マウス TRPM2 アイソフォームの機能解析、および full-length マウス TRPM2 への影響に関する研究

抄録

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 to date. The present study investigated whether these isoforms function as oxidative stress-sensitive Ca²⁺ channels and 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 ER-associated degradation (ERAD) 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 the other isoforms. This decrease in the expression of full-length mTRPM2 was recovered by the proteasomal inhibitor, MG132. 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 ERAD. The present study will provide important information on the functional nature of mTRPM2 isoforms for elucidation of their roles in physiological and patho-physiological responses in vivo using mouse models.