title: Functional rescue of Kallmann syndrome-associated prokineticin receptor 2 (PKR2) mutants deficient in trafficking.
abstract: Mutations in the G protein-coupled prokineticin receptor 2 (PKR2) are known to cause Kallmann syndrome and idiopathic hypogonadotropic hypogonadism 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 Kallmann syndrome-associated, intracellularly retained mutant PKR2 receptors can be functionally rescued, suggesting a potential treatment strategy for patients bearing such mutations.
authors.affiliation: From the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China, the Department of Basic Medical Sciences, Changsha Medical University, Changsha, Hunan 410219, China.
authors.forename: Dan-Na
authors.initials: DN
authors.lastname: Chen
authors.affiliation: From the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China.
authors.forename: Yan-Tao
authors.initials: YT
authors.lastname: Ma
authors.affiliation: From the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China.
authors.forename: Huadie
authors.initials: H
authors.lastname: Liu
authors.affiliation: the Department of Pharmacology, University of California, Irvine, California 92697.
authors.forename: Qun-Yong
authors.initials: QY
authors.lastname: Zhou
authors.affiliation: From the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China, the Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, Hubei 437100, China, and lijiada@sklmg.edu.cn.
authors.forename: Jia-Da
authors.initials: JD
authors.lastname: Li
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D003451:Cryoprotective Agents / Q000494:pharmacology; D005990:Glycerol / Q000494:pharmacology; D057809:HEK293 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D017436:Kallmann Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D021381:Protein Transport / Q000235:genetics; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C000592231:A457 compound; D003451:Cryoprotective Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D008565:Membrane Proteins; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D005990:Glycerol
keywords: G Protein-coupled Receptor (GPCR); Kallmann Syndrome; Molecular Chaperone; PKR2; Protein Misfolding; Signal Transduction; Trafficking
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