The long term objectives of this project are to identify the proteins that form retinal gap junctions and to understand the molecular mechanisms of their regulation. Gap junctions, ubiquitous mediators of intercellular communication, play a prominent role in the visual system. Most types of retinal neurons are connected by gap junctions and their modulation during visual adaptation has profound effects on sensitivity and receptive field properties of many neurons and influences the path of signal flow in the mammalian rod circuit. At least two pathways are known to modulate certain retinal gap junctions: a dopamine/PKA and a nitric oxide/PKG pathway. In order to understand fully the regulation of retinal gap junctions, molecular characterization of the gap junction properties and their modulation is needed. We have cloned two perch retinal gap junction proteins, connexins (Cx) 35 and 34.7, which have defined the new gamma branch of the connexin gene family. These are the first connexins to be found primarily in retinal and brain neurons. We now plan to study how the gamma connexins contribute to the gap junctional properties observed in retinal neurons. The general strategy we will use is to identify characteristic molecular and biophysical properties of the connexins in isolated systems and relate them to properties of the gap junctions in the retina. The specific objectives of this proposal are (1) to identify the cells expressing each connexin; (2) to identify and characterize mammalian homologous of the gamma connexins; (3) to examine the differences in permeability properties of the closely related gamma connexins; and (4) to characterize the regulation of the connexins by protein kinases. A variety of biochemical, biophysical, and molecular techniques will be employed to achieve these goals. These studies will provide a detailed analysis of the regulation of this critical group of connexins that play a vital role in the retinal circuitry. The results will lay the groundwork for understanding defects in gap junctional coupling that may lead to neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012857-03
Application #
6498351
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Hunter, Chyren
Project Start
2000-02-01
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
3
Fiscal Year
2002
Total Cost
$225,354
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
O'Brien, John; Bloomfield, Stewart A (2018) Plasticity of Retinal Gap Junctions: Roles in Synaptic Physiology and Disease. Annu Rev Vis Sci 4:79-100
O'Brien, John (2017) Design principles of electrical synaptic plasticity. Neurosci Lett :
Yoshikawa, Shunichi; Vila, Alejandro; Segelken, Jasmin et al. (2017) Zebrafish connexin 79.8 (Gja8a): A lens connexin used as an electrical synapse in some neurons. Dev Neurobiol 77:548-561
Miller, Adam C; Whitebirch, Alex C; Shah, Arish N et al. (2017) A genetic basis for molecular asymmetry at vertebrate electrical synapses. Elife 6:
Vila, Alejandro; Whitaker, Christopher M; O'Brien, John (2017) Membrane-associated guanylate kinase scaffolds organize a horizontal cell synaptic complex restricted to invaginating contacts with photoreceptors. J Comp Neurol 525:850-867
Curti, Sebastian; O'Brien, John (2016) Characteristics and plasticity of electrical synaptic transmission. BMC Cell Biol 17 Suppl 1:13
Sun, Kaiqi; Zhang, Yujin; D'Alessandro, Angelo et al. (2016) Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia. Nat Commun 7:12086
Rash, J E; Kamasawa, N; Vanderpool, K G et al. (2015) Heterotypic gap junctions at glutamatergic mixed synapses are abundant in goldfish brain. Neuroscience 285:166-93
Wang, Helen Yanran; Lin, Ya-Ping; Mitchell, Cheryl K et al. (2015) Two-color fluorescent analysis of connexin 36 turnover: relationship to functional plasticity. J Cell Sci 128:3888-97
Zhang, Zhijing; Li, Hongyan; Liu, Xiaoqin et al. (2015) Circadian clock control of connexin36 phosphorylation in retinal photoreceptors of the CBA/CaJ mouse strain. Vis Neurosci 32:E009

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