title: cGMP/Protein Kinase G Signaling Suppresses Inositol 1,4,5-Trisphosphate Receptor Phosphorylation and Promotes Endoplasmic Reticulum Stress in Photoreceptors of Cyclic Nucleotide-gated Channel-deficient Mice.
abstract: Photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. We have shown endoplasmic reticulum (ER) stress-associated apoptotic cone death and increased phosphorylation of the ER Ca(2+) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in CNG channel-deficient mice. We also presented a remarkable elevation of cGMP and an increased activity of the cGMP-dependent protein kinase (protein kinase G, PKG) in CNG channel deficiency. This work investigated whether cGMP/PKG signaling regulates ER stress and IP3R1 phosphorylation in CNG channel-deficient cones. Treatment with PKG inhibitor and deletion of guanylate cyclase-1 (GC1), the enzyme producing cGMP in cones, were used to suppress cGMP/PKG signaling in cone-dominant Cnga3(-/-)/Nrl(-/-) mice. We found that treatment with PKG inhibitor or deletion of GC1 effectively reduced apoptotic cone death, increased expression levels of cone proteins, and decreased activation of Müller glial cells. Furthermore, we observed significantly increased phosphorylation of IP3R1 and reduced ER stress. Our findings demonstrate a role of cGMP/PKG signaling in ER stress and ER Ca(2+) channel regulation and provide insights into the mechanism of cone degeneration in CNG channel deficiency.
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Butler
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
authors.forename: Arjun
authors.initials: A
authors.lastname: Thapa
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
authors.forename: Josh
authors.initials: J
authors.lastname: Belcher
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah 84132.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
authors.affiliation: Center for Integrated Protein Science Munich and Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.affiliation: Center for Integrated Protein Science Munich and Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104. Electronic address: xi-qin-ding@ouhsc.edu.
authors.forename: Xi-Qin
authors.initials: XQ
authors.lastname: Ding
mesh_terms: D000818:Animals; D017209:Apoptosis; D050976:Basic-Leucine Zipper Transcription Factors / Q000172:deficiency / Q000235:genetics; D002227:Carbazoles / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000172:deficiency / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D063928:Ependymoglial Cells / Q000166:cytology / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D006162:Guanylate Cyclase / Q000172:deficiency / Q000235:genetics; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D002227:Carbazoles; C518237:Cnga3 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; D005136:Eye Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; C025389:Itpr1 protein, mouse; C084884:Nrl protein, mouse; D047428:Protein Kinase Inhibitors; D011956:Receptors, Cell Surface; D013873:Thionucleotides; C110715:guanylate cyclase 1; C073601:KT 5823; C083763:8-bromoguanosino-3',5'-cyclic monophosphorothioate; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP
keywords: calcium channel; cyclic GMP (cGMP); endoplasmic reticulum stress (ER stress); photoreceptor; protein kinase G (PKG)