Molecular mechanisms of retinal ON-bipolar cell signaling
视网膜ON-双极细胞信号传导的分子机制
基本信息
- 批准号:10087938
- 负责人:
- 金额:$ 50.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAfferent NeuronsAmacrine CellsCationsCell physiologyCellsCoupledDark AdaptationDataDendritesDetectionDiglyceridesDiseaseDrug TargetingElectrophysiology (science)ElectroretinographyExposure toFoundationsFrequenciesG-Protein Signaling PathwayG-Protein-Coupled ReceptorsGRM5 geneGRM6 geneGTP-Binding Protein alpha Subunits, GsGenesGeneticGlutamatesGoalsHealthImageKnockout MiceKnowledgeLightLightingMass Spectrum AnalysisMeasuresMediatingMembraneMolecularMusMutationNeuronsNight BlindnessOutputPRKCA genePathway interactionsPharmacologyPhospholipase CPhosphorylationPhotonsPhotoreceptorsPlayPotassium ChannelPresynaptic TerminalsProcessProductionPropertyProteinsPublishingRecoveryRegulationResearchRetinaRetinal ConeRodRoleSignal PathwaySignal TransductionSignaling ProteinSiteStimulusSynapsesSystemTRPM1 geneTestingVertebratesVisionVisualVisual impairmentVisual system structureWorkbasecell typeforestganglion cellhuman modellight intensitylight transmissionmouse modelnervous system disordernovelpatch clampprotein functionreceptorresponseretinal neuronretinal rodssensory systemside effecttargeted agentvirtual
项目摘要
The retina is exposed to light intensities that vary over nine orders of magnitude, from a cloudy night in a
forest to a sunny day on a snowy mountainside, and to images of varying contrast and frequency. To optimize
vision over this entire range, the response properties of the retina change as a function of the stimuli at both
the cellular and network level, a process termed adaptation. The long-term goal of the proposed research is
to explain the molecular basis for regulation of the light response in retinal ON-bipolar cells. These
cells mediate the transmission of light responses between photoreceptors and ganglion cells and are key sites
of adaptation. Rod bipolar cells receive light-driven synaptic input from rod photoreceptors and drive retinal
output via synapses onto AII amacrine cells. While dark-adapted rod bipolar cells can transmit single photon
responses in starlight, they are also able to transmit contrast changes in moderate background light. The
mechanisms which optimize rod bipolar cell function under different lighting conditions remain unknown. Our
recent work suggests that a novel mGlu5-based pathway operating in parallel to the primary light-response
pathway may modulate the ON-bipolar cell responses. Further, we have identified a potassium channel,
Kv11.1, that appears to regulate dark adaptation, and may be regulated by PKCα, which is abundantly
expressed in rod bipolar cells.
In the dark, photoreceptors release glutamate onto dendrites of ON-bipolar cells, and decrease glutamate
release in response to light stimuli. The light response of ON-bipolar cells is mediated by a unique, sign-
inverting pathway initiated by mGlu6, a G protein-coupled receptor in the ON-bipolar cell dendrites. In the dark,
tonic activation of the mGlu6 pathway maintains the TRPM1 cation channel in a closed state. In response to
light stimuli, mGlu6 is inactivated, allowing TRPM1 channels to open and depolarize the cell. The mGlu6-
TRPM1 pathway is conserved in all vertebrates, and mutations in mGlu6 and TRPM1 cause congenital
stationary night blindness (CSNB) in humans and mouse models. Despite its central importance in vision,
the molecular mechanisms by which the primary excitatory pathway is modulated under different
conditions remain unknown. Based on analogy with other systems, and our Preliminary Studies, we
hypothesize that mGlu5 receptors, Kv11.1 channels and PKCα modulate the output of the mGlu6-TRPM1
pathway.
视网膜暴露在光强度变化超过九个数量级,从多云的夜晚,
从森林到白雪皑皑的山坡上的阳光明媚的一天,以及不同对比度和频率的图像。优化
在整个范围内的视觉,视网膜的响应特性作为两个刺激的函数而变化。
蜂窝和网络级,这一过程称为自适应。拟议研究的长期目标是
解释视网膜ON双极细胞光反应调节的分子基础。这些
细胞介导光感受器和神经节细胞之间的光反应传递,
适应性。视杆双极细胞接受来自视杆光感受器的光驱动突触输入,
通过突触输出到AII无长突细胞。而暗适应的视杆细胞双极细胞可以传输单光子
虽然它们在星光下的响应很小,但它们也能够在中等背景光下传输对比度变化。的
在不同光照条件下优化视杆双极细胞功能的机制仍然未知。我们
最近的研究表明,一种新的mGlu 5为基础的途径平行于初级光反应,
信号通路可以调节ON-双极细胞的反应。此外,我们还发现了一个钾通道,
Kv11.1,它似乎调节暗适应,并可能受到PKCα的调节,而PKCα在暗适应中大量表达。
在视杆双极细胞中表达。
在黑暗中,光感受器将谷氨酸释放到ON双极细胞的树突上,并减少谷氨酸
对光刺激的反应释放。ON双极细胞的光反应是由一个独特的信号介导的,
反转途径启动mGlu 6,G蛋白偶联受体在ON双极细胞树突。在黑暗中,
mGlu 6通路的紧张性激活使TRPM 1阳离子通道保持在关闭状态。响应于
在光刺激下,mGlu 6失活,允许TRPM 1通道打开并使细胞去活化。mGlu6-
TRPM 1通路在所有脊椎动物中是保守的,mGlu 6和TRPM 1的突变导致先天性
静止性夜盲症(CSNB)在人类和小鼠模型。尽管它在视觉上至关重要,
在不同的条件下,初级兴奋性通路被调节的分子机制
情况仍然不明。根据与其他系统的类比和我们的初步研究,我们
假设mGlu 5受体、Kv11.1通道和PKCα调节mGlu 6-TRPM 1的输出,
通路
项目成果
期刊论文数量(0)
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会议论文数量(0)
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ROBERT M DUVOISIN其他文献
ROBERT M DUVOISIN的其他文献
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{{ truncateString('ROBERT M DUVOISIN', 18)}}的其他基金
Melanoma-associated retinopathy: detection and mechanisms
黑色素瘤相关视网膜病变:检测和机制
- 批准号:
10404956 - 财政年份:2020
- 资助金额:
$ 50.57万 - 项目类别:
Melanoma-associated retinopathy: detection and mechanisms
黑色素瘤相关视网膜病变:检测和机制
- 批准号:
10197934 - 财政年份:2020
- 资助金额:
$ 50.57万 - 项目类别:
Melanoma-associated retinopathy: detection and mechanisms
黑色素瘤相关视网膜病变:检测和机制
- 批准号:
10617761 - 财政年份:2020
- 资助金额:
$ 50.57万 - 项目类别:
Molecular mechanisms of retinal ON-bipolar cell signaling
视网膜ON-双极细胞信号传导的分子机制
- 批准号:
10596061 - 财政年份:2019
- 资助金额:
$ 50.57万 - 项目类别:
Molecular mechanisms of retinal ON-bipolar cell signaling
视网膜ON-双极细胞信号传导的分子机制
- 批准号:
10334420 - 财政年份:2019
- 资助金额:
$ 50.57万 - 项目类别:
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