Overexpression Of Sigma - 1 Receptor Inhibition Of Adam17 And Adam10 Function Research

The sigma-1 receptor is an important molecular chaperone which involves in ER Iipid metabolisms/transport, ion channel and cells survive. Such profits have linked sigma-1 receptors to many nervous system diseases (such as ALS, depression, Alzheimer’s disease), stroke, and cancer. ALS is a neurodegenerative disorder characterized by loss of motor neurons in central nervous system. In 3 ALS-FTD/FTD families, sequencing revealed a mutation in the SIGMAR1 gene affecting a highly conserved amino acid located in the transmembrane domain of the encoded protein, sigma-1 receptor. However, how this mutation affects the motor neuron is still unknown.ADAM 10 and ADAM 17 are membrane-anchored proteases involved the shedding process of many substrates, such as ligands of the epidermal growth factor receptor (EGFR), Notch1, LI cell adhesion molecule, APP, etc. And they have been reported to be involved in many diseases pathology. Both proteases functions can be affected by lipid rafts. Currently, it is not so clear whether sigma-1 receptor would affect ADAM10/ADAM17 function. As a transmembrane protein itself, upregulation of sigma-1 receptors affect the levels of plasma membrane lipid rafts by changing the lipid components therein. The membrane reconstitution thus induced by sigma-1 receptors in turn affects functions of proteins residing in plasma membrane lipid rafts. Therefore, it is very likely sigma-1 receptor can affect ADAM 10/ADAM17 functions. Given the circumstances that those metal loproteases function can be affected by lipid raft which can be modified by sigma-1 receptor, it is very likely that sigma-1 receptor can also affect their function. By using an alkaline phosphatase tagged substrate reporter system, we have showed that overexpression sigma-1 receptor in different cell lines can diminish ADAM 17 and ADAM 10 dependent shedding. Meanwhile, the expression of ADAM 17 and ADAM 10 are not changed. Further, the distribution of Flottin-1 and Caveolin-1 are affected by overexpressing sigma-1 receptor.