Dexras1 blocks receptor-mediated heterologous sensitization of adenylyl cyclase 1.
Dexras1 blocks receptor-mediated heterologous sensitization of adenylyl cyclase 1.
复制标题
Dexras1 阻断受体介导的腺苷酸环化酶 1 异源致敏作用。
DOI：
10.1016/j.bbrc.2005.05.041
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发表时间：
2005
影响因子：
3.1
通讯作者：
Watts,ValJ
中科院分区：
文献类型：
--
作者：
Nguyen,ChauH;Watts,ValJ
Dexras 1/AGS 1/RasD 1是单体G蛋白Ras超家族的成员，并已被建议破坏受体-G蛋白信号传导。我们检测了Dexras 1调节多巴胺D2 L受体对HEK 293细胞中腺苷酸环化酶（AC）1型的调节的能力。Dexras 1（IC 50，2.4± 1.3 nM，50±1%抑制）未改变D2 L受体介导的A23187刺激的AC 1活性急性抑制（IC 50，4.0 ± 1.4 nM; 50 ± 3%抑制）;然而，Dexras 1可将D2 L受体介导的ERK 1/2急性激活阻断约50%。在基础和A23187刺激条件下，D2 L受体持续激活诱导的AC 1异源性增敏作用可被Dexras 1完全阻断。致敏作用的阻断是浓度依赖性的，并且在核苷酸结合缺陷型Dexras 1G 31 V突变体中未观察到。通过β-肾上腺素能受体激酶（βARK-ct）的C-末端证实，AC 1的增敏作用是Gβγ依赖性的。这些数据表明，Dexras 1选择性调节受体介导的Gβγ信号通路。
Dexras1/AGS1/RasD1 is a member of the Ras superfamily of monomeric G proteins and has been suggested to disrupt receptor-G protein signaling. We examined the ability of Dexras1 to modulate dopamine D2Lreceptor regulation of adenylyl cyclase (AC) type 1 in HEK293 cells. Acute D2Lreceptor-mediated inhibition of A23187-stimulated AC1 activity (IC50, 4.0±1.4nM; 50±3% inhibition) was not altered in the presence of Dexras1 (IC50, 2.4±1.3nM, 50±1% inhibition); however, Dexras1 blocked acute D2Lreceptor-mediated activation of ERK 1/2 by approximately 50%. Heterologous sensitization of AC1 induced by persistent activation of D2Lreceptors was completely blocked by Dexras1 under basal and A23187-stimulated conditions. The block of sensitization was concentration-dependent and was not observed with a nucleotide binding-deficient Dexras1G31V mutant. Sensitization of AC1 was Gβγ-dependent as demonstrated using the C-terminus of β-adrenergic receptor kinase (βARK-ct). These data suggest that Dexras1 selectively regulates receptor-mediated Gβγ signaling pathways.