Modulation of calcium signalling in NMDARs and kainate receptors by knocking down of TSG101

As evidence for the NMDA receptor hypofunction theory of schizophrenia grows, more attention is being paid to restoring correct glutamatergic signalling as a therapy option leading to development of novel antipsychotics. The ESCRT proteins groups are involved in sorting ubiquitinated membrane receptors to lysosomes, which is a key method for reducing cell surface receptor signalling. The research illustrates the effect of knocking down and overexpression of TSG101 and VPS4a genes on the function of ESCRTs machinery and the expression of NMDA receptors. The average number of NMDA receptors on the cell surface is heavily influenced by the length of time they spend there, as well as the rates of starting endocytosis followed by degradation. Accumulation of NMDA receptors, because of knocking down of TSG101, is mostly reflexed in more surface expression of the receptors. Knocking down of TSG101 showed a high level of calcium signalling of accumulated NMDA receptors which was enough to alleviate the blocking action of Phencyclidine on the receptors. Hyperactivation of epidermal growth factor receptor (EGFR), a receptor tyrosine kinase essential for cell proliferation and survival, accompanied by increased EGFR accumulation is observed in cells treated with the negative
dominant of VPS4a and TSG101 knockdown. Our findings define TSG101, as a novel regulator of neuronal membrane receptors trafficking, which may provide a new therapeutic strategy for the treatment of neurodegenerative and psychotic diseases.