論文 - 詳細
| RRC ID | 72582 |
|---|---|
| 著者 | Kashio M, Masubuchi S, Tominaga M. |
| タイトル | Protein kinase C-mediated phosphorylation of transient receptor potential melastatin type 2 Thr738 counteracts the effect of cytosolic Ca2+ and elevates the temperature threshold. |
| ジャーナル | J Physiol |
| Abstract |
KEY POINTS:The transient receptor potential melastatin type 2 (TRPM2) ion channel is temperature-sensitive and Ca2+ -permeable. Endogenous factors and pathways such as redox signaling can regulate TRPM2 activity at body temperature under physiological and pathophysiological conditions. In this study, we report the novel finding that cytosolic Ca2+ lowers the temperature threshold for TRPM2 activation in a concentration-dependent manner. Protein kinase C (PKC)-mediated phosphorylation of TRPM2 at amino acid Thr782 elevates the temperature threshold for activation by counteracting the effects of cytosolic Ca2+ . These findings provide structure-based evidence to understand how temperature thresholds of thermo-sensitive TRP channels are determined and regulated. ABSTRACT:Transient receptor potential melastatin type 2 (TRPM2) channel is a non-selective cation channel that has high Ca2+ permeability. TRPM2 is sensitive to warm temperatures and is expressed in cells and tissues that are maintained at core body temperature. TRPM2 activity is also regulated by endogenous factors including redox signaling, cytosolic Ca2+ and adenosine diphosphate ribose (ADPR). Due to its wide expression and function at core body temperature, these endogenous factors could regulate TRPM2 activity at body temperature under physiological and pathophysiological conditions. We previously reported that cellular redox signaling can lower TRPM2 temperature thresholds, but the mechanism that regulates these thresholds is unclear. Here we used biochemical and electrophysiological techniques to explore another regulatory mechanism for TRPM2 temperature thresholds that is mediated by TRPM2 phosphorylation. Our results show that: (1) the temperature threshold for TRPM2 activation is lowered by cytosolic Ca2+ ; (2) protein kinase C (PKC)-mediated phosphorylation of TRPM2 counteracts the effect of cytosolic Ca2+ ; (3) Thr738 in mouse TRPM2 that lies near the Ca2+ binding site in the cytosolic cleft of the transmembrane domain is a potential phosphorylation site that may be involved in phosphorylation-mediated elevation of TRPM2 thresholds. These findings provide structure-based evidence to understand how temperature thresholds of thermo-sensitive TRP channels (thermo-TRPs) are determined and regulated. Abstract figure legend The transient receptor potential melastatin type 2 (TRPM2) ion channel is Ca2+ -permeable and has temperature sensitivity in the body temperature range. Endogenous factors and pathways such as redox signaling can regulate TRPM2 activity at body temperature under physiological and pathophysiological conditions. In this study, we report the novel finding that cytosolic Ca2+ lowers the temperature threshold for TRPM2 activation in a concentration-dependent manner. Protein kinase C (PKC)-mediated phosphorylation of TRPM2 elevates the threshold by counteracting the effects of cytosolic Ca2+ . Thr738 in mouse TRPM2 lies near the Ca2+ binding site in the cytosolic cleft of the transmembrane domain and is a potential phosphorylation site that may be involved in phosphorylation-mediated elevation of TRPM2 thresholds. These findings provide structure-based evidence to understand how temperature thresholds of thermo-sensitive TRP channels are determined and regulated. This article is protected by copyright. All rights reserved. |
| 巻・号 | 600(19) |
| ページ | 4287-4302 |
| 公開日 | 2022-10-1 |
| DOI | 10.1113/JP283350 |
| PMID | 36042566 |
| MeSH | Adenosine Diphosphate Ribose / metabolism Amino Acids / metabolism Animals Calcium / metabolism Cations / metabolism Mice Phosphorylation Protein Kinase C / metabolism TRPM Cation Channels* / metabolism Temperature |
| リソース情報 | |
| ヒト・動物細胞 | 293T(RCB2202) |