Mouse transient receptor potential melastatin 2 (TRPM2) isoform 7 attenuates full-length mouse TRPM2 activity through reductions in its expression by targeting it to ER-associated degradation

Abstract

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.