当前位置：
X-MOL 学术
›
Cell. Signal.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Differential regulation of β2-adrenoceptor and adenosine A2B receptor signalling by GRK and arrestin proteins in arterial smooth muscle.
Cellular Signalling ( IF 4.4 ) Pub Date : 2018-07-31 , DOI: 10.1016/j.cellsig.2018.07.013 Craig A Nash 1 , Carl P Nelson 1 , Rajendra Mistry 1 , Christian Moeller-Olsen 1 , Elena Christofidou 1 , R A John Challiss 1 , Jonathon M Willets 1
Cellular Signalling ( IF 4.4 ) Pub Date : 2018-07-31 , DOI: 10.1016/j.cellsig.2018.07.013 Craig A Nash 1 , Carl P Nelson 1 , Rajendra Mistry 1 , Christian Moeller-Olsen 1 , Elena Christofidou 1 , R A John Challiss 1 , Jonathon M Willets 1
Affiliation
|
Generation of cAMP through Gs-coupled G protein-coupled receptor (GPCR) [e.g. β2-adrenoceptor (β2AR), adenosine A2B receptor (A2BR)] activation, induces arterial smooth muscle relaxation, counteracting the actions of vasoconstrictors. Gs-coupled GPCR signalling is regulated by G protein-coupled receptor kinases (GRK) and arrestin proteins, and dysregulation of Gs/GPCR signalling is thought play a role in the development of hypertension, which may be a consequence of enhanced GRK2 and/or arrestin expression. However, despite numerous studies indicating that β2AR and A2BR can be substrates for GRK/arrestin proteins, currently little is known regarding GRK/arrestin regulation of these endogenous receptors in arterial smooth muscle. Here, endogenous GRK isoenzymes and arrestin proteins were selectively depleted using RNA-interference in rat arterial smooth muscle cells (RASM) and the consequences of this for β2AR- and A2BR-mediated adenylyl cyclase (AC) signalling were determined by assessing cAMP accumulation. GRK2 or GRK5 depletion enhanced and prolonged β2AR/AC signalling, while combined deletion of GRK2/5 has an additive effect. Conversely, activation of AC by A2BR was regulated by GRK5, but not GRK2. β2AR desensitization was attenuated following combined GRK2/GRK5 knockdown, but not by depletion of individual GRKs, arrestins, or by inhibiting PKA. Arrestin3 (but not arrestin2) depletion enhanced A2BR-AC signalling and attenuated A2BR desensitization, while β2AR-AC signalling was regulated by both arrestin isoforms. This study provides a first demonstration of how different complements of GRK and arrestin proteins contribute to the regulation of signalling and desensitization of these important receptors mediating vasodilator responses in arterial smooth muscle.
中文翻译：
动脉平滑肌中 GRK 和抑制蛋白对 β2-肾上腺素受体和腺苷 A2B 受体信号传导的差异调节。
通过 Gs 偶联 G 蛋白偶联受体 (GPCR) [例如 β2-肾上腺素受体 (β2AR)、腺苷 A2B 受体 (A2BR)] 激活产生 cAMP，诱导动脉平滑肌松弛，抵消血管收缩剂的作用。Gs 偶联的 GPCR 信号由 G 蛋白偶联受体激酶 (GRK) 和抑制蛋白调节，Gs/GPCR 信号的失调被认为在高血压的发展中起作用，这可能是 GRK2 和/或增强的结果抑制表达。然而，尽管大量研究表明 β2AR 和 A2BR 可以作为 GRK/arrestin 蛋白的底物，但目前关于 GRK/arrestin 对动脉平滑肌中这些内源性受体的调节知之甚少。这里，使用大鼠动脉平滑肌细胞 (RASM) 中的 RNA 干扰选择性地去除内源性 GRK 同工酶和抑制蛋白，并通过评估 cAMP 积累来确定 β2AR 和 A2BR 介导的腺苷酸环化酶 (AC) 信号传导的后果。GRK2 或 GRK5 缺失增强和延长 β2AR/AC 信号传导，而 GRK2/5 的组合缺失具有累加效应。相反，A2BR 对 AC 的激活受 GRK5 调节，但不受 GRK2 调节。联合 GRK2/GRK5 敲低后，β2AR 脱敏作用减弱，但不是通过消耗单个 GRK、抑制素或抑制 PKA。Arrestin3（但不是 Arrestin2）的消耗增强了 A2BR-AC 信号传导并减弱了 A2BR 脱敏，而 β2AR-AC 信号传导受两种抑制素亚型的调节。
更新日期：2018-07-31
中文翻译：
动脉平滑肌中 GRK 和抑制蛋白对 β2-肾上腺素受体和腺苷 A2B 受体信号传导的差异调节。
通过 Gs 偶联 G 蛋白偶联受体 (GPCR) [例如 β2-肾上腺素受体 (β2AR)、腺苷 A2B 受体 (A2BR)] 激活产生 cAMP，诱导动脉平滑肌松弛，抵消血管收缩剂的作用。Gs 偶联的 GPCR 信号由 G 蛋白偶联受体激酶 (GRK) 和抑制蛋白调节，Gs/GPCR 信号的失调被认为在高血压的发展中起作用，这可能是 GRK2 和/或增强的结果抑制表达。然而，尽管大量研究表明 β2AR 和 A2BR 可以作为 GRK/arrestin 蛋白的底物，但目前关于 GRK/arrestin 对动脉平滑肌中这些内源性受体的调节知之甚少。这里，使用大鼠动脉平滑肌细胞 (RASM) 中的 RNA 干扰选择性地去除内源性 GRK 同工酶和抑制蛋白，并通过评估 cAMP 积累来确定 β2AR 和 A2BR 介导的腺苷酸环化酶 (AC) 信号传导的后果。GRK2 或 GRK5 缺失增强和延长 β2AR/AC 信号传导，而 GRK2/5 的组合缺失具有累加效应。相反，A2BR 对 AC 的激活受 GRK5 调节，但不受 GRK2 调节。联合 GRK2/GRK5 敲低后，β2AR 脱敏作用减弱，但不是通过消耗单个 GRK、抑制素或抑制 PKA。Arrestin3（但不是 Arrestin2）的消耗增强了 A2BR-AC 信号传导并减弱了 A2BR 脱敏，而 β2AR-AC 信号传导受两种抑制素亚型的调节。
京公网安备 11010802027423号