaminergic neurons after 6-OHDA infusion. The nuclear translocation of cathepsin L and up-regulation of LC3, a protein involved in autophagy, were observed in nigral DA neurons. Olomoucine, a cyclin dependent kinase (CDK) inhibitor, reduced contralateral rotations and the loss of TH-positive neurons in substantia nigra induced by lesion with 6-OHDA. Pretreatment of rats or primary DA neurons with olomoucine resulted in a partial blockade of nuclear translocation of cathepsin L. Olomoucine also increased the expression of punctate LC3 immunoreactivity, indicating activation of autophagy. These findings suggest that olomoucine may exert neuroprotective effects through inhibiting cathepsin L nuclear translocation and activating autophagy.
Loss of cholinergic neurons and/or dysfunction of the glutamatergic system in the central nervous system cause learning impairment in experimental Alzheimer's (Alz) disease animals and Alz patients. ...Furthermore, the impaired cholinergic system is likely implicated in depressive behaviors in Alz patients. Neurogenesis persistently occurs in the forebrain subventricular zone (SVZ) and hippocampal subgranular zone (SGZ) in rodent and human brains. Notably, impaired neurogenesis in those regions is implicated not only in memory deficits but also in depressive behaviors. We have recently found that olfactory bulbectomized (OBX) mice reveal memory impairment and depressive behaviors. Using this attractive OBX mice model, we discovered a novel cognitive enhancer, spiroimidazo1,2-apyridine-3,2-indan-2(3H)-one (ZSET1446/ST101), that is a new azaindolizinone derivative without inhibitory action on acetylcholine esterase (AChE). Interestingly, ZSET1446 improved learning and memory by potentiating nicotine-induced ACh release in the hippocampus of amyloid-beta infused rats. In addition, ZSET1446 restored OBX-induced cognitive deficits in mice. Furthermore, chronic ZSET1446 administration significantly rescues decreased neuronal precursor cell proliferation seen in the dentate gyrus of OBX mice. Consistent with enhanced neurogenesis, chronic ZSET1446 administration improved depressive behavior assessed using the tail suspension test in OBX mice. Protein kinase B (Akt) and extracellular signal-regulated kinase pathways likely mediate ZSET1446-induced neurogenesis. These results suggest that ZSET1446 action via stimulation of the cholinergic system elicits improvement of the depression and cognitive impairment observed in Alz disease patients.
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