Abstract
PKCs are serine/threonine kinases sub-divided into three categories, namely, conventional, novel and atypical. Depending upon the isoform some have been reported to regulate insulin signaling positively and some negatively, in peripheral insulin responsive tissues like, skeletal muscles, adipocytes and hepatocytes through PI3K-Akt pathway, leading to glucose uptake. Though, peripheral tissues have been extensively studied, neuronal insulin signaling is less explored. Neuronal insulin signaling is required for maintaining cognitive abilities including synaptic plasticity and memory formation. Therefore, it is important to explore the role of PKC in neuronal insulin signaling. The objective of the present study was to elucidate the role of PKC in regulating insulin signaling in neuronal cells in vitro. To study that, differentiated Neuro-2a (N2a) cells were cultured in vitro and treated with or without phorbol 12-myristate 13-acetate (PMA), a well-known activator of PKC, with or without insulin stimulation and the effect was tested on the insulin signaling proteins. PKC when activated by PMA (400nM) and stimulated with insulin (100nM), down-regulated the activity of Akt by 25% (serine-473) and 20% (threonine-308). Testing of further downstream insulin signaling molecules under the same conditions demonstrated decrease in activity of AS160 by 20% and GSK3β by 20%. However, there was no change in the activity of GSK3α, suggesting a specificity of PKC towards GSK3β in neurons. To determine the functionality of these phosphorylations/activations, glucose uptake measurement showed that PKC decreased glucose uptake by 25%. Taken together these data strongly demonstrates for the first time that PKC negatively regulates insulin signaling cascade via Akt-AS160-GSK3β-glucose uptake pathway in neuronal cells. Further knowledge in this regard will pave the way for future understanding of insulin signaling in neuronal system and possibly neurodegenerative disorders. Disclosure D. Mishra: None. C.S. Dey: None. Funding Council of Scientific and Industrial Research, Government of India, New Delhi; Department of Science and Technology (SR/SO/HS-238/2012, SR/S2/JCB-24/2008(G))
Published Version
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