GO:0098909 regulation of cardiac muscle cell action potential involved in regulation of contraction: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0098909 describes the biological process that modulates the frequency, rate or extent of action potential creation, propagation or termination in a cardiac muscle cell, specifically contributing to the regulation of its contraction.
• Cardiac action potentials are shaped by the coordinated activity of ion channels, transporters and calcium-handling proteins, including SCN5A, CACNA1C, KCNQ1, KCNH2, ATP2A2, RYR2 and SLC8A1.
• Calcium-induced calcium release and sodium-calcium exchange are central mechanisms linking action potential regulation to contraction.
• Dysregulation of this process underlies tachyarrhythmias, sudden cardiac death and septic cardiomyopathy.
• Transcriptional programs involving TBX5, NKX2-5 and other cardiac transcription factors establish the conduction system and set the stage for action potential regulation.
• CRISPR-based knockout, point-mutation, knock-in and overexpression models enable causal testing of genes in this process, while CRISPR library screening and bioinformatics can identify novel regulators.
Description
The regulation of cardiac muscle cell action potential involved in regulation of contraction (GO:0098909) is a fundamental biological process that ensures the heart's electrical activity is finely tuned to meet the mechanical demands of the body. This process encompasses any modulation of the frequency, rate or extent of action potential creation, propagation or termination in cardiac muscle cells, specifically in the context of regulating contraction. It is essential for normal cardiac rhythm and function, and its disruption is a hallmark of numerous cardiac pathologies. Researchers study this process to understand how ion channels, transporters and signaling pathways coordinate to maintain cardiac output and to identify therapeutic targets for arrhythmias and heart failure. The complexity of this regulation involves multiple ion currents, calcium handling, and paracrine influences, making it a rich area for both basic and translational research.
regulation of cardiac muscle cell action potential involved in regulation of contraction At A Glance
| GO ID | GO:0098909 |
|---|---|
| GO term | regulation of cardiac muscle cell action potential involved in regulation of contraction |
| Ontology | biological_process |
| Synonym | None |
| Major function | Modulates the frequency, rate or extent of action potential creation, propagation or termination in cardiac muscle cells to regulate contraction. |
| Key ion channels | SCN5A, CACNA1C, KCNQ1, KCNH2, HCN4. |
| Key calcium-handling proteins | RYR2, ATP2A2, SLC8A1, ITPR1/2. |
| Related processes | Calcium signaling, cardiac conduction, excitation-contraction coupling. |
| Disease relevance | Arrhythmias, sudden cardiac death, septic cardiomyopathy. |
What Is GO:0098909?
GO:0098909 is defined as any process that modulates the frequency, rate or extent of action potential creation, propagation or termination in a cardiac muscle cell contributing to the regulation of its contraction. In simpler terms, it is the set of mechanisms that control the electrical impulses in heart muscle cells, which in turn determine how strongly and how often the heart contracts.
Why Is regulation of cardiac muscle cell action potential involved in regulation of contraction Important in Cell Biology?
Understanding GO:0098909 is critical because it sits at the intersection of electrical signaling and mechanical contraction in the heart. Dysregulation of this process can lead to life-threatening arrhythmias and sudden cardiac death, as well as contribute to heart failure and septic cardiomyopathy. Moreover, the process is a major target for antiarrhythmic drugs and is essential for interpreting cardiac safety in drug development. Research into this term also informs regenerative medicine efforts, as proper action potential regulation is required for functional cardiomyocytes derived from stem cells.
• Maintains normal cardiac rhythm and excitation-contraction coupling.
• Dysregulation causes tachyarrhythmias and sudden cardiac death.
• Involved in septic heart dysfunction and paracrine regulation.
• Target for antiarrhythmic and cardiotonic drugs.
• Essential for proper development of the cardiac conduction system.
• Key to understanding calcium and sodium dysregulation in heart disease.
• Relevant to stem cell-derived cardiomyocyte maturation and safety pharmacology.
• Provides mechanistic insights into inherited channelopathies.
• Links electrical activity to metabolic and paracrine signals.
• Enables identification of novel therapeutic targets via CRISPR screens.
What Happens During regulation of cardiac muscle cell action potential involved in regulation of contraction?
Initiation of the action potential
In simple terms: The heart cell starts an electrical signal when sodium channels open.
The cardiac action potential begins with a rapid depolarization phase driven by sodium influx through voltage-gated sodium channels, primarily SCN5A. This phase is modulated by the availability of sodium channels and the resting membrane potential, which is maintained by the sodium-potassium pump and other transporters. The frequency of action potential initiation is influenced by pacemaker currents, such as the funny current (If) carried by HCN channels, particularly in the sinoatrial node.
Plateau and calcium handling
In simple terms: Calcium entering the cell triggers more calcium release, shaping the long plateau of the heart's electrical signal.
The plateau phase of the cardiac action potential is characterized by a balance between inward calcium current through L-type calcium channels (CACNA1C) and outward potassium currents. Calcium influx triggers calcium-induced calcium release from the sarcoplasmic reticulum via ryanodine receptor 2 (RYR2), a process essential for contraction. The sodium-calcium exchanger (SLC8A1) also contributes to calcium homeostasis and membrane potential regulation. Inositol 1,4,5-trisphosphate receptors (ITPRs) provide additional calcium signaling that can modulate action potential and contraction.
Repolarization and termination
In simple terms: Potassium channels open to end the electrical signal and reset the cell.
Repolarization is mediated by the activation of various potassium channels, including KCNQ1 (slow delayed rectifier) and KCNH2 (rapid delayed rectifier), which allow potassium efflux to restore the resting membrane potential. The rate of repolarization affects the action potential duration and refractory period, which are critical for preventing arrhythmias. Dysregulation of these potassium currents can lead to prolonged QT interval and tachyarrhythmias.
Modulation by signaling pathways
In simple terms: Hormones and other signals can speed up or slow down the heart's electrical activity.
The action potential and contraction are modulated by beta-adrenergic signaling, which enhances calcium influx and release, and by paracrine factors released from endothelial cells and fibroblasts. Transcriptional regulation by cardiac transcription factors such as TBX5 and NKX2-5 establishes the expression patterns of ion channels and calcium-handling proteins, thereby setting the intrinsic properties of the conduction system. These regulatory layers ensure that cardiac output adapts to physiological demands.
Key Genes Involved in GO:0098909 regulation of cardiac muscle cell action potential involved in regulation of contraction
The following genes encode key ion channels, transporters, calcium-handling proteins and transcription factors that are central to the regulation of cardiac muscle cell action potential involved in regulation of contraction.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SCN5A | Voltage-gated sodium channel alpha subunit, mediates rapid depolarization | Mutations cause Brugada syndrome and long QT syndrome; target for antiarrhythmic drugs. |
| CACNA1C | L-type calcium channel alpha-1C subunit, mediates calcium influx during plateau | Mutations linked to Timothy syndrome and Brugada syndrome; key for calcium-induced calcium release. |
| KCNQ1 | Slow delayed rectifier potassium channel, contributes to repolarization | Mutations cause long QT syndrome type 1; target for IKs modulators. |
| KCNH2 | Rapid delayed rectifier potassium channel, contributes to repolarization | Mutations cause long QT syndrome type 2; common off-target for drug cardiotoxicity. |
| HCN4 | Hyperpolarization-activated cyclic nucleotide-gated channel, pacemaker current | Mutations cause sinus node dysfunction; important for heart rate regulation. |
| RYR2 | Ryanodine receptor 2, mediates calcium release from sarcoplasmic reticulum | Mutations cause catecholaminergic polymorphic ventricular tachycardia; central to calcium-induced calcium release. |
| ATP2A2 | SERCA2a calcium pump, reuptakes calcium into sarcoplasmic reticulum | Dysregulation contributes to heart failure; target for gene therapy. |
| SLC8A1 | Sodium-calcium exchanger, regulates calcium efflux and membrane potential | Involved in arrhythmias and heart failure; modulates action potential duration. |
| ITPR1 | Inositol 1,4,5-trisphosphate receptor type 1, releases calcium from internal stores | Modulates cardiac calcium signaling and hypertrophy. |
| ITPR2 | Inositol 1,4,5-trisphosphate receptor type 2, releases calcium from internal stores | Contributes to nuclear calcium signaling and gene regulation. |
| TBX5 | T-box transcription factor, regulates conduction system development | Mutations cause Holt-Oram syndrome; key for conduction gene expression. |
| NKX2-5 | Homeobox transcription factor, regulates cardiac development and conduction | Mutations associated with congenital heart disease and arrhythmias. |
| GJA1 | Connexin 43, gap junction protein for electrical coupling | Essential for action potential propagation; remodeling in heart failure. |
| GJA5 | Connexin 40, gap junction protein in conduction system | Important for fast conduction in Purkinje fibers. |
| ATP1A1 | Na+/K+-ATPase alpha-1 subunit, maintains resting membrane potential | Regulates sodium and potassium gradients; target for cardiac glycosides. |
| ATP1A2 | Na+/K+-ATPase alpha-2 subunit, maintains resting membrane potential | Contributes to calcium regulation via sodium-calcium exchanger. |
| ADRB1 | Beta-1 adrenergic receptor, mediates sympathetic modulation | Polymorphisms influence heart rate and response to beta-blockers. |
| ADRB2 | Beta-2 adrenergic receptor, mediates sympathetic modulation | Modulates contractility and action potential duration. |
How Is regulation of cardiac muscle cell action potential involved in regulation of contraction Regulated?
The process of regulating cardiac muscle cell action potential is itself subject to multiple layers of regulation. Transcriptional control by TBX5 and NKX2-5 establishes the expression of ion channel and calcium-handling genes during development and in the adult heart. Post-translational modifications, such as phosphorylation by protein kinases A and C, modulate the activity of ion channels and transporters in response to beta-adrenergic stimulation. Calcium-dependent signaling pathways, including those involving calmodulin and calcineurin, can feedback on ion channel function and gene expression. Paracrine factors released by endothelial cells and fibroblasts, such as nitric oxide and endothelin-1, also influence action potential and contraction. Additionally, the sodium-calcium exchanger and sodium-potassium pump are regulated by intracellular sodium and calcium levels, linking electrical activity to metabolic state.
regulation of cardiac muscle cell action potential involved in regulation of contraction and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SCN5A | Brugada syndrome, long QT syndrome | Knockout or point-mutation iPSC-derived cardiomyocytes. |
| KCNH2 | Long QT syndrome type 2 | Knock-in of patient mutations in HEK293 or cardiomyocytes. |
| RYR2 | Catecholaminergic polymorphic ventricular tachycardia | Knock-in mouse or iPSC-derived cardiomyocytes. |
| ATP2A2 | Heart failure, calcium handling defects | Overexpression or knockout in cardiomyocytes. |
| TBX5 | Holt-Oram syndrome, conduction defects | Knockout or knock-in in zebrafish or mouse. |
Arrhythmias and sudden cardiac death
Dysregulation of cardiac action potential regulation is a primary cause of tachyarrhythmias and sudden cardiac death. Sodium and calcium dysregulation can lead to afterdepolarizations and triggered activity, while potassium channel dysfunction prolongs repolarization and increases the risk of torsades de pointes. Mutations in SCN5A, KCNQ1, KCNH2 and RYR2 are well-established causes of inherited arrhythmia syndromes.
Septic cardiomyopathy
In septic heart, paracrine regulation of cardiac myocytes is altered, leading to depressed contractility and arrhythmias. Inflammatory mediators can modulate ion channel function and calcium handling, contributing to action potential abnormalities. Understanding these mechanisms may reveal therapeutic targets for septic cardiomyopathy.
Heart failure and calcium handling
Heart failure is associated with impaired calcium handling, including reduced SERCA2a activity and increased sodium-calcium exchanger expression, which can alter action potential duration and increase arrhythmia risk. These changes are part of maladaptive remodeling that contributes to disease progression.
Channelopathies and congenital heart disease
Congenital mutations in ion channel genes or transcription factors such as TBX5 and NKX2-5 can cause channelopathies and conduction defects. For example, TBX5 mutations lead to Holt-Oram syndrome, which includes conduction abnormalities. These genetic insights guide diagnosis and potential gene-based therapies.
From regulation of cardiac muscle cell action potential involved in regulation of contraction-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of SCN5A alter action potential duration? | CRISPR knockout in iPSC-derived cardiomyocytes. |
| Does a specific KCNH2 mutation cause long QT? | Point mutation knock-in in HEK293 or cardiomyocytes. |
| Can overexpression of ATP2A2 rescue calcium handling? | Overexpression in cardiomyocytes or mouse heart. |
| What is the role of ITPR2 in nuclear calcium signaling? | Knockout or tagged knock-in in cardiomyocytes. |
| Does TBX5 regulate conduction gene expression? | Knockout or knock-in in zebrafish or mouse. |
| Can a CRISPR screen identify novel regulators of action potential? | Genome-wide CRISPR library screening in cardiomyocytes. |
How to Study the regulation of cardiac muscle cell action potential involved in regulation of contraction Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Patch-clamp | Action potential duration, ion currents | Functional characterization of ion channels in cardiomyocytes. |
| Calcium imaging | Intracellular calcium transients | Assessment of calcium handling and release. |
| Multi-electrode array | Extracellular field potentials, conduction velocity | High-throughput drug screening and arrhythmia detection. |
| RNA-seq | Gene expression profiles | Identification of transcriptional networks in conduction system. |
| Proteomics | Protein abundance and modifications | Quantification of ion channel and transporter proteins. |
| CRISPR screen | Gene function at scale | Discovery of novel regulators of action potential. |
| Bioinformatics | Pathway and network analysis | Integration of multi-omics data to prioritize targets. |
| Voltage-sensitive dyes | Membrane potential changes | Optical mapping of action potential propagation. |
Electrophysiology
Patch-clamp techniques measure action potentials and ion currents in isolated cardiomyocytes, providing direct functional readouts of GO:0098909. Multi-electrode arrays and voltage-sensitive dyes enable higher-throughput assessment of action potential propagation in monolayers.
Calcium imaging
Fluorescent calcium indicators, such as Fura-2 or Fluo-4, allow visualization of calcium transients and sparks in cardiomyocytes, linking action potential regulation to calcium handling. This method is essential for studying calcium-induced calcium release and its modulation.
Transcriptomics and proteomics
RNA sequencing and proteomics can quantify expression of ion channels, transporters and signaling proteins in cardiac tissue or derived cardiomyocytes, revealing molecular correlates of action potential regulation. These approaches help identify transcriptional networks controlled by TBX5 and NKX2-5.
CRISPR screening and bioinformatics
Genome-wide CRISPR knockout or activation screens combined with electrophysiological or calcium imaging readouts can identify novel regulators of cardiac action potential and contraction. Bioinformatics analysis of screen data, such as pathway enrichment and network modeling, prioritizes candidate genes for further study.
How CRISPR Can Be Used to Study GO:0098909 regulation of cardiac muscle cell action potential involved in regulation of contraction
Knockout
CRISPR knockout of genes such as SCN5A, KCNQ1 or RYR2 in cardiomyocytes or animal models can reveal their essential roles in action potential regulation and contraction. Knockout studies help determine causality and compensatory mechanisms.
Point Mutation
Introducing patient-specific point mutations (e.g., in KCNH2 or SCN5A) using CRISPR base editing or homology-directed repair allows precise modeling of channelopathies and assessment of drug responses. These models are valuable for personalized medicine.
Knock-in
Knock-in of reporter genes or epitope tags (e.g., tagging RYR2 or ITPR2) enables live-cell imaging and biochemical isolation of protein complexes involved in action potential regulation. This approach provides spatial and temporal resolution.
Overexpression
CRISPR activation or transgenic overexpression of genes like ATP2A2 can rescue calcium handling defects and improve contractility in heart failure models. Overexpression studies help identify therapeutic targets.
How EDITGENE Supports regulation of cardiac muscle cell action potential involved in regulation of contraction Research
Researchers studying regulation of cardiac muscle cell action potential involved in regulation of contraction-related genes often need to determine whether a candidate gene is causally involved in the process or merely correlated with it. EDITGENE provides a comprehensive suite of CRISPR-based services to enable such causal investigations, from single-gene knockout to genome-wide screening, all supported by expert bioinformatics.
Contact EDITGENE today to design your custom CRISPR model for regulation of cardiac muscle cell action potential involved in regulation of contraction research.
Frequently Asked Questions About regulation of cardiac muscle cell action potential involved in regulation of contraction
What is GO:0098909?
GO:0098909 is a Gene Ontology biological process term defined as any process that modulates the frequency, rate or extent of action potential creation, propagation or termination in a cardiac muscle cell contributing to the regulation of its contraction.
What genes are involved in regulation of cardiac muscle cell action potential?
Key genes include SCN5A, CACNA1C, KCNQ1, KCNH2, HCN4, RYR2, ATP2A2, SLC8A1, ITPR1, ITPR2, TBX5, NKX2-5, GJA1, GJA5, ATP1A1, ATP1A2, ADRB1 and ADRB2.
How does calcium signaling regulate cardiac action potential?
Calcium influx through L-type calcium channels triggers calcium release from the sarcoplasmic reticulum via RYR2, shaping the plateau phase and linking excitation to contraction. Sodium-calcium exchange and IP3 receptors further modulate calcium and membrane potential.
What diseases are associated with dysregulation of cardiac action potential?
Dysregulation is linked to tachyarrhythmias, sudden cardiac death, long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, heart failure and septic cardiomyopathy.
What research methods are used to study GO:0098909?
Common methods include patch-clamp electrophysiology, calcium imaging, multi-electrode arrays, RNA-seq, proteomics, CRISPR screens and bioinformatics.
How can CRISPR help study cardiac action potential regulation?
CRISPR knockout, point mutation, knock-in and overexpression models allow causal testing of genes in cardiomyocytes, while CRISPR screens can identify novel regulators.
What is the role of SCN5A in cardiac action potential?
SCN5A encodes the alpha subunit of the voltage-gated sodium channel responsible for the rapid depolarization phase of the cardiac action potential.
How does KCNH2 contribute to repolarization?
KCNH2 encodes the rapid delayed rectifier potassium channel (IKr), which mediates potassium efflux during repolarization and is critical for action potential duration.
What is the significance of RYR2 in cardiac contraction?
RYR2 is the ryanodine receptor that releases calcium from the sarcoplasmic reticulum, a key step in calcium-induced calcium release and excitation-contraction coupling.
Can EDITGENE provide custom CRISPR models for cardiac genes?
Yes, EDITGENE offers knockout, point mutation, knock-in, overexpression, CRISPR library screening and bioinformatics services tailored to cardiac action potential research.
Conclusion
GO:0098909 encompasses the intricate regulation of cardiac muscle cell action potentials that ultimately controls contraction. This process is fundamental to normal heart function and its dysregulation leads to serious cardiac diseases. Advances in CRISPR-based models and multi-omics approaches are accelerating the discovery of new mechanisms and therapeutic targets. EDITGENE stands ready to support researchers with customized CRISPR services to dissect this process further.
References
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- 5. Demydenko K et al.. 2022. Inositol 1,4,5-trisphosphate receptors in cardiomyocyte physiology and disease.. Philos Trans R Soc Lond B Biol Sci 377(1864):20210319 PMID: 36189803
- 6. Blaustein MP et al.. 1999. Sodium/calcium exchange: its physiological implications.. Physiol Rev 79(3):763-854 PMID: 10390518
- 7. Corda S et al.. 1998. Paracrine regulation of cardiac myocytes in normal and septic heart.. J Crit Care 13(1):39-47 PMID: 9556126
- 8. Wagner S et al.. 2015. Role of sodium and calcium dysregulation in tachyarrhythmias in sudden cardiac death.. Circ Res 116(12):1956-70 PMID: 26044250
