Related Experiment Video
Updated: Sep 3, 2025
09:26
Optical Mapping of Intra-Sarcoplasmic Reticulum Ca2+ and Transmembrane Potential in the Langendorff-perfused Rabbit Heart
Published on: September 10, 2015
9.4K
The RalGAPα1-RalA signal module protects cardiac function through regulating calcium homeostasis
Sangsang Zhu1, Chao Quan1, Ruizhen Wang1
1State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, China.
Nature Communications
|July 25, 2022
Summary
Ral-GTPase activating protein RalGAPα1 regulates SERCA2 activity in heart cells. Its deficiency worsens heart failure, while activating RalA improves cardiac function, offering new therapeutic targets for heart failure.
Area of Science:
- Cardiology
- Molecular Biology
- Cellular Physiology
Background:
- Sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2) dysfunction is central to heart failure.
- While SERCA2 activity is modulated by various factors, its precise regulation remains incompletely understood.
Purpose of the Study:
- To identify novel regulators of SERCA2 in cardiomyocytes.
- To elucidate the mechanism by which RalGAPα1 influences SERCA2 activity and cardiac function.
Main Methods:
- Investigated the role of RalGAPα1 and its downstream target RalA in regulating SERCA2 activity in cardiomyocytes.
- Utilized pressure overload models in mice to assess cardiac function and SERCA2 activity in the absence or presence of RalGAPα1.
- Examined the interaction between RalGAPα1, RalA, and SERCA2 using biochemical and cellular assays.
Main Results:
- RalGAPα1 deficiency exacerbates pressure overload-induced cardiac dysfunction and heart failure.
- RalGAPα1 directly interacts with SERCA2, and its absence impairs SERCA2 activity, prolonging cytosolic calcium levels.
- GDP-bound RalA, not GTP-bound RalA, directly binds and activates SERCA2.
- Overexpression of a GDP-bound RalA mutant preserves cardiac function in a heart failure mouse model.
Conclusions:
- RalGAPα1 is a critical regulator of SERCA2 in cardiomyocytes, influencing cardiac contractility and calcium handling.
- Targeting the RalGAPα1-RalA-SERCA2 pathway presents a promising therapeutic strategy for heart failure.
Related Concept Videos
01:22Activation and Inactivation of G Proteins
7.5K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
7.5K
01:16Calmodulin-dependent Signaling
5.2K
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
5.2K
01:21G-Protein Gated Ion Channels
4.8K
GPCRs are primarily responsible for our sense of smell, taste, and vision. The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory...
Sensory...
4.8K
01:27Feedback Regulation of Calcium Concentration
3.5K
Calcium is an essential signaling molecule required for various cellular functions. Calcium pumps and ion channels on cell and organellar membranes, such as those on the endoplasmic reticulum (ER), regulate calcium concentrations inside the cell. They remain closed, keeping the cytosolic calcium levels low at a resting state.
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
3.5K
01:24Small GTPases - Ras and Rho
4.2K
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
4.2K
01:25Rab Cascades
2.7K
Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.
2.7K