Bromopyrroles (BrPyr) are synthesized naturally by marine sponge symbionts and produced anthropogenically as byproducts of wastewater treatment. BrPyr interact with ryanodine receptors (RYRs) and sarco/endoplasmic reticulum (SR/ER) Ca²⁺-ATPase (SERCA). Influences of BrPyr on the neuronal network activity remain uncharted. BrPyr analogues with differing spectra of RYR/SERCA activities were tested using RYR-null or RYR1-expressing HEK293 and murine cortical neuronal/glial cocultures (NGCs) loaded with Fluo-4 to elucidate their mechanisms altering Ca²⁺ dynamics. The NGC electrical spike activity (ESA) was measured from NGCs plated on multielectrode arrays. Nanomolar tetrabromopyrrole (TBP, 1) potentiated caffeine-triggered Ca²⁺ release independent of extracellular [Ca²⁺] in RYR1-HEK293, whereas higher concentrations produce slow and sustained rise in cytoplasmic [Ca²⁺] independent of RYR1 expression. TBP, 2,3,5-tribromopyrrole (2), pyrrole (3), 2,3,4-tribromopyrrole (4), and ethyl 4-bromopyrrole-2-carboxylate (5) added acutely to NGC showed differential potency; rank order TBP (IC₅₀ ≈ 220 nM) > 2 ≫ 5, whereas 3 and 4 were inactive at 10 μM. TBP >2 μM elicited sustained elevation of cytoplasmic [Ca²⁺] and loss of neuronal viability. TBP did not alter network ESA. BrPyr from marine and anthropogenic sources are ecological signaling molecules and emerging anthropogenic pollutants of concern to environmental and human health that potently alter ER Ca²⁺ dynamics and warrant further investigation in vivo.

中文翻译：

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海洋和人为溴吡咯通过靶向 Ryanodine 受体和 Sarco/内质网 Ca2+-ATPase 改变小鼠皮层神经元网络的细胞 Ca2+ 动力学

溴吡咯 (BrPyr) 由海洋海绵共生体自然合成，并作为废水处理的副产品人为生产。^{BrPyr 与兰尼碱受体 (RYR) 和肌细胞/内质网 (SR/ER) Ca 2+} -ATPase (SERCA)相互作用。BrPyr 对神经元网络活动的影响仍然未知。使用 RYR-null 或表达 RYR1 的 HEK293 和载有 Fluo-4 的鼠皮层神经元/神经胶质共培养物 (NGC) 测试具有不同 RYR/SERCA 活性光谱的 BrPyr 类似物，以阐明它们改变 Ca 2+ 动力学的^机制。NGC 电尖峰活动 (ESA) 是从镀在多电极阵列上的 NGC 测量的。纳摩尔四溴吡咯 (TBP, 1 ) 增强咖啡因触发的 Ca ²⁺在 RYR1-HEK293 中，释放与细胞外 [Ca ²⁺ ] 无关，而较高浓度会导致细胞质 [Ca ²⁺ ] 缓慢且持续升高，与 RYR1 表达无关。TBP、2,3,5-三溴吡咯 ( 2 )、吡咯 ( 3 )、2,3,4-三溴吡咯 ( 4 ) 和 4-溴吡咯-2-羧酸乙酯 ( 5 ) 急剧添加到 NGC 中显示出不同的效力；排序TBP (IC ₅₀ ≈ 220 nM) > 2 ≫ 5，而3和4在 10 μM 时无活性。TBP >2 μM 引起细胞质 [Ca ²⁺] 和神经元活力的丧失。TBP没有改变网络 ESA。来自海洋和人为来源的 BrPyr 是生态信号分子和与环境和人类健康有关的新兴人为污染物，可有效改变 ER Ca ²⁺动力学并需要在体内进行进一步研究。