Ca ²⁺/H ⁺ exchange, lumenal Ca ²⁺ release and Ca ²⁺/ATP coupling ratios in the sarcoplasmic reticulum ATPase

Abstract

The Ca ²⁺ transport ATPase (SERCA) of sarcoplasmic reticulum (SR) plays an important role in muscle cytosolic signaling, as it stores Ca ²⁺ in intracellular membrane bound compartments, thereby lowering cytosolic Ca ²⁺ to induce relaxation. The stored Ca ²⁺ is in turn released upon membrane excitation to trigger muscle contraction. SERCA is activated by high affinity binding of cytosolic Ca ²⁺, whereupon ATP is utilized by formation of a phosphoenzyme intermediate, which undergoes protein conformational transitions yielding reduced affinity and vectorial translocation of bound Ca ²⁺. We review here biochemical and biophysical evidence demonstrating that release of bound Ca ²⁺ into the lumen of SR requires Ca ²⁺/H ⁺ exchange at the low affinity Ca ²⁺ sites. Rise of lumenal Ca ²⁺ above its dissociation constant from low affinity sites, or reduction of the H ⁺ concentration by high pH, prevent Ca ²⁺/H ⁺ exchange. Under these conditions Ca ²⁺ release into the lumen of SR is bypassed, and hydrolytic cleavage of phosphoenzyme may yield uncoupled ATPase cycles. We clarify how such Ca ²⁺pump slippage does not occur within the time length of muscle twitches, but under special conditions and in special cells may contribute to thermogenesis.