Sphingoid Bases Regulate the Sigma-1 Receptor-Sphingosine and N,N'-Dimethylsphingosine Are Endogenous Agonists.
Sphingoid Bases Regulate the Sigma-1 Receptor-Sphingosine and N,N'-Dimethylsphingosine Are Endogenous Agonists.
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DOI：
10.3390/ijms24043103
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发表时间：
2023-02-04
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
具有生物活性的鞘磷脂和Sigma-1受体(S1R)伴侣普遍存在于哺乳动物细胞膜中。调节S1R的内源化合物对于控制S1R对细胞应激的反应是重要的。在这里，我们在完整的视网膜色素上皮细胞(ARPE-19)中使用具有生物活性的狮身人面像碱基鞘氨醇(SPH)或引起疼痛的二甲基SPH衍生物N，N‘-二甲基鞘氨醇(DMS)来询问S1R。根据改进的天然凝胶方法，在SPH或DMS存在下，基础和拮抗剂(BD-1047)稳定的S1R寡聚体解离为原构体(Pre-084作为对照)。因此，我们推测SPH和DMS是内源性S1R激动剂。在SPH和DMS与S1R原核的电子对接中，SPH和DMS与Cupinβ桶中的Asp126和Glu172以及C18烷链与结合部位(包括螺旋4和5中的残基)的广泛van der Waals相互作用都显示出很强的相关性。平均对接自由能SPH为8.73-8.93千卡/摩尔，DMS为8.56-8.15千卡/摩尔，计算的结合常数为~40 nM和~120 nM。我们假设SPH、DMS和类似的狮身人面像碱基通过膜双层途径进入S1Rβ桶。我们进一步认为，作为SPH的主要来源的细胞内膜神经酰胺浓度的酶控制决定了内源性SPH和DMS对S1R的可用性，并随后控制了同一细胞和/或细胞环境中的S1R活性。
Both bioactive sphingolipids and Sigma-1 receptor (S1R) chaperones occur ubiquitously in mammalian cell membranes. Endogenous compounds that regulate the S1R are important for controlling S1R responses to cellular stress. Herein, we interrogated the S1R in intact Retinal Pigment Epithelial cells (ARPE-19) with the bioactive sphingoid base, sphingosine (SPH), or the pain-provoking dimethylated SPH derivative, N,N’-dimethylsphingosine (DMS). As informed by a modified native gel approach, the basal and antagonist (BD-1047)-stabilized S1R oligomers dissociated to protomeric forms in the presence of SPH or DMS (PRE-084 as control). We, thus, posited that SPH and DMS are endogenous S1R agonists. Consistently, in silico docking of SPH and DMS to the S1R protomer showed strong associations with Asp126 and Glu172 in the cupin beta barrel and extensive van der Waals interactions of the C18 alkyl chains with the binding site including residues in helices 4 and 5. Mean docking free energies were 8.73–8.93 kcal/mol for SPH and 8.56–8.15 kcal/mol for DMS, and calculated binding constants were ~40 nM for SPH and ~120 nM for DMS. We hypothesize that SPH, DMS, and similar sphingoid bases access the S1R beta barrel via a membrane bilayer pathway. We further propose that the enzymatic control of ceramide concentrations in intracellular membranes as the primary sources of SPH dictates availability of endogenous SPH and DMS to the S1R and the subsequent control of S1R activity within the same cell and/or in cellular environments.
影响因子：
4.7
作者：
Brindley RL;Bauer MB;Hartley ND;Horning KJ;Currie KPM
通讯作者：
Currie KPM
影响因子：
5
作者：
Romeo G;Bonanno F;Wilson LL;Arena E;Modica MN;Pittalà V;Salerno L;Prezzavento O;McLaughlin JP;Intagliata S
通讯作者：
Intagliata S