The Ca²⁺-ATPase pump facilitates bidirectional proton transport across the sarco/endoplasmic reticulum

Ca²⁺ transport across the sarco/endoplasmic reticulum (SR) plays an essential role in intracellular Ca²⁺ homeostasis, signalling, cell differentiation and muscle contractility. During SR Ca²⁺ uptake and release, proton fluxes are required to balance the charge deficit generated by the exchange of Ca²⁺ and other ions across the SR. During Ca²⁺ uptake by the SR Ca²⁺-ATPase (SERCA), two protons are countertransported from the SR lumen to the cytosol, thus partially compensating for the charge moved by Ca²⁺ transport. Studies have shown that protons are also transported from the cytosol to the lumen during Ca²⁺ 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 Ca²⁺ 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.