TRP channels in supramolecular complexes with Inorganic Polyphosphate and Polyhyd

无机多磷酸盐和多羟基化合物超分子复合物中的 TRP 通道

基本信息

批准号：
8505506
负责人：
Eleonora Zakharian
金额：
$ 29.24万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8505506
关键词：
Afferent Neurons Agonist Amino Acids Binding Binding Sites Biochemical Calcium Channel Cations Complex Data Development Disease Drug Design Electrophysiology (science)Enzymatic Biochemistry Enzymes Esthesia Excision Fluorescence Spectroscopy Goals Hydrolysis Image Ion Channel Ions Ligand Binding Membrane Membrane Proteins Menthol Methods Modeling Modification Molecular Molecular Biology Molecular Chaperones Molecular Genetics Nature Neurons Pathologic Processes Pathway interactions Peripheral Nervous System Physiological Physiological Processes Play Polyesters Polymers Polyphosphates Polyps Property Proteins Regulation Research Role Site-Directed Mutagenesis Spectrum Analysis Stimulus Structure Techniques Temperature Testing base beta-Hydroxybutyrate cold temperature insight member novel patch clamp porin receptor response sensor tool voltage

项目摘要

DESCRIPTION (provided by applicant): TRPM8 channels in supramolecular complexes with Inorganic Polyphosphate and Polyhydroxybutyrate The main objective of this proposal is to understand the nature, function and mechanism of TRP channels in supramolecular complexes. TRP channels are calcium-permeable cation channels that play significant roles in a great variety of physiological and pathological processes. In this project we will focus on studying one of the members of melastatin subfamily TRP channels, TRPM8. The cold and menthol receptor, TRPM8, expressed in sensory neurons and is involved in the pathway of thermosensation. The activity of TRPM8 channels is regulated by a variety of factors, including cool temperatures, ligand binding, voltage, pH, etc. reflecting diverse stimuli and mechanisms of these regulators. We propose that such a diversity of stimuli and mechanisms of these channels can be explained by the complexity of the TRPM8 protein itself. In our preliminary results we reveal that TRPM8 is associated with inorganic polyphosphate (polyP) and polyhydroxybutyrate (PHB), and furthermore this complex modifies functional properties of the channel. PolyP and PHB are ubiquitous homopolymers that possess important molecular properties in the formation of the simplest model of ion channel. The polyP/PHB complexes have been found in association with a number of membrane proteins, including ion channels and porins. Moreover, these complexes were shown to be important for normal functioning of their hosts. Here we postulate that TRPM8 exists in a supramolecular complex with polyP and PHB and that such an ensemble might be a common feature of other TRP channels. To test this hypothesis we will apply biochemical and biophysical analysis, electrophysiology, enzymology, molecular genetics, molecular spectroscopy and fluorescence spectroscopy methods. The specific aims of this proposal are: (I) assess the association of polyhydroxybutyrate with TRPM8 and role of the polyester in temperature sensation of TRPM8; (II) examine the physiological role of inorganic polyphosphate in TRPM8 channel function. The proposed study will open new directions and insights on TRP channels as supramolecular complexes and it will be of an immense importance for understanding of the molecular mechanisms for such interactions and their regulation in the function of these channels during physiological and pathological processes.

描述（由申请人提供）：具有无机多磷酸盐和多羟基丁酸超分子复合物中的TRPM8通道。该提案的主要目标是了解超分子复合物中TRP通道的性质，功能和机制。 TRP通道是钙渗透的阳离子通道，在各种生理和病理过程中起着重要作用。在这个项目中，我们将专注于研究Melastatin亚家族TRP通道TRPM8的一名成员。冷和薄荷醇受体TRPM8在感觉神经元中表达，并参与热效率的途径。 TRPM8通道的活性受多种因素的调节，包括凉爽的温度，配体结合，电压，pH等。反映了这些调节剂的各种刺激和机制。我们建议，可以通过TRPM8蛋白本身的复杂性来解释这些通道的这种刺激和机制。在我们的初步结果中，我们揭示了TRPM8与无机多磷酸盐（息肉）和多羟基丁酸（PHB）有关，并且此复合物还修饰了通道的功能性能。息肉和PHB是无处不在的均聚物，在最简单的离子通道模型的形成中具有重要的分子特性。已经发现了与许多膜蛋白（包括离子通道和孔蛋白）相关的息肉/PHB复合物。此外，这些复合物被证明对于宿主的正常功能很重要。在这里，我们假设TRPM8存在于具有息肉和PHB的超分子复合物中，并且这种合奏可能是其他TRP通道的共同特征。为了检验该假设，我们将采用生化和生物物理分析，电生理学，酶学，分子遗传学，分子光谱和荧光光谱法。该提案的具体目的是：（i）评估多羟基丁酸与TRPM8的关联以及聚酯在TRPM8温度感觉中的作用；（ii）检查无机多磷酸在TRPM8通道功能中的生理作用。拟议的研究将作为超分子复合物开放新的方向和见解，对于理解这种相互作用的分子机制及其在生理和病理过程中这些通道功能中的调节非常重要。