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: 3767797
• 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/3767797
• 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

Beta-adrenergic receptor (betaAR) stimulation has profound modulatory effects on the cardiac contraction. It has been well documented that both the beta1 and beta2 AR subtypes are coupled to adenylcyclase and that their stimulation by beta1 and beta2 AR specific agonist leads to an increase in cAMP. Stimulation of other heart cell receptors, e.g. prostaglandin, also leads to an increase in cAMP but has no effect on contraction, presumably because the cAMP pool affected is not associated with membranous cAMP activation and is not linked to heart cell Ca2+ regulation. It is widely recognized that stimulation of beta AR's leads to an increase in the particulate (membrane bound) cAMP levels and protein kinase (PK) phosphorylation of key proteins involved in excitation-contraction coupling. However, whether beta2 AR stimulation increases particulate cAMP and cAMP dependent phosphorylation is not known. In this regard we have recently shown that the beta2 AR mediated effects on Ca2+, contraction and L type Ca2+ channels in rat heart cells differ markedly from those elicited by beta1 AR stimulation. In this project we further demonstrated that the beta2 effects on Ca2+ and contraction in these cells are not mediated by cAMP. This conclusion is based on the measurement of total and particulate cAMP levels and the discoupling between the increase of cAMP levels and increases in cell contraction and Cai transient. Furthermore, phosphorylation of sarcoplasmic reticulum (SR) phospholamban was dramatically increased by beta1 AR stimulation, but not by beta2AR stimulation. Thus, beta1 and beta2AR are coupled to cellular effects of altered Ca2+ homeostasis and contraction via different signal transduction pathways.

β-肾上腺素能受体（β AR）刺激具有深刻的调节作用， 对心脏收缩的影响 有充分的证据表明， β 1和β 2 AR亚型均与腺苷酸环化酶偶联， β 1和β 2 AR特异性激动剂的刺激导致 cAMP的增加。 刺激其他心脏细胞受体，例如 前列腺素，也导致cAMP的增加，但对 收缩，大概是因为受影响的cAMP池不是 与膜cAMP激活相关，与心脏无关 细胞钙离子调节。 人们普遍认为，刺激β AR导致颗粒（膜结合）cAMP增加 水平和蛋白激酶（PK）磷酸化的关键蛋白质参与 兴奋-收缩耦合。 然而，beta2 AR是否 刺激增加颗粒cAMP和cAMP依赖性 磷酸化是未知的。 在这方面，我们最近表明 β 2 AR介导对Ca ~（2+）、收缩和L型Ca ~（2+）的影响， 在大鼠心脏细胞中的通道明显不同于由 β 1 AR刺激。 在这个项目中，我们进一步证明， β 2对Ca 2+的影响和这些细胞中的收缩不是介导的 的cAMP。 这一结论是基于对总的和 颗粒cAMP水平和增加之间的脱钩 cAMP水平和细胞收缩和Cai瞬时增加。 此外，肌浆网（SR） 受磷蛋白通过β 1 AR刺激显著增加，但 而不是通过β 2AR刺激。 因此，beta1和beta2 AR偶联， 改变的Ca 2+稳态和收缩的细胞效应， 不同的信号转导途径。