Investigation on P-Glycoprotein Function and Its Interacting Proteins under Simulated Microgravity

Abstract

P-glycoprotein (P-gp) could maintain stability of the nerve system by effluxing toxins out of the blood-brain barrier. Whether it plays a very important role in drug brain distribution during space travel is not yet known. The present study was aimed at investigating P-gp function, expression, and its interacting proteins in a rat brain under simulated microgravity (SMG) by comparative proteomics approach. Rats were tail-suspended to induce short- (7-day) and long-term (21-day) microgravity. P-gp function was assessed by measuring the P-gp ATPase activity and the brain-to-plasma concentration ratio of rhodamine 123. P-gp expression was evaluated by Western blot. 21d-SMG significantly enhanced P-gp efflux activity and expression in rats. Label-free proteomics strategy identified 26 common differentially expressed proteins (DEPs) interacting with P-gp in 7d- and 21d-SMG groups. Most of the DEPs mainly regulated ATP hydrolysis coupled transmembrane transport and so on. Interaction analysis showed that P-gp might potentially interact with heat shock proteins, sodium/potassium ATP enzyme, ATP synthase, microtubule-associated proteins, and vesicle fusion ATPase. The present study firstly reported P-gp function, expression, and its potentially interacting proteins exposed to simulated microgravity. These findings might be helpful not only for further study on nerve system stability but also for the safe and effective use of P-gp substrate drugs during space travel.