Palmitoylation stabilizes unliganded rod opsin

被引:43
作者
Maeda, Akiko [1 ,2 ]
Okano, Kiichiro [1 ]
Park, Paul S. -H. [1 ,2 ]
Lem, Janis [3 ,4 ]
Crouch, Rosalie K. [5 ]
Maeda, Tadao [1 ,2 ]
Palczewski, Krzysztof [1 ]
机构
[1] Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Ophthalmol, Cleveland, OH 44106 USA
[3] Tufts Med Ctr, Dept Ophthalmol, Boston, MA 02111 USA
[4] Tufts Med Ctr, Mol Cardiol Res Inst, Boston, MA 02111 USA
[5] Med Univ S Carolina, Dept Ophthalmol, Charleston, SC 29403 USA
基金
美国国家卫生研究院;
关键词
G protein-coupled receptor; light damage; rhodopsin; S-palmitoylation; vision; PROTEIN-COUPLED RECEPTORS; BOVINE RHODOPSIN; MOUSE MODEL; ACYLATION; MICE; DEPALMITOYLATION; PALMITYLATION; HYDROXYLAMINE; RETINOPATHY; MEMBRANES;
D O I
10.1073/pnas.1000640107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
S-palmitoylation is a conserved feature in many G protein-coupled receptors (GPCRs) involved in a broad array of signaling processes. The prototypical GPCR, rhodopsin, is S-palmitoylated on two adjacent C-terminal Cys residues at its cytoplasmic surface. Surprisingly, absence of palmitoylation has only a modest effect on in vitro or in vivo signaling. Here, we report that palmitoylation-deficient (Palm(-/-)) mice carrying two Cys to Thr and Ser mutations in the opsin gene displayed profound light-induced retinal degeneration that first involved rod and then cone cells. After brief bright light exposure, their retinas exhibited two types of deposits containing nucleic acid and invasive phagocytic macrophages. When Palm(-/-) mice were crossed with Lrat(-/-) mice lacking lecithin: retinol acyl transferase to eliminate retinoid binding to opsin and thereby rendering the eye insensitive to light, rapid retinal degeneration occurred even in 3- to 4-week-old animals. This rapid degeneration suggests that nonpalmitoylated rod opsin is unstable. Treatment of 2-week-old Palm(-/-)Lrat(-/-) mice with an artificial chromophore precursor prevented this retinopathy. In contrast, elimination of signaling to G protein in Palm(-/-)Gnat1(-/-) mice had no effect, indicating that instability of unpalmitoylated opsin lacking chromophore rather than aberrant signal transduction resulted in retinal pathology. Together, these observations provide evidence for a structural role of rhodopsin S-palmitoylation that may apply to other GPCRs as well.
引用
收藏
页码:8428 / 8433
页数:6
相关论文
共 31 条
[1]   Palmitylation of cone opsins [J].
Ablonczy, Zsolt ;
Kono, Masahiro ;
Knapp, Daniel R. ;
Crouch, Rosalie K. .
VISION RESEARCH, 2006, 46 (27) :4493-4501
[2]   Pharmacological and rAAV gene therapy rescue of visual functions in a blind mouse model of leber congenital amaurosis [J].
Batten, ML ;
Imanishi, Y ;
Tu, DC ;
Doan, T ;
Zhu, L ;
Pang, JJ ;
Glushakova, L ;
Moise, AR ;
Baehr, W ;
Van Gelder, RN ;
Hauswirth, WW ;
Rieke, F ;
Palczewski, K .
PLOS MEDICINE, 2005, 2 (11) :1177-1189
[3]   Lecithin-retinol acyltransferase is essential for accumulation of all-trans-retinyl esters in the eye and in the liver [J].
Batten, ML ;
Imanishi, Y ;
Maeda, T ;
Tu, DC ;
Moise, AR ;
Bronson, D ;
Possin, D ;
Van Gelder, RN ;
Baehr, W ;
Palczewski, K .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (11) :10422-10432
[4]   Atomic-force microscopy: Rhodopsin dimers in native disc membranes [J].
Fotiadis, D ;
Liang, Y ;
Filipek, S ;
Saperstein, DA ;
Engel, A ;
Palczewski, K .
NATURE, 2003, 421 (6919) :127-128
[5]   Evidence for two apoptotic pathways in light-induced retinal degeneration [J].
Hao, WS ;
Wenzel, A ;
Obin, MS ;
Chen, CK ;
Brill, E ;
Krasnoperova, NV ;
Eversole-Cire, P ;
Kleyner, Y ;
Taylor, A ;
Simon, MI ;
Grimm, C ;
Remé, C ;
Remé, CE ;
Lem, J .
NATURE GENETICS, 2002, 32 (02) :254-260
[6]   Noninvasive two-photon imaging reveals retinyl ester storage structures in the eye [J].
Imanishi, Y ;
Batten, ML ;
Piston, DW ;
Baehr, W ;
Palczewski, K .
JOURNAL OF CELL BIOLOGY, 2004, 164 (03) :373-383
[7]   PALMITOYLATION OF BOVINE OPSIN AND ITS CYSTEINE MUTANTS IN COS CELLS [J].
KARNIK, SS ;
RIDGE, KD ;
BHATTACHARYA, S ;
KHORANA, HG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (01) :40-44
[8]   Retinopathy in mice induced by disrupted all-trans-retinal clearance [J].
Maeda, Akiko ;
Maeda, Tadao ;
Golczak, Marcin ;
Palczewski, Krzysztof .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (39) :26684-26693
[9]   Involvement of All-trans-retinal in Acute Light-induced Retinopathy of Mice [J].
Maeda, Akiko ;
Maeda, Tadao ;
Golczak, Marcin ;
Chou, Steven ;
Desai, Amar ;
Hoppel, Charles L. ;
Matsuyama, Shigemi ;
Palczewski, Krzysztof .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (22) :15173-15183
[10]   Loss of cone photoreceptors caused by chromophore depletion is partially prevented by the artificial chromophore pro-drug, 9-cis-retinyl acetate [J].
Maeda, Tadao ;
Cideciyan, Artur V. ;
Maeda, Akiko ;
Golczak, Marcin ;
Aleman, Tomas S. ;
Jacobson, Samuel G. ;
Palczewski, Krzysztof .
HUMAN MOLECULAR GENETICS, 2009, 18 (12) :2277-2287