Can proton pumping by SERCA enhance the regulatory role of phospholamban and sarcolipin?

• Phospholamban and sarcolipin do not permeabilize lipid bilayers to cations at pH 7.
• Phospholamban and sarcolipin permeabilize lipid bilayers to monovalent cations at pH ≤ 6.
• This explains the physiological role of SERCA proton pumping.

The effect of the incorporation of phosphorylated phospholamban (pPLN) and sarcolipin (SLN) in mercury-supported self-assembled lipid monolayers and in lipid bilayers tethered to mercury via a hydrophilic spacer was investigated by voltammetric techniques and electrochemical impedance spectroscopy. It was shown that pPLN and SLN do not permeabilize lipid bilayers toward ions at physiological pH. However, they exert a permeabilizing action toward inorganic monovalent cations such as K+ and Tl+, but not toward divalent cations such as Ca2+ and Cd2 +, following a small decrease in pH. This behavior can be associated with their regulatory action on the Ca-ATPase of the sarcoplasmic reticulum (SERCA). SERCA pumps two Ca2+ ions from the cytosol to the lumen of the sarcoplasmic reticulum (SR) and two protons in the opposite direction, causing a transient decrease of pH in the immediate vicinity of its cytoplasmic domain. This decrease is expected to activate the liberated pPLN molecules and SLN to make the SR membrane leakier toward K+ and Na+ and the SLN ion channel to translocate small inorganic anions, such as Cl−. The effect of pPLN and SLN, which becomes synergic when they are both present in the SR membrane, is expected to favor a rapid equilibration of ions on both sides of the membrane.

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