Allosteric Modulation of HCN Channels
HCN 通道的变构调制
基本信息
- 批准号:10689299
- 负责人:
- 金额:$ 43.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffinityBindingBiophysical ProcessBladderCardiacCell physiologyCellsCharacteristicsChemosensitizationClosure by clampCo-ImmunoprecipitationsColonCouplingCyclic AMPCyclic NucleotidesCytoplasmic TailDataDependenceDetectionDevelopmentDrug TargetingElectrophysiology (science)EpilepsyFDA approvedFluorescenceFutureGoalsGuanylate kinaseHCN1 geneHCN4 geneHeart failureInositolIntegral Membrane ProteinInterstitial Cell of CajalLymphoidMeasuresMembraneMembrane PotentialsMembrane ProteinsMental DepressionModelingMolecularMolecular ConformationMolecular Sieve ChromatographyMuscle CellsNeurogenic BladderNeuronsPacemakersPeripheralPharmaceutical PreparationsPhysiologicalPhysiologyPropertyProtein IsoformsProteinsRegulationRoleSensorySignal PathwaySinoatrial NodeSiteSpecificitySubstrate InteractionSystemTestingcell typeexperimental studygain of functiongastrointestinalimprovedinhibitorinnovationinorganic phosphateinsightivabradineloss of functionmotility disordernew therapeutic targetnodal myocytenovelnovel therapeuticspainful neuropathypatch clamptargeted treatmentvoltagevoltage gated channel
项目摘要
PROJECT SUMMARY
Hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels are critical determinants of
membrane potential and excitability in many types of cells throughout the body, including cardiac pacemaker
cells, central and peripheral neurons, many types of sensory cells, and interstitial cells of Cajal in the colon and
bladder. Consistent with this widespread distribution, HCN channels have been identified as potential drug
targets for treatment of a long list of conditions including angina, heart failure, epilepsy, neuropathic pain,
depression, gastrointestinal dysmotility, and neurogenic bladder. However, the single FDA-approved HCN
channel drug (ivabradine) is limited, owing in part to its non-selective block of all four mammalian HCN
channels isoforms and its off-target block of Kv11.1 (hERG), Nav1.5, and Cav1.2 channels. The need for new,
isoform-specific HCN channel activators and inhibitors has been widely recognized but the lack of information
about allosteric and isoform-specific regulation of HCN channels is a roadblock to the development of novel
therapeutics.
The long-term goals of this project are to identify naturally-occurring, allosteric regulators of HCN channels
and to understand their mechanisms of action. Achieving these goals will advance understanding of the
physiological and molecular functions of HCN channels and aid in the development of new HCN channel
drugs. The current proposal focuses on our exciting discovery of LRMP and IRAG as two novel, isoform-
specific protein interaction partners of HCN4 channels. LRMP and IRAG are homologous ER transmembrane
proteins that have large cytoplasmic domains. Importantly, LRMP and IRAG only modulate the HCN4 isoform.
Moreover, the two proteins have opposing effects on HCN4: LRMP causes a loss-of-function (LOF) by
decreasing the canonical depolarizing shift in voltage-dependence induced by cAMP while IRAG causes gain-
of-function (GOF) by shifting the basal voltage dependence of HCN4 to more positive potentials. Preliminary
data establish that IRAG is co-expressed with HCN4 in cardiac pacemaker cells. Proposed aims will identify
interaction sites on the three proteins, determine the molecular mechanisms for the distinct and isoform-
specific effects, and evaluate their role in pacemaker cells.
项目总结
超极化激活的环核苷酸敏感(HCN)通道是
全身多种细胞的膜电位和兴奋性,包括心脏起搏器
细胞、中枢和外周神经元、多种感觉细胞和Cajal间质细胞。
膀胱。与这种广泛的分布一致,hcn通道已被确定为潜在的药物。
治疗一系列疾病的目标,包括心绞痛、心力衰竭、癫痫、神经性疼痛、
抑郁、胃肠动力障碍和神经性膀胱。然而,FDA批准的单一HCN
通道药物(伊夫拉定)是有限的,部分原因是它对所有四种哺乳动物的HCN都没有选择性阻断
Kv11.1(HERG)、NaV1.5和Cav1.2通道的通道异构体及其脱靶阻断。对新的、
异构体特异性HCN通道激活剂和抑制剂已被广泛认识,但缺乏信息
关于HCN通道的变构和异构体特异性调节是新药开发的障碍
治疗学。
该项目的长期目标是确定HCN通道的自然发生的变构调节因子
并了解它们的作用机制。实现这些目标将促进对
HCN通道的生理和分子功能及其对新的HCN通道的作用
毒品。目前的提议集中在我们令人兴奋的发现LRMP和IRAG作为两个新的,异构体-
HCN4通道的特异性蛋白质相互作用伙伴。LRMP和IRAG是同源的内质网跨膜
具有大的细胞质结构域的蛋白质。重要的是,LRMP和IRAG只调节HCN4亚型。
此外,这两种蛋白质对HCN4有相反的作用:LRMP通过以下途径导致功能丧失(LOF)
减少cAMP引起的电压依赖的典型去极化漂移,而IRAG引起增益-
通过将HCN4的基础电压依赖转移到更多的正电位来实现功能(GOF)。初步
数据表明,在心脏起搏细胞中,IRAG与HCN4共表达。建议的目标将确定
这三种蛋白质上的相互作用部位,决定了不同和异构体的分子机制。
并评估它们在起搏器细胞中的作用。
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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CATHERINE PROENZA其他文献
CATHERINE PROENZA的其他文献
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{{ truncateString('CATHERINE PROENZA', 18)}}的其他基金
Ion Channels in Context: Structure and function in native cells and macromolecular complexes
上下文中的离子通道:天然细胞和大分子复合物的结构和功能
- 批准号:
10467403 - 财政年份:2022
- 资助金额:
$ 43.23万 - 项目类别:
Regulation of excitability in sinoatrial myocytes
窦房肌细胞兴奋性的调节
- 批准号:
10656412 - 财政年份:2008
- 资助金额:
$ 43.23万 - 项目类别:
Function and Regulation of HCN Channels in Sinoatrial Myocytes
窦房肌细胞HCN通道的功能和调控
- 批准号:
7763879 - 财政年份:2008
- 资助金额:
$ 43.23万 - 项目类别:
Function and Regulation of HCN Channels in Sinoatrial Myocytes
窦房肌细胞HCN通道的功能和调控
- 批准号:
7380345 - 财政年份:2008
- 资助金额:
$ 43.23万 - 项目类别:
Function and Regulation of HCN Channels in Sinoatrial Myocytes
窦房肌细胞HCN通道的功能和调控
- 批准号:
8206603 - 财政年份:2008
- 资助金额:
$ 43.23万 - 项目类别:
Function and Regulation of HCN Channels in Sinoatrial Myocytes
窦房肌细胞HCN通道的功能和调控
- 批准号:
8887663 - 财政年份:2008
- 资助金额:
$ 43.23万 - 项目类别:
Function and Regulation of HCN Channels in Sinoatrial Myocytes
窦房肌细胞HCN通道的功能和调控
- 批准号:
7554620 - 财政年份:2008
- 资助金额:
$ 43.23万 - 项目类别:
Regulation of excitability in sinoatrial myocytes
窦房肌细胞兴奋性的调节
- 批准号:
10474956 - 财政年份:2008
- 资助金额:
$ 43.23万 - 项目类别:
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