COMPARISON BETA2 VS BETA1 ADRENOCEPTOR STIMULATION IN RAT CARDIOCYTE STIMULATION

大鼠心肌细胞刺激中BETA2 与BETA1 肾上腺素受体刺激的比较

• 批准号: 3745465
• 负责人: R P XIAO
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3745465
• 关键词: action potentials; adenylate cyclase; beta adrenergic receptor; beta antiadrenergic agent; biological signal transduction; calcium channel; calcium flux; calcium indicator; cyclic AMP; evoked potentials; heart cell; heart contraction; heart pharmacology; laboratory rat; membrane potentials; myocardium; phosphorylation; prostaglandins; sarcoplasmic reticulum; single cell analysis; stimulant /agonist; voltage /patch clamp

The beta-adrenergic receptor mediated modulation of myocardial performance, a major component of cardiovascular reserve function, declines with aging i health and in heart failure due to a variety of causes. While signal transduction mechanisms for the beta1AR stimulation have been intensively studied, little information exerts as to the specific mechanisms that coupl beta2AR stimulation to its cellular responses. It has been well established that both beta1- and beta2-adrenoceptor (AR) subtypes increase the activity of adenylyl cyclase via an interaction with Gs, raising the internal cAMP concentration. However, our initial studies of this project have demonstrated that while both beta1AR and beta2AR stimulation increase total cellular cAMP to a similar extent in rat ventricular myocytes, the effects of beta2AR stimulation on ICa, Cabeta2+ transient and contraction are largely dissociated from its effect to increase cAMP content. Furthermore, while the beta2-adrenergic agonist, zinterol, significantly increases ICa, Ca2+ transient and contraction amplitudes in dog cardiac cells, it has no effect on the cellular cAMP production. These results suggest that beta2AR might be coupled to signaling pathway(s) other than the Gsalpha-mediated activation of adenylyl cyclase. Pertussis toxin (PTX) is a useful tool to eliminate signal transduction via some Gi or Go proteins. Our subsequent studies have shown that pertussis toxin (PTX) pretreatment specifically potentiates the responses of rat heart cells to beta2AR stimulated increase in Ca2+ transient, contraction and Ca2+ current (ICa). In contrast, neithe the baseline ICa, Ca2+ transient or contraction in the absence of betaAR stimulation, nor the beta1AR-mediated augmentation of these parameters are significantly altered by PTX treatment. These results indicate that in the absence of PTX, substantial coupling occurs between beta2AR and a PTX- sensitive G-protein, exerting a negative feedback on the cellular responses to beta2AR stimulation. Thus, distinct betaR subtype actions reside, at least in part, in the different receptor-G protein interaction. The difference provides a potential therapeutic strategy to reverse, in part, the decline in cardiac reserve with aging and heart failure.

β-肾上腺素能受体介导的心肌功能调节， 心血管储备功能的主要组成部分，随着年龄的增长而下降， 健康和心力衰竭由于各种原因。 而信号 β 1 AR刺激的转导机制已被广泛研究， 研究，很少有信息施加到具体的机制，耦合， β 2 AR刺激其细胞反应。这是公认的 β 1-和β 2-肾上腺素受体（AR）亚型都增加了 腺苷酸环化酶通过与Gs的相互作用，提高内部cAMP 浓度. 然而，我们对这个项目的初步研究 表明，虽然β 1 AR和β 2 AR刺激增加总 在大鼠心室肌细胞中， β 2 AR刺激对伊卡、Cabeta 2+瞬变和收缩的影响 这在很大程度上与其增加cAMP含量的作用无关。 此外，委员会认为， 而β 2-肾上腺素能激动剂锌特罗显著增加伊卡， 在狗心肌细胞中，Ca 2+瞬变和收缩幅度，它没有 对细胞cAMP产生的影响。 这些结果表明，β 2 AR 可能与Galpha介导的信号通路以外的信号通路偶联。 腺苷酸环化酶的活化。 百日咳毒素（PTX）是一种有用的工具， 通过一些Gi或Go蛋白消除信号转导。 我们随后 研究表明，百日咳毒素（PTX）预处理， 增强大鼠心脏细胞对β 2 AR刺激的增加的反应 Ca 2+瞬变、收缩和Ca 2+电流（伊卡）。 相比之下，Neithe 在不存在β AR的情况下，基线伊卡、Ca 2+瞬变或收缩 刺激，也不是β 1 AR介导的这些参数的增加， 经PTX治疗后有显著改变。 这些结果表明，在 在不存在PTX的情况下，在β 2AR和PTX之间发生实质性偶联。 敏感的G蛋白，对细胞反应产生负反馈 β 2AR刺激。 因此，不同的betaR亚型作用存在于， 至少部分地，在不同的受体-G蛋白相互作用中。 的 差异提供了一种潜在的治疗策略，部分地， 随着年龄增长和心力衰竭，心脏储备下降。