Reply to Ahluwalia et al.: Contributions of melatonin receptors are tissue-dependent.
Reply to Ahluwalia et al.: Contributions of melatonin receptors are tissue-dependent.
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回复 Ahluwalia 等人：褪黑激素受体的贡献是组织依赖性的。
DOI：
10.1073/pnas.1800449115
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发表时间：
2018
影响因子：
11.1
通讯作者：
Friedlander,RobertM
中科院分区：
文献类型：
--
作者：
Suofu,Yalikun;Carlisle,DianeL;Vilardaga,Jean-Pierre;Friedlander,RobertM
In our recent publication (1), we advance the previous findings regarding melatonin type 1 (MT1) receptor in brain mitochondria. We demonstrate that melatonin is synthesized in brain mitochondria and signals through the MT1 receptor located in the outer mitochondrial membrane (MM). We further show that melatonin binds mitochondria MT1, which in turn activates inhibitory Gi proteins in the intermembrane space and inhibits stress-mediated cytochrome c release (1, 2). We have exclusively worked with neurons or brain tissue, and have therefore not performed experiments in other cell types at this stage. In the letter from Ahluwalia et al.(3), the authors propose that melatonin receptors, especially MT2, are located in MMs of gastric endothelial cells (GEC). Their data expand the knowledge of melatonin receptors beyond brain and neuronal mitochondria. Furthermore, the authors find that melatonin increases both MT1 and MT2 protein levels in GEC cell mitochondria (3). In a previous study we demonstrated that melatonin administration inhibited the mutant huntingtin-induced reduction of MT1 protein and mRNA, but not MT2 protein and mRNA in the R6/2 murine brain (2), suggesting that dysfunctional melatonin signaling through MT1 in the murine brain may be relevant to neurodegeneration and may be amenable to modulation by exposure to exogenous melatonin. In our more recent study (1), we found that luzindole, which inhibits MT1 and MT2, decreased melatonin’s ability to inhibit cytochrome c release while the MT2 receptor-specific antagonist, 4P-PDOT, was unable to do so. These data indicate that luzindole antagonized melatonin’s inhibitory effect on cytochrome c release due to its inhibition of MT1 and not MT2 in the brain. These findings by Ahluwalia et al.(3) and our studies (1, 2, 4) indicate that the contribution of melatonin receptors and its signaling pathways can presumably be cell-and tissue-dependent. However, it must be pointed out that caution needs to be taken when interpreting data obtained using MT1 antibodies. Extensive MT1 antibody validation data in our laboratory and by others (5) suggest that none of the currently commercially available MT1 antibodies that we tested are specific to the MT1 protein. Thus, work showing localization of endogenous melatonin receptors using antibody-based methods must be validated by including robust controls, such as tissues from knockout MT1 and MT2 mice to demonstrate antibody reliability.
