Heterodimerization with the prostacyclin receptor triggers thromboxane receptor relocation to lipid rafts.
Heterodimerization with the prostacyclin receptor triggers thromboxane receptor relocation to lipid rafts.
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DOI：
10.1161/atvbaha.112.300536
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Smyth EM
中科院分区：
文献类型：
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作者：
Ibrahim S;McCartney A;Markosyan N;Smyth EM
前列环素和血栓素分别通过称为IP和TP的受体介导相反的心血管作用。当与IP二聚化时，TP转变为IP样功能。IP定位于富含胆固醇的膜筏，但TP和IPTP异二聚体定位尚未确定。我们研究了这些受体的膜定位和筏在受体功能中的作用。通过测量从海肾荧光素酶融合受体到荧光标记筏的能量转移，在COS-7细胞中检查IP、TP和IPTP异二聚体的微区分布。IP筏协会得到确认。TP被筏排除，但在与IP二聚化后重新分布到筏中。信号的IP和IPTP异二聚体，但不是TP单独，被抑制后筏破坏胆固醇消耗。胆固醇富集也选择性抑制IP和IPTP功能。平滑肌细胞和巨噬细胞中的天然IP和IPTP信号传导对胆固醇操纵同样敏感，而来自高胆固醇血症小鼠的巨噬细胞显示抑制的IP和IPTP功能。IP和TP在不同的微域中起作用。IPTP异二聚体中TP的筏掺入可能促进其信号传导转变。我们推测，IP和IPTP信号的变化，膜胆固醇的扰动可能有助于心血管疾病与高胆固醇血症。
Prostacyclin and thromboxane mediate opposing cardiovascular actions through receptors termed IP and TP, respectively. When dimerized with IP, the TP shifts to IP-like function. IP localizes to cholesterol-enriched membrane rafts but TP and IPTP heterodimer localization is not defined. We examined these receptors’ membrane localization and the role of rafts in receptor function. Microdomain distribution of IP, TP and IPTP heterodimers, was examined in COS-7 cells by measuring energy transfer from renilla luciferase fused receptors to fluorescently labeled rafts. IP raft association was confirmed. TP was raft excluded but redistributed to rafts upon dimerization with IP. Signaling of the IP and IPTP heterodimer, but not TP alone, was suppressed following raft disruption by cholesterol depletion. Cholesterol enrichment also selectively suppressed IP and IPTP function. Native IP and IPTP signaling in smooth muscle cells and macrophages was similarly sensitive to cholesterol manipulation while macrophages from hypercholesterolemic mice displayed suppressed IP and IPTP function. IP and TP function within distinct microdomains. Raft incorporation of TP in the IPTP heterodimer likely facilitates its signaling shift. We speculate that changes in IP and IPTP signaling following perturbation of membrane cholesterol may contribute to cardiovascular disease associated with hypercholesterolemia.