Abstract

To investigate the molecular events that regulate visual adaptation, mouse genetics will be used to target specific components of phototransduction. Electrophysiological measurements of the photoreceptors from these genetically-engineered mice will be used to study the role of particular components under in vivo conditions and under real-time kinetics. Biochemical assays will be used in conjunction with these measurements to delineate the molecular mechanisms behind the physiologic phenotypes. Using this multi-disciplinary approach, the investigator proposes: (1) to systematically remove the known Ca2+-feedback loops by targeted disruption of Ca2+ binding proteins that are thought to mediate the feedback; and (2) to eliminate regulation by Ca2+-calmodulin on the cyclic GMP (cGMP)-gated channel, using mice harboring a target mutation on the beta-subunit of the cGMP-gated channel that disrupts the overall adaptation process, and assess the role of Ca2+-feedback in regulating visual adaptation. Further studies will investigate the recovery mechanisms involving guanylate cyclases (GCs) and guanylate cyclase activating proteins (GCAPs) in rod photoreceptor response. Finally, the relationship between elevated cGMP and photoreceptor cell-death will be investigated.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012703-02
Application #
6179294
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Mariani, Andrew P
Project Start
1999-09-17
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$323,866
Indirect Cost

  Institution

Name
University of Southern California
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089

  Publications

Sakurai, Keisuke; Chen, Jeannie; Khani, Shahrokh C et al. (2015) Regulation of mammalian cone phototransduction by recoverin and rhodopsin kinase. J Biol Chem 290:9239-50
Sakurai, Keisuke; Chen, Jeannie; Kefalov, Vladimir J (2011) Role of guanylyl cyclase modulation in mouse cone phototransduction. J Neurosci 31:7991-8000
Chen, Jeannie; Woodruff, Michael L; Wang, Tian et al. (2010) Channel modulation and the mechanism of light adaptation in mouse rods. J Neurosci 30:16232-40
Nair, K Saidas; Hanson, Susan M; Mendez, Ana et al. (2005) Light-dependent redistribution of arrestin in vertebrate rods is an energy-independent process governed by protein-protein interactions. Neuron 46:555-67
Sampath, Alapakkam P; Strissel, Katherine J; Elias, Rajesh et al. (2005) Recoverin improves rod-mediated vision by enhancing signal transmission in the mouse retina. Neuron 46:413-20
Makino, Clint L; Dodd, R L; Chen, J et al. (2004) Recoverin regulates light-dependent phosphodiesterase activity in retinal rods. J Gen Physiol 123:729-41
Mendez, Ana; Lem, Janis; Simon, Melvin et al. (2003) Light-dependent translocation of arrestin in the absence of rhodopsin phosphorylation and transducin signaling. J Neurosci 23:3124-9
Burns, Marie E; Mendez, Ana; Chen, Jeannie et al. (2002) Dynamics of cyclic GMP synthesis in retinal rods. Neuron 36:81-91
Mendez, Ana; Chen, Jeannie (2002) Mouse models to study GCAP functions in intact photoreceptors. Adv Exp Med Biol 514:361-88
Mendez, A; Burns, M E; Sokal, I et al. (2001) Role of guanylate cyclase-activating proteins (GCAPs) in setting the flash sensitivity of rod photoreceptors. Proc Natl Acad Sci U S A 98:9948-53

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