The Underlying Mechanism of Modulation of Transient Receptor Potential Melastatin 3 by protons.
The Underlying Mechanism of Modulation of Transient Receptor Potential Melastatin 3 by protons.
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DOI：
10.3389/fphar.2021.632711
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发表时间：
2021
影响因子：
5.6
通讯作者：
Du J
中科院分区：
文献类型：
--
作者：
Hossain Saad MZ;Xiang L;Liao YS;Reznikov LR;Du J
瞬时受体电位melastatin 3通道（TRPM 3）是一种钙离子可渗透的非选择性阳离子通道，在调节胰腺β细胞葡萄糖稳态中起重要作用。然而，TRPM 3在生理和病理条件下如何调节还知之甚少。在这项研究中，我们发现细胞内和细胞外质子都通过其在孔区域的结合位点阻断TRPM 3。我们证明，外部质子阻断TRPM 3的抑制pH 50为5.5。而内部质子以6.9的抑制pH 50抑制TRPM 3。我们确定了三个可滴定的残基，D1059，D1062和D1073，在前庭的通道孔，有助于pH值的敏感性。D1073 Q的突变使低外部pH 5.5的TRPM 3电流从野生型的62 ± 3%降低到D1073 Q突变体的25 ± 6.0%。这些结果表明，D1073对pH敏感性至关重要。此外，我们发现D1059或D1062的单一突变增强pH敏感性。总之，我们的研究结果确定了负责TRPM 3的pH调节的分子决定因素。质子对TRPM 3的抑制可能表明TRPM 3门控及其生理/病理功能的内源性机制。
Transient receptor potential melastatin 3 channel (TRPM3) is a calcium-permeable nonselective cation channel that plays an important role in modulating glucose homeostasis in the pancreatic beta cells. However, how TRPM3 is regulated under physiological and pathological conditions is poorly understood. In this study, we found that both intracellular and extracellular protons block TRPM3 through its binding sites in the pore region. We demonstrated that external protons block TRPM3 with an inhibitory pH50 of 5.5. whereas internal protons inhibit TRPM3 with an inhibitory pH50 of 6.9. We identified three titratable residues, D1059, D1062, and D1073, at the vestibule of the channel pore that contributes to pH sensitivity. The mutation of D1073Q reduced TRPM3 current by low external pH 5.5 from 62 ± 3% in wildtype to 25 ± 6.0% in D1073Q mutant. These results indicate that D1073 is essential for pH sensitivity. In addition, we found that a single mutation of D1059 or D1062 enhanced pH sensitivity. In summary, our findings identify molecular determinants respionsible for the pH regulation of TRPM3. The inhibition of TRPM3 by protons may indicate an endogenous mechanism governing TRPM3 gating and its physiological/pathological functions.
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发表时间：
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影响因子：
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