Stimulation of Ca(2+)‐ATPase Transport Activity by a Small‐Molecule Drug

The sarco(endo)plasmic reticulum Ca(2+)−ATPase (SERCA) hydrolyzes ATP to transport Ca(2+) from the cytoplasm to the sarcoplasmic reticulum (SR) lumen, thereby inducing muscle relaxation. Dysfunctional SERCA has been related to various diseases. The identification of small‐molecule drugs that can activate SERCA may offer a therapeutic approach to treat pathologies connected with SERCA malfunction. Herein, we propose a method to study the mechanism of interaction between SERCA and novel SERCA activators, i. e. CDN1163, using a solid supported membrane (SSM) biosensing approach. Native SR vesicles or reconstituted proteoliposomes containing SERCA were adsorbed on the SSM and activated by ATP concentration jumps. We observed that CDN1163 reversibly interacts with SERCA and enhances ATP‐dependent Ca(2+) translocation. The concentration dependence of the CDN1163 effect provided an EC(50)=6.0±0.3 μM. CDN1163 was shown to act directly on SERCA and to exert its stimulatory effect under physiological Ca(2+) concentrations. These results suggest that CDN1163 interaction with SERCA can promote a protein conformational state that favors Ca(2+) release into the SR lumen.