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.