Biophysical Properties of Nav1.5
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Questions and Answers

What is the primary role of Nav1.5 in the human heart?

  • Driving the sodium current (INa) (correct)
  • Facilitating calcium absorption
  • Regulating blood pressure
  • Causing muscle contractions

    • Nav1.5 consists solely of α subunits.

    False (B)

    What genetic locus is associated with Brugada syndrome according to recent genome-wide association analyses?

    SCN5A

    The primary consequence of the M1875T-SCN5A mutation in familial atrial fibrillation is an increase in __________.

    <p>early sodium current</p> Signup and view all the answers

    Which experimental technique is useful for exploring cardiac electrophysiology?

    <p>High resolution optical mapping (B)</p> Signup and view all the answers

    The SCN5A gene is integral to the function of Nav1.5.

    <p>True (A)</p> Signup and view all the answers

    Nav1.5 is primarily expressed in the __________.

    <p>human myocardium</p> Signup and view all the answers

    Which of the following is NOT a focus of research mentioned regarding Nav1.5?

    <p>Environmental effects on heart health (D)</p> Signup and view all the answers

    What gene encodes the Nav1.5 protein?

    <p>SCN5A (B)</p> Signup and view all the answers

    Type 3 Long QT syndrome is caused by gain-of-function mutations in the SCN5A gene.

    <p>True (A)</p> Signup and view all the answers

    What syndrome is characterized by loss-of-function mutations in the SCN5A gene?

    <p>Brugada syndrome</p> Signup and view all the answers

    Match the syndromes with their characteristics:

    <p>Long QT syndrome = Prolongs action potential duration Brugada syndrome = Loss-of-function mutations Early repolarisation syndrome = Elusive genetic factors Congenital sick sinus syndrome = Heart rhythm abnormalities</p> Signup and view all the answers

    Which of the following is NOT a genetic polymorphism of SCN5A?

    <p>Hypertrophic cardiomyopathy (D)</p> Signup and view all the answers

    The MAPRE2 gene has been identified as a responsible factor for Brugada syndrome.

    <p>True (A)</p> Signup and view all the answers

    What characteristic ECG finding can occur in Brugada syndrome?

    <p>Unmasked by sodium-channel blockers</p> Signup and view all the answers

    What effect does Type 3 Long QT syndrome have on the QT interval?

    <p>It prolongs the QT interval. (D)</p> Signup and view all the answers

    Which drug has been reported to increase mortality compared to placebo control?

    <p>Flecainide (A)</p> Signup and view all the answers

    Flecainide has a wide therapeutic window.

    <p>False (B)</p> Signup and view all the answers

    What is one major adverse event associated with the 'pill-in-pocket' approach using anti-arrhythmic drugs?

    <p>QRS duration prolongation or Brugada syndrome or Cardiogenic shock</p> Signup and view all the answers

    A common polymorphism in SCN5A, known as ______, may increase sensitivity to propafenone.

    <p>R1193Q</p> Signup and view all the answers

    Match the following genetic variations with their associated effects:

    <p>R1193Q = Increased sensitivity to propafenone M1875T = Decreased sensitivity to flecainide MAPRE2 = Identified gene for Brugada syndrome SCN5A = Involved in biophysical diversity and arrhythmias</p> Signup and view all the answers

    What is one effect of point mutations in the C-terminus of SCN5A α subunit?

    <p>Decreased sensitivity to flecainide (C)</p> Signup and view all the answers

    The polymorphism R1193Q in SCN5A does not have any significant clinical implications.

    <p>False (B)</p> Signup and view all the answers

    What are the effects on biophysical properties associated with MAPRE KO hiPSC-CMs?

    <p>Reduced Vmax and APDs</p> Signup and view all the answers

    Anti-arrhythmic drugs often have a narrow therapeutic ______.

    <p>window</p> Signup and view all the answers

    Which of the following is NOT a reported major adverse event from the use of flecainide at therapeutic doses?

    <p>Myocardial infarction (C)</p> Signup and view all the answers

    Flashcards

    Nav1.5

    The pore-forming subunit of the voltage-gated sodium channel in the human heart.

    Cardiac sodium channel

    A channel in the heart, made of alpha (α) and beta (β) subunits, responsible for sodium current (INa).

    Sodium current (INa)

    The flow of sodium ions across the heart cells membrane due to the sodium channel.

    Voltage-gated sodium channel

    A protein that opens and closes its channel in response to changes in voltage across the cell membrane.

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    Myocardium

    The heart muscle.

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    Brugada syndrome

    A genetic disorder causing abnormal heart rhythms.

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    Genetic polymorphisms

    Variations in genes, often associated with disease susceptibility.

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    Experimental techniques

    Methods used to study cardiac electrophysiology.

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    Cardiac electrophysiology

    The study of the electrical activity of the heart.

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    α and β subunits

    The components of the cardiac sodium channel.

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    Nav1.5 gating

    The process controlling the opening and closing of the sodium channels in the heart (Nav1.5).

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    SCN5A gene

    The gene that encodes for the Nav1.5 sodium channel protein.

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    Long QT syndrome (LQTS)

    A heart condition caused by mutations in genes, including SCN5A, that affect the electrical signals in the heart and cause prolonged electrical activity.

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    Type 3 LQTS

    A type of Long QT syndrome (LQTS) caused by mutations that make the sodium channels (Nav1.5) more active, extending the heart's electrical activity.

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    Brugada syndrome (BrS)

    A heart condition caused by mutations in genes, including SCN5A, that affect the electrical signals in the heart, and present with characteristic ECG changes.

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    BrS type 1

    A type of Brugada syndrome (BrS) caused by problems with sodium channel function (loss-of-function mutations).

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    Optical mapping

    A technique using fluorescence to visualize and measure electrical activity in cardiac tissues.

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    Action potential duration (APD)

    The length of time an action potential lasts in a heart cell.

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    Conduction velocity

    The speed at which electrical signals travel through the heart.

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    Gain-of-function mutations

    Genetic mutations that enhance the activity of a protein.

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    MAPRE2

    A protein recently discovered to be involved in Brugada Syndrome. Mutations in MAPRE2 lead to reduced sodium current and repolarization in heart cells.

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    Reduced Vmax

    A slower rate of depolarization in heart cells, meaning it takes longer for the cell to reach its peak voltage. This can contribute to arrhythmias.

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    Reduced APD

    Shorter action potential duration in heart cells, meaning they repolarize faster. This can also lead to arrhythmias.

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    Anti-arrhythmic drug limitations

    Anti-arrhythmic drugs have a narrow therapeutic window, meaning the difference between a therapeutic dose and a harmful dose is small. They can also cause pro-arrhythmia, meaning they can worsen arrhythmias.

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    Flecainide and encainide

    Anti-arrhythmic drugs that, despite their initial use for ventricular arrhythmias, were found to increase mortality when used after myocardial infarction.

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    ‘Pill-in-pocket’ approach risks

    Using single oral doses of anti-arrhythmic drugs like flecainide or propafenone can lead to major adverse events such as prolonged QRS duration, Brugada syndrome, and cardiogenic shock.

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    R1193Q polymorphism

    A common genetic variation in the SCN5A gene that makes individuals more sensitive to the effects of propafenone, leading to the development of Brugada syndrome.

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    M1875T mutation

    A genetic mutation that decreases sensitivity to flecainide. It is associated with familial atrial fibrillation.

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    Biophysical diversity in SCN5A

    There are natural variations in the electrical properties of the sodium channel gene (SCN5A) in different parts of the heart. This means that electrical signals may travel differently in different areas of the heart.

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    SCN5A and Brugada syndrome

    The SCN5A gene encodes the sodium channel, and mutations in this gene are commonly associated with the development of Brugada syndrome.

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    Study Notes

    Biophysical properties of Nav1.5

    • The cardiac sodium channel, Na 1.5, is composed of α and β subunits
    • α subunit is the pore-forming subunit of voltage-gated sodium channels in the human myocardium
    • The function of Na 1.5 drives the sodium current (INa) in the heart

    Learning Outcomes

    • Describe the biophysical properties of Nav1.5
    • Describe genetic polymorphisms in SCN5A and their clinical implications
    • Describe appropriate experimental techniques to explore cardiac electrophysiology
    • Barc et al. (2022) identified new Brugada syndrome risk loci and sodium channel regulation.
    • S. O. B. et al. (2022) found that flecainide effectiveness increases due to changes in sodium channels.
    • O'Reilly et al. (2023) showed that a SCN5A mutation (M1875T) increases early sodium current.
    • O'Shea et al. (2022) used optical mapping to study cardiac electrophysiology in models.
    • Wisedchaisri et al. (2019) investigated voltage-gated sodium channel structure and gating.

    What is Na 1.5?

    • The cardiac sodium channel is composed of α and β subunits
    • Na 1.5 is the pore-forming subunit in human myocardium
    • INa is the function that drives sodium current in the heart
    • Described as resting state, activated, inactivated and resting (closed) phases.
    • Depolarization and repolarization states are also featured in this process.

    SCN5A

    • Na 1.5 is encoded by the gene SCN5A
    • This gene (SCN5A) produces the protein that forms the pore of Na 1.5

    Genetic Polymorphisms of SCN5A

    • Long QT syndrome (LQTS)
    • Brugada syndrome (BrS)
    • Early repolarization syndrome
    • Congenital sick sinus syndrome
    • Familial atrial fibrillation
    • Sudden infant death syndrome

    Long QT Syndrome

    • Type 3 LQTS is caused by gain-of-function mutations in SCN5A.
    • More than 200 mutations exist.
    • Prolongs action potential duration (APD) which increases QT interval.

    Brugada Syndrome

    • BrS type 1 is caused by loss-of-function mutations in SCN5A
    • Characteristic ECG patterns can occur spontaneously
    • Can be unmasked with sodium channel blockers
    • MAPRE2 gene identified recently as having a possible role

    Additional Brugada info

    • Remaining genes involved are elusive.
    • MAPRE2 is a newly identified gene related to Brugada
    • Conduction velocity and action potential upstroke are reduced in patients
    • Other mutations reduce INa at all holding potentials

    Optical mapping for cardiac electrophysiology

    • Fluorescence technique using potentiometric dyes measures changes in various regions
    • Used in whole tissues/hearts.
    • Allows quantification of local/regional or global electrophysiology in paced specimens.

    The problem with anti-arrhythmic drugs

    • Many have narrow therapeutic windows
    • Can lead to pro-arrhythmia by increasing electrical sensitivity of certain cardiac regions.

    Major adverse events with the 'pill-in-pocket' approach

    • At therapeutic doses of single oral dose of flecainide or propafenone:
    • QRS duration prolongation
    • Brugada syndrome (BrS)
    • Cardiogenic shock
    • Flecainide originally used to treat ventricular arrhythmias after myocardial infarction.
    • Flecainide increased mortality compared to placebo.

    Polymorphisms in SCN5A

    • Propafenone can induce a Brugada syndrome ECG pattern in patients with SCN5A polymorphisms.
    • Some polymorphisms increase individual sensitivity to propafenone.

    Point mutations in SCN5A

    • Can decrease sensitivity to flecainide (M1875T).
    • Heterozygous point mutations are associated with familial AF.

    Biophysical diversity in SCN5A

    • There are natural differences in biophysical properties of SCN5A proteins
    • Differences in properties and pharmacological sensitivity to flecainide.
    • Possible cause is due to differential expressions/production of the pore-forming subunit protein (Na 1.5).

    What we discussed

    • Na 1.5 gating and structure
    • Exploring connections between SCN5A and clinical implications of genetic polymorphisms
    • Techniques used for pre-clinical research into genetic polymorphisms

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    Biophysical Properties of Nav1.5 PDF

    Description

    Explore the biophysical properties of the cardiac sodium channel Nav1.5, including its structure, function, and genetic polymorphisms. This quiz will cover experimental techniques and clinical implications related to SCN5A mutations and their impact on cardiac electrophysiology.

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