Regulation of cardiovascular calcium channel activity by post-translational modifications or interacting proteins
Kelvin Wei Zhern Loh1,2, Mui Cheng Liang1, Tuck Wah Soong3,4,5
1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117593, Singapore.
Abstract:
Voltage-gated calcium channels are the major pathway for Ca2+ influx to initiate the contraction of smooth and cardiac muscles. Alterations of calcium channel function have been implicated in multiple cardiovascular diseases, such as hypertension, atrial fibrillation, and long QT syndrome. Post-translational modifications do expand cardiovascular calcium channel structure and function to affect processes such as channel trafficking or polyubiquitination by two E3 ubiquitin ligases, Ret finger protein 2 (Rfp2) or murine double minute 2 protein (Mdm2). Additionally, biophysical property such as Ca2+-dependent inactivation (CDI) could be altered through binding of calmodulin, or channel activity could be modulated via S-nitrosylation by nitric oxide and phosphorylation by protein kinases or by interacting protein partners, such as galectin-1 and Rem. Understanding how cardiovascular calcium channel function is post-translationally remodeled under distinctive disease conditions will provide better information about calcium channel-related disease mechanisms and improve the development of more selective therapeutic agents for cardiovascular diseases.
Insights
Voltage-gated calcium channels regulate muscle contraction. Post-translational modifications impact their function, offering insights into cardiovascular diseases and new therapeutic targets.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Biochemistry
Background:
- Voltage-gated calcium channels are crucial for smooth and cardiac muscle contraction.
- Dysfunctional calcium channels are linked to cardiovascular diseases like hypertension and long QT syndrome.
Purpose of the Study:
- To explore how post-translational modifications remodel cardiovascular calcium channel function in disease states.
- To enhance understanding of calcium channel-related disease mechanisms and inform therapeutic development.
Main Methods:
- Investigated post-translational modifications including polyubiquitination by E3 ligases (Rfp2, Mdm2).
- Examined alterations in biophysical properties like Ca2+-dependent inactivation (CDI) via calmodulin binding.
- Analyzed modulation of channel activity through S-nitrosylation, phosphorylation, and protein interactions (galectin-1, Rem).
Main Results:
- Post-translational modifications significantly alter cardiovascular calcium channel structure and function.
- Specific modifications affect channel trafficking, ubiquitination, Ca2+ inactivation, and overall activity.
- Interactions with calmodulin, nitric oxide, protein kinases, galectin-1, and Rem modulate channel function.
Conclusions:
- Understanding post-translational remodeling of cardiovascular calcium channels is key to elucidating disease mechanisms.
- This knowledge can guide the development of more selective therapeutic agents for cardiovascular diseases.
Related Concept Videos
01:16Calmodulin-dependent Signaling
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
01:18Antihypertensive Drugs: Action of Calcium Channel Blockers
01:27Feedback Regulation of Calcium Concentration
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
02:04Covalently Linked Protein Regulators
These groups modify specific amino acids in a protein....
02:04Covalently Linked Protein Regulators
02:24Regulation of Expression Occurs at Multiple Steps
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...