Modulation of Visual Transduction and Retinal Disease by Bicarbonate
碳酸氢盐对视觉传导和视网膜疾病的调节
基本信息
- 批准号:9253640
- 负责人:
- 金额:$ 33.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-30 至 2018-08-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
SUMMARY
Retinal rods and cones signal the presence of light by hydrolyzing cGMP which then closes cyclic
nucleotide gated cation channels in the plasma membrane. An inward Na+ current is interrupted and the cell
hyperpolarizes. It has been shown that bicarbonate can increase the flash response amplitude and quicken
response kinetics. However, many features of this modulation are not understood including: the full
magnitudes of the effects, the dose-response relations, the intra-retinal sources of bicarbonate for
photoreceptors, the pathway(s) for access of bicarbonate to the outer segment, differences between rods
and cones, and the mechanism of bicarbonate action. Using single cell recording and biochemical assays,
we will tackle each of these issues. Rods have an anion exchanger in their outer segments that normally
extrudes bicarbonate. But by removing extracellular Cl-, we can force the anion exchanger in rod outer
segments to take up bicarbonate. We will then describe how bicarbonate affects the amplitude and kinetics
of both bright flash and dim flash responses in single cell recordings of membrane current. The bright,
saturating flash response provides a measure of the circulating current. Responses kinetics vary with flash
strength but become invariant with very low flash strengths, so the dim flash response is useful for analysis
of response kinetics. To find out how bicarbonate normally accesses the rod outer segment when
extracellular Cl- is present, we will change the recording configuration: outer segment inside the pipette vs
inner segment inside the pipette, isolated rod vs rods attached to a piece of retina. We will explore
endogenous bicarbonate modulation of phototransduction in cones by applying a carbonic anhydrase
inhibitor while recording from isolated cones and cones attached to pieces of retina and begin to elucidate
conditions in which dynamic modulation comes into play. To fully characterize the effects of bicarbonate on
cones for comparison to results from rods, we will carry out experiments with exogenous bicarbonate,
similar to those proposed for rods except that a carbonic anhydrase will be present. In elucidating the
mechanism of bicarbonate, we will consider three targets: guanylate cyclase, PDE, cyclic nucleotide gated
channel. The first two targets will be evaluated in biochemical assays, while the third will be tested in
excised membrane patch recordings. Some evidence already suggests that bicarbonate stimulates ROS-
GC1 activity. It then becomes important to find out whether ROS-GC2 is similarly affected, to define the
bicarbonate binding site of each ROS-GC, and to determine the calcium dependence of bicarbonate
stimulation when the calcium sensing subunits GCAPs and S100B are bound to ROS-GCs. A long term
goal is to dissect the molecular mechanisms that shape the photon response under light and dark adapted
conditions and to understand their roles, be it causative or modulatory, in retinal disease.
总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('CLINT L MAKINO', 18)}}的其他基金
Rod outer segment structure: determinants and its effect on the photon response
杆外段结构:决定因素及其对光子响应的影响
- 批准号:
10562765 - 财政年份:2022
- 资助金额:
$ 33.86万 - 项目类别:
Rod outer segment structure: determinants and its effect on the photon response
杆外段结构:决定因素及其对光子响应的影响
- 批准号:
10445270 - 财政年份:2020
- 资助金额:
$ 33.86万 - 项目类别:
Rod outer segment structure: determinants and its effect on the photon response
杆外段结构:决定因素及其对光子响应的影响
- 批准号:
10238092 - 财政年份:2020
- 资助金额:
$ 33.86万 - 项目类别:
Rod outer segment structure: determinants and its effect on the photon response
杆外段结构:决定因素及其对光子响应的影响
- 批准号:
10650776 - 财政年份:2020
- 资助金额:
$ 33.86万 - 项目类别:
Rod outer segment structure: determinants and its effect on the photon response
杆外段结构:决定因素及其对光子响应的影响
- 批准号:
10033593 - 财政年份:2020
- 资助金额:
$ 33.86万 - 项目类别:
Modulation of Visual Transduction and Retinal Disease by Bicarbonate
碳酸氢盐对视觉传导和视网膜疾病的调节
- 批准号:
8759813 - 财政年份:2014
- 资助金额:
$ 33.86万 - 项目类别:
Modulation of Visual Transduction and Retinal Disease by Bicarbonate
碳酸氢盐对视觉传导和视网膜疾病的调节
- 批准号:
9123637 - 财政年份:2014
- 资助金额:
$ 33.86万 - 项目类别:
Light Adaptation in Vertebrate Rod Photoreceptors
脊椎动物杆状感光器的光适应
- 批准号:
6635691 - 财政年份:2001
- 资助金额:
$ 33.86万 - 项目类别:
Light Adaptation in Vertebrate Rod Photoreceptors
脊椎动物杆状感光器的光适应
- 批准号:
6741883 - 财政年份:2001
- 资助金额:
$ 33.86万 - 项目类别:
Light Adaptation in Vertebrate Rod Photoreceptors
脊椎动物杆状感光器的光适应
- 批准号:
6518667 - 财政年份:2001
- 资助金额:
$ 33.86万 - 项目类别:
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