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Cell Physiology of Na,K-ATPase

Na,K-ATP酶的细胞生理学

基本信息

批准号：
8878545
负责人：
CRAIG GATTO
金额：
$ 34.8万
依托单位：
ILLINOIS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878545
关键词：
Address Amino Acids Arrhythmia Biochemistry Biological Biology Calcium Calcium Signaling Cardiac Cardiac Glycosides Cell Nucleus Cell Surface Receptors Cell membrane Cell physiology Cells Confocal Microscopy Congestive Heart Failure Coupled Cytoplasm Data Data Analyses Digitalis preparation Doctor of Philosophy Electrolyte Balance Endoplasmic Reticulum Enzymes Epileptogenesis Epithelial Cells Etiology Eukaryota Event Excision Familial Hemiplegic Migraine Fluid Balance Foundations Glucose Goals Homeostasis Hypertension Impaired Renal Function Integral Membrane Protein Intestines Intracellular Membranes Investigation Journals Kidney Laboratories Learning Link Location Manuscripts Mediating Membrane Mentors Methods Molecular Biology Muscle Na(+)-K(+)-Exchanging ATPase Nerve Neurons Nuclear Nuclear Envelope Nucleoplasm Nutrient Patients Physiological Physiology Play Polycystic Kidney Diseases Progress Reports Protein Isoforms Proteins Pump Regulation Reporting Research Role Scientist Signal Transduction Signaling Molecule Site Sodium Students System Testing Time Transmembrane Transport Work Writing abstracting basolateral membrane clinically relevant design improved meetings novel public health relevance research study solute trafficking uptake

项目摘要

DESCRIPTION (provided by applicant): The sodium-potassium adenosine triphosphatase (i.e. Na,K-ATPase) is responsible for controlling cellular fluid and electrolyte balance in higher eukaryotes. The Na,K-ATPase is a heterodimeric integral membrane protein consisting a catalytic α -subunit (~1000 amino acids) and a glycosylated β -subunit (~300 amino acids). During some physiological states, this single enzyme is responsible for utilizing nearly 40% of the cells energy. In kidney and intestinal epithelial cells the Na,K-ATPase is strictly delivered t the basolateral membrane providing directional uptake of Na and other solutes (e.g. glucose, amino acids). Recently, several laboratories have reported that in addition to solute transport, the Na,K- ATPase is a cell-surface receptor for cardiac glycoside-mediating Src signaling. Some of these alternative physiological roles of the Na,K-ATPase mandate that the enzyme be delivered to specific sub- plasma membrane pools, which raises as yet unaddressed questions pertaining to Na,K-ATP maturation and membrane targeting. The planned experiments in this proposal will focus on the cell physiological roles of Na,K-ATPase, focusing on a novel intracellular physiological function. Our previous work revealed for the first time that the Na pump is completely functional once assembled within the endoplasmic reticulum. However, the potential physiological role of this intracellular activity remained a mystery. Now recent evidence has emerged demonstrating that the Na/Ca exchanger plays a role in nuclear calcium homeostasis in some cells which immediately suggests that there must be a sodium concentration gradient across the nuclear envelope to drive this secondary active transporter. In this application, we focus on demonstrating that this intracellular [Na+] gradient is established and maintained by the Na,K-ATPase functioning intracellularly. Indeed, we provide preliminary data showing that the Na,K-ATPase resides within the nuclear envelope in HEK-293 cells and is catalytically active in this membrane. The specific aims addressed in this proposal will provide important new information about Na,K-ATPase and provide the foundation for a new avenue of investigation regarding intracellular membrane transport to regulate nucleoplasmic Ca2+ signaling. These aims are: 1) Determine the biology fo intracellular Na,K-ATPase and its nuclear function, 2)Define intracellularly, the physical interactions between Na,K-ATPase and Na,Ca Eachanger and their functional consequences, and 3) Elucidate novel cellular mechanisms that target and retain Na,K-ATPase in the nuclear envelope. We will combine molecular biology, cell physiology, biochemistry, and confocal microscopy to accomplish our scientific goals. The Na,K-ATPase is the pharmacological target for cardiac glycosides, a therapy for congestive heart failure and arrhythmias. Considering the mounting evidence that cellular distribution of Na,K- ATPase plays a key role in its physiology, the work proposed here will be crucial to understanding and resolving the etiology of clinically relevant problems. Specifically, disregulation of the Na,K-ATPase has been attributed to hypertension, congestive heart failure, familial hemiplegic migraine, epileptogenesis, and polycystic kidney disease.

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Broad substrate specificity of phosphotransbutyrylase from Listeria monocytogenes: A potential participant in an alternative pathway for provision of acyl CoA precursors for fatty acid biosynthesis.

DOI：
10.1016/j.bbalip.2016.06.003
发表时间：
2016-09
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Sirobhushanam S;Galva C;Sen S;Wilkinson BJ;Gatto C
通讯作者：
Gatto C

NO control: nitric oxide directly regulates substrate delivery to NOS. Focus on "Nitric oxide can acutely modulate its biosynthesis through a negative feedback mechanism on L-arginine transport in cardiac myocytes".

NO 控制：一氧化氮直接调节底物向 NOS 的输送。

DOI：
10.1152/ajpcell.00191.2010
发表时间：
2010
期刊：
American journal of physiology. Cell physiology
影响因子：
0
作者：
Gatto,Craig
通讯作者：
Gatto,Craig

On the effect of hyperaldosteronism-inducing mutations in Na/K pumps.

DOI：
10.1085/jgp.201711827
发表时间：
2017-11-06
期刊：
The Journal of general physiology
影响因子：
0
作者：
Meyer DJ;Gatto C;Artigas P
通讯作者：
Artigas P

Interrelationships between Fatty Acid Composition, Staphyloxanthin Content, Fluidity, and Carbon Flow in the Staphylococcus aureus Membrane.

DOI：
10.3390/molecules23051201
发表时间：
2018-05-17
期刊：
Molecules (Basel, Switzerland)
影响因子：
0
作者：
Tiwari KB;Gatto C;Wilkinson BJ
通讯作者：
Wilkinson BJ

Utilization of multiple substrates by butyrate kinase from Listeria monocytogenes.

单核细胞增生李斯特菌丁酸激酶利用多种底物。

DOI：
10.1016/j.bbalip.2016.12.001
发表时间：
2017
期刊：
Biochimica et biophysica acta. Molecular and cell biology of lipids
影响因子：
0
作者：
Sirobhushanam,Sirisha;Galva,Charitha;Saunders,LaurenP;Sen,Suranjana;Jayaswal,Radheshyam;Wilkinson,BrianJ;Gatto,Craig
通讯作者：
Gatto,Craig