Cardiomyocyte S1P1 receptor-mediated extracellular signal-related kinase signaling and desensitization.
Cardiomyocyte S1P1 receptor-mediated extracellular signal-related kinase signaling and desensitization.
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DOI：
10.1097/fjc.0b013e3181a7b58a
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发表时间：
2009-06
影响因子：
3
通讯作者：
Karliner JS
中科院分区：
文献类型：
--
作者：
Tao R;Hoover HE;Zhang J;Honbo N;Alano CC;Karliner JS
我们研究了鞘氨醇-1-磷酸（S1 P）脱敏细胞外信号相关激酶（ERK）的能力，ERK是一种与心脏抗凋亡反应相关的丝裂原活化蛋白激酶。在分离的成年小鼠心肌细胞中，S1 P（10 nM-5 μM）以时间和剂量依赖性方式诱导ERK磷酸化。S1 P对ERK的刺激可被S1 P1/3亚型受体拮抗剂（VPC 23019）、Gi蛋白抑制剂（百日咳毒素）和丝裂原活化蛋白激酶/ERK激酶抑制剂（PD 98059）完全抑制。选择性S1 P3受体拮抗剂（CAY 10444）对S1 P诱导的ERK激活无影响。选择性S1 P1激动剂SEW 2871也诱导ERK磷酸化。用100 nM S1 P预孵育1小时后，用100 nM S1 P再刺激的ERK激活受到抑制，但第二天完全恢复，表明受体再循环。在蛋白激酶Cε缺失的心肌细胞中获得了类似的结果。用非选择性S1 P受体激动剂FTY 720处理1小时也降低了响应于随后的S1 P刺激的磷酸化ERK表达。与S1 P相反，在过夜暴露后，FTY 720的一些脱敏持续存在。用外源性S1 P预处理可减少缺氧/复氧诱导的细胞死亡。这种增强的存活率被PD 98059、VPC 23019或百日咳毒素预处理所消除。因此，外源性S1 P诱导快速和可逆的S1 P1介导的ERK磷酸化。S1 P诱导的成年小鼠心肌细胞存活需要通过S1 P1-Gi途径介导的ERK激活。
We examined the ability of sphingosine-1-phosphate (S1P) to desensitize extracellular signal–related kinase (ERK), a mitogen-activated protein kinase linked to antiapoptotic responses in the heart. In isolated adult mouse cardiomyocytes, S1P (10 nM–5 μM) induced ERK phosphorylation in a time- and dose-dependent manner. S1P stimulation of ERK was completely inhibited by an S1P1/3 subtype receptor antagonist (VPC23019), by a Gi protein inhibitor (pertussis toxin) and by a mitogen-activated protein kinase/ERK kinase inhibitor (PD98059). A selective S1P3 receptor antagonist (CAY10444) had no effect on S1P-induced ERK activation. The selective S1P1 agonist SEW2871 also induced ERK phosphorylation. Activation of ERK by restimulation with 100 nM S1P was suppressed after 1 hour of preincubation with 100 nM S1P but recovered fully the next day, suggesting receptor recycling. Similar results were obtained in protein kinase Cε-null cardiomyocytes. Treatment with the nonselective S1P receptor agonist FTY720 for 1 hour also reduced phospho-ERK expression in response to subsequent S1P stimulation. In contrast to S1P, some desensitization to FTY720 persisted after overnight exposure. Cell death induced by hypoxia/reoxygenation was reduced by pretreatment with exogenous S1P. This enhanced survival was abrogated by pretreatment with PD98059, VPC23019, or pertussis toxin. Thus, exogenous S1P induces rapid and reversible S1P1-mediated ERK phosphorylation. S1P-induced adult mouse cardiomyocyte survival requires ERK activation mediated via an S1P1–Gi pathway.