Transient receptor potential melastatin 2 (TRPM2) assembles into tetramers to function as an oxidative stress-sensitive Ca²⁺ channel at the surface membrane. Limited information is currently available on the 10 protein isoforms of mouse TRPM2 (mTRPM2) identified. This study investigated whether these isoforms function as Ca²⁺ channels and examined their effects on full-length mTRPM2 activity using the HEK 293 cell exogenous expression system. Only full-length mTRPM2, isoform 1 localized to the surface membrane and was activated by oxidative stress. Isoform 7 was clearly recognized by protein quality control systems and degraded by endoplasmic reticulum-associated degradation after transmembrane proteolysis. In the co-expression system, the activation and expression of full-length mTRPM2 were attenuated by its co-expression with isoform 7, but not with the other isoforms. This decrease in the expression of full-length mTRPM2 was recovered by the proteasomal inhibitor. The present results suggest that isoforms other than isoform 1 did not function as oxidative stress-sensitive channels and also that only isoform 7 attenuated the activation of full-length mTRPM2 by targeting it to endoplasmic reticulum-associated degradation. The present study will provide important information on the functional nature of mTRPM2 isoforms for the elucidation of their roles in physiological and patho-physiological responses in vivo using mouse models.

中文翻译：

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小鼠瞬时受体电位 melastatin 2 (TRPM2) 亚型 7 通过靶向 ER 相关降解来减少其表达，从而减弱全长小鼠 TRPM2 活性

瞬时受体电位 melastatin 2 (TRPM2) 组装成四聚体，充当表面膜上的氧化应激敏感 Ca ^2+通道。目前关于已鉴定的小鼠TRPM2 ( m TRPM2) 10 种蛋白质亚型的信息有限。本研究调查了这些亚型是否充当 Ca ²⁺通道，并使用 HEK 293 细胞外源表达系统检查了它们对全长m TRPM2 活性的影响。仅全长m TRPM2（亚型 1）定位于表面膜并被氧化应激激活。同工型 7 被蛋白质质量控​​制系统清楚地识别，并在跨膜蛋白水解后被内质网相关降解所降解。在共表达系统中，全长m TRPM2 的激活和表达因与异构体 7 共表达而减弱，但与其他异构体共表达则不减弱。全长m TRPM2 表达的减少可通过蛋白酶体抑制剂恢复。目前的结果表明，除异构体 1 以外的异构体不能发挥氧化应激敏感通道的作用，而且只有异构体 7通过靶向内质网相关降解来减弱全长m TRPM2 的激活。本研究将提供有关m TRPM2 亚型功能性质的重要信息，以利用小鼠模型阐明它们在体内生理和病理生理反应中的作用。