Functional Rescue of Kallmann Syndrome-associated PKR2 Receptor Mutants Deficient in Trafficking [Signal Transduction]

April 21st, 2014 by Chen, D.-N., Ma, Y.-T., Liu, H., Zhou, Q.-Y., Li, J.-D.

Mutations in the G-protein coupled prokineticin receptor 2 (PKR2) are known to cause Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH) manifesting with delayed puberty and infertility. Some of the mutant receptors are not routed to the cell surface, instead they are trapped in the cellular secretory pathway. The cell-permeant agonists/antagonists have been used to rescue some membrane receptors that are not targeted onto the cell membrane. Here, we chose three disease-associated mutations (W178S, G234D and P290S), which all resulted in retention of PKR2 intracellularly. We show that a small molecule PKR2 antagonist (A457) dramatically increased cell surface expression and rescued the function of P290S PKR2, but had no effect on W178S and G234D PKR2. Furthermore, we also tested chemical chaperone glycerol on the cell surface expression and function of PKR2 mutants. Treatment with 10% glycerol significantly increased the cell surface expression and signaling of P290S and W178S PKR2. These data demonstrate that some KS-associated, intracellularly retained mutant PKR2 receptors can be functionally rescued, suggesting a potential treatment strategy for patients bearing such mutations.