Espinoza-Fonseca L Michel
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
Mol Biosyst. 2017 Mar 28;13(4):633-637. doi: 10.1039/c7mb00065k.
Ca transport across the sarco/endoplasmic reticulum (SR) plays an essential role in intracellular Ca homeostasis, signalling, cell differentiation and muscle contractility. During SR Ca uptake and release, proton fluxes are required to balance the charge deficit generated by the exchange of Ca and other ions across the SR. During Ca uptake by the SR Ca-ATPase (SERCA), two protons are countertransported from the SR lumen to the cytosol, thus partially compensating for the charge moved by Ca transport. Studies have shown that protons are also transported from the cytosol to the lumen during Ca release, but a transporter that facilitates proton transport into the SR lumen has not been described. In this article we propose that SERCA forms pores that facilitate bidirectional proton transport across the SR. We describe the location and structure of water-filled pores in SERCA that form cytosolic and luminal pathways for protons to cross the SR membrane. Based on this structural information, we suggest mechanistic models for proton translocation to the cytosol during active Ca transport, and into the SR lumen during SERCA inhibition by endogenous regulatory proteins. Finally, we discuss the physiological consequences of SERCA-mediated bidirectional proton transport across the SR membrane of muscle and non-muscle cells.
钙离子跨肌浆网/内质网（SR）的转运在细胞内钙离子稳态、信号传导、细胞分化和肌肉收缩性中起着至关重要的作用。在肌浆网摄取和释放钙离子的过程中，需要质子流来平衡因钙离子和其他离子跨肌浆网交换而产生的电荷亏缺。在肌浆网钙离子ATP酶（SERCA）摄取钙离子期间，两个质子从肌浆网腔反向转运至胞质溶胶，从而部分补偿因钙离子转运而移动的电荷。研究表明，在钙离子释放过程中质子也从胞质溶胶转运至肌浆网腔，但尚未描述促进质子转运至肌浆网腔的转运体。在本文中，我们提出SERCA形成了促进质子双向跨肌浆网转运的孔道。我们描述了SERCA中充满水的孔道的位置和结构，这些孔道形成了质子穿过肌浆网膜的胞质溶胶和腔途径。基于此结构信息，我们提出了在钙离子主动转运期间质子转运至胞质溶胶以及在内源性调节蛋白抑制SERCA期间质子转运至肌浆网腔的机制模型。最后，我们讨论了SERCA介导的质子双向跨肌肉和非肌肉细胞肌浆网膜转运的生理后果。
