Nogo A expression in the adult enteric nervous system.

Neuronal plasticity plays an important role in physiological and pathological processes within the gastrointestinal (GI) tract. Nogo A is a major contributor to the negative effect central nervous system (CNS) myelin has on neurite outgrowth after injury and may also play a role in maintaining synaptic connections in the healthy CNS. Nogo A is highly expressed during neuronal development but in the CNS declines postnatally concomitantly with a loss of regenerative potential while ganglia of the Peripheral Nervous System (PNS) retain Nogo A. The enteric nervous system shares a number of features in common with the CNS, thus the peripheral distribution of factors affecting plasticity is of interest. We have investigated the distribution of Nogo in the adult mammalian gastrointestinal tract. Nogo A mRNA and protein are detectable in the adult rat GI tract. Nogo A is expressed heterogeneously in enteric neurons throughout the GI tract though expression levels appear not to be correlated with neuronal sub-type. The pattern of expression is maintained in cultured myenteric plexus from the guinea-pig small intestine. As is seen in developing neurons of the CNS, enteric Nogo A is present in both neuronal cell bodies and axons. Our results point to a hitherto unsuspected role for Nogo A in enteric neuronal physiology.

Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription.

BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3. RESULTS: SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3alpha in vitro, with K(i)s of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3beta with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a beta-catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-3 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase. CONCLUSIONS: SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease.