Stimulation of Ca²⁺‐ATPase Transport Activity by a Small‐Molecule Drug

Abstract

The sarco(endo)plasmic reticulum Ca 2 + À 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.

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

“…The stimulation of SERCA2a activity, as a novel therapeutic measure to relieve cardiac dysfunction in heart failure without arrhythmogenic effects, is a promising strategy to be used in combination with other rst-line therapeutic agents such as β-blockers and ACE inhibitors 42 . Until recently, only a few compounds were known to stimulate SERCA: CDN1163 (stimulates Ca 2+ transport) 43,19 , CP-154526 (increases the apparent Ca 2+ a nity of SERC2a) 44 , Ro 41-0960 (increases SERCA maximal activity in high Ca 2+ ) 44 , and istaroxime (stimulates SERCA activity) 45 . However, our recent HTS using Ca 2+ -ATPase activity as the target HTS assay identi ed ~ 19 new activators of SERCA 28 , and we identi ed nine activator compounds in the present study.…”

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

“…The stimulation of SERCA2a activity, as a novel therapeutic measure to relieve cardiac dysfunction in heart failure without arrhythmogenic effects, is a promising strategy to be used in combination with other first-line therapeutic agents such as β-blockers and ACE inhibitors 42 . Until recently, only a few compounds were known to stimulate SERCA: CDN1163 (stimulates Ca 2+ transport) 43,19 , CP-154526 (increases the apparent Ca 2+ affinity of SERC2a) 44 , Ro 41-0960 (increases SERCA maximal activity in high Ca 2+ ) 44 , and istaroxime (stimulates SERCA activity) 45 . However, our recent HTS using Ca 2+ -ATPase activity as the target HTS assay identified ~19 new activators of SERCA 28 , and we identified nine activator compounds in the present study.…”

Acute activation of SERCA with CDN1163 attenuates IgE‐mediated mast cell activation through selective impairment of ROS and p38 signaling

“…CDN1163, a quinoline derivative, has been well documented as an allosteric activator of SERCA, leading to enhanced ATP-dependent shuttling of cytoplasmic Ca 2+ into the sarco/endoplasmic reticulum. 17,24 Currently, our understanding of SERCA functionality in mast cells is focused on the use of thapsigargin, a SERCA inhibitor, that mediates mast cell activation by increasing cytosolic Ca 2+ levels. 25 Here, we investigated the effects of SERCA activation on allergen-induced mast cell activation by targeting the protein with CDN1163.…”

“…Recently, the quinoline derivative, CDN1163, was identified as a reversible SERCA activator that works by enhancing ATP-dependent Ca 2+ translocation. 17 The potential therapeutic effects of CDN1163 have been investigated in various inflammatory-driven disease models such as Duchenne muscular dystrophy, Parkinson's disease, and diabetes, where it has been shown to reduce cytosolic Ca 2+ concentrations, alleviate ER stress, and restore mitochondrial function. [18][19][20] In this study, we characterized the effects of SERCA activation with CDN1163 in IgE-sensitized murine bone marrow-derived mast cells (BMMCs) stimulated with allergen via IgE-FcεRI under stem cell factor (SCF) potentiation.…”

“…Therefore, pharmacologically stimulating SERCA to induce Ca 2+ reuptake would limit cytosolic Ca 2+ signals in response to allergen‐induced activation and could be a potential novel approach to treat allergic pathologies. Recently, the quinoline derivative, CDN1163, was identified as a reversible SERCA activator that works by enhancing ATP‐dependent Ca 2+ translocation 17 . The potential therapeutic effects of CDN1163 have been investigated in various inflammatory‐driven disease models such as Duchenne muscular dystrophy, Parkinson's disease, and diabetes, where it has been shown to reduce cytosolic Ca 2+ concentrations, alleviate ER stress, and restore mitochondrial function 18–20 …”