Mechanisms of ATP Release from RBC's

红细胞释放 ATP 的机制

• 批准号: 7252563
• 负责人: RANDY SPRAGUE
• 金额: $ 31.23万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7252563
• 关键词: Adenylate Cyclase; Autacoids; Blood Circulation; Blood Flow Velocity; Blood Vessels; Blood flow; Caliber; Cell membrane; Cells; Charge; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Development; Erythrocytes; Exposure to; Failure; Figs - dietary; Funding; GTP-Binding Protein beta Subunits; GTP-Binding Proteins; Generations; Goals; Hematocrit procedure; Heterotrimeric G Protein Subunit; Heterotrimeric GTP-Binding Proteins; Human; Hypertension; Laboratories; Lead; Lung; Mechanics; Mediating; Metabolic; Microcirculatory Bed; Modeling; Nitric Oxide; Numbers; Oryctolagus cuniculus; Oxygen measurement, partial pressure, arterial; Participant; Pathway interactions; Physiological; Property; Protein Isoforms; Pulmonary Circulation; Purinoceptor; Rate; Regulation; Reporting; Research Design; Role; Series; Signal Transduction; Signal Transduction Pathway; Source; Stimulus; Tissues; Vascular Smooth Muscle; Vascular resistance; Vasodilation; Work; adenylyl cyclase 2; cell type; novel; response

DESCRIPTION (provided by applicant): The long-term objective of this laboratory is to define the role of the red blood cell (RBC) as a participant in the control of vascular resistance. Previously, we reported that, in the pulmonary circulation of the rabbit, RBCs of either rabbits or healthy humans were a required component of the perfusate in order to demonstrate flow-induced endogenous nitric oxide (NO) synthesis. This property of RBCs was found to reside in the ability of these cells to release ATP in response to a physiological stimulus (deformation). In this construct, as the RBC is deformed by the velocity of blood flow through a vessel and/or by reductions in vascular caliber, it releases ATP which stimulates endothelial NO synthesis resulting in an increase in vascular caliber. In addition to deformation, exposure of RBCs to reduced oxygen tension stimulates ATP release. It was proposed that, via this property, RBCs participate in the regulation of blood flow within a tissue such that blood flow is matched to metabolic need. ATP release from the RBC requires a specific release mechanism. We have demonstrated that a signal-transduction pathway that includes the cystic fibrosis transmembrane conductance regulator (CFTR), protein kinase A, adenylyl cyclase/cAMP and the heterotrimeric G proteins Gs and Gi is responsible for deformation-induced ATP release from rabbit and human RBCs. The overall goal of our work remains the definition of the contribution of the RBC to the local control of vascular caliber. The aims of the current proposal are to demonstrate that 1) mechanical deformation and exposure to reduced 02 stimulate a common signal-transduction pathway for ATP release, 2) decreases in cell deformability result in failure to release ATP in response to these stimuli, 3) RBCs of rabbits and humans posses adenylyl cyclase isoforms and G protein beta subunits that can interact resulting in cAMP generation, and 4) pharmacological agents and endogenous autacoids that activate heterotrimeric G proteins or stabilize RBC cAMP stimulate ATP release from RBCs of rabbit and healthy humans.

描述（由申请人提供）：该实验室的长期目标是将红细胞（RBC）的作用定义为控制血管抗性的参与者。以前，我们报道说，在兔子的肺循环中，兔子或健康人的RBC是灌注液的必需成分，以证明流动诱导的内源性一氧化氮（NO）合成。发现RBC的这种特性存在于这些细胞对生理刺激（变形）释放ATP的能力。在该构建体中，由于RBC通过血液流动的速度和/或血管口径减少而变形，因此它释放出ATP，从而刺激内皮无合成，从而导致血管口径的增加。除了变形外，RBC暴露于减少的氧气张力还会刺激ATP释放。有人提出，通过此特性，RBC参与组织内血流的调节，使血流与代谢需求相匹配。从RBC释放ATP需要特定的释放机制。我们已经证明，包括囊性纤维化跨膜电导调节剂（CFTR），蛋白激酶A，腺苷酸环化酶/CAMP和GI蛋白GS和GI的信号变形途径负责从Rabbit和Hulbbit和Human RBCS中释放ATP的ATP释放。我们工作的总体目标是RBC对局部控制血管口径的贡献的定义。 The aims of the current proposal are to demonstrate that 1) mechanical deformation and exposure to reduced 02 stimulate a common signal-transduction pathway for ATP release, 2) decreases in cell deformability result in failure to release ATP in response to these stimuli, 3) RBCs of rabbits and humans posses adenylyl cyclase isoforms and G protein beta subunits that can interact resulting in cAMP generation, and 4)激活异三聚体G蛋白或稳定RBC CAMP的药理学剂和内源性自闭症刺激兔子和健康人的RBC释放ATP。

项目成果

Rabbit erythrocytes release ATP and dilate skeletal muscle arterioles in the presence of reduced oxygen tension.

在氧张力降低的情况下，兔红细胞释放 ATP 并扩张骨骼肌小动脉。

• DOI: 10.1016/s1734-1140(09)70020-9
• 发表时间: 2009
• 期刊: Pharmacological reports : PR
• 作者: Sprague,RandyS;Hanson,MadelynS;Achilleus,David;Bowles,ElizabethA;Stephenson,AlanH;Sridharan,Meera;Adderley,Shaquria;Procknow,Jesse;Ellsworth,MaryL
• 通讯作者: Ellsworth,MaryL

NO inhibits signal transduction pathway for ATP release from erythrocytes via its action on heterotrimeric G protein Gi.

NO 通过作用于异源三聚体 G 蛋白 Gi 来抑制红细胞释放 ATP 的信号转导途径。

• DOI: 10.1152/ajpheart.00161.2004
• 发表时间: 2004
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Olearczyk,JeffreyJ;Stephenson,AlanH;Lonigro,AndrewJ;Sprague,RandyS
• 通讯作者: Sprague,RandyS

The Rho kinase inhibitor Y-27632 increases erythrocyte deformability and low oxygen tension-induced ATP release.

Rho 激酶抑制剂 Y-27632 增加红细胞变形性和低氧张力诱导的 ATP 释放。

• DOI: 10.1152/ajpheart.00603.2011
• 发表时间: 2011
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Thuet,KM;Bowles,EA;Ellsworth,ML;Sprague,RS;Stephenson,AH
• 通讯作者: Stephenson,AH

Inhibition of ATP release from erythrocytes: a role for EPACs and PKC.

红细胞 ATP 释放的抑制：EPAC 和 PKC 的作用。

• DOI: 10.1111/j.1549-8719.2010.00073.x
• 发表时间: 2011
• 期刊: Microcirculation (New York, N.Y. : 1994)
• 作者: Adderley,ShaquriaP;Sridharan,Meera;Bowles,ElizabethA;Stephenson,AlanH;Sprague,RandyS;Ellsworth,MaryL
• 通讯作者: Ellsworth,MaryL

Diamide decreases deformability of rabbit erythrocytes and attenuates low oxygen tension-induced ATP release.

Diamide 可降低兔红细胞的变形性并减弱低氧张力诱导的 ATP 释放。

• DOI: 10.1258/ebm.2010.010118
• 发表时间: 2010
• 期刊: Experimental biology and medicine (Maywood, N.J.)
• 作者: Sridharan,Meera;Sprague,RandyS;Adderley,ShaquriaP;Bowles,ElizabethA;Ellsworth,MaryL;Stephenson,AlanH
• 通讯作者: Stephenson,AlanH