Biophysical Properties of Nav1.5

Biophysical Properties of Nav1.5

• Nav1.5 is a cardiac sodium channel, composed of α and β subunits
• It's the pore-forming subunit of voltage-gated sodium channels in human myocardium
• Its function drives sodium current (I_Na) in the heart
• The gene SCN5A encodes Nav1.5

Learning Outcomes

• Describe the biophysical properties of Nav1.5
• Describe genetic polymorphisms in SCN5A and their clinical implications
• Describe suitable experimental techniques for exploring cardiac electrophysiology

Recommended Reading

• Barc et al. (2022): Genome-wide association analyses identified new Brugada syndrome risk loci and a novel mechanism of sodium channel regulation in disease
• S. O. B. et al. (2022): Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels
• O’Reilly et al. (2023): Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens flecainide effect
• O’Shea et al. (2022): High resolution optical mapping of cardiac electrophysiology in pre-clinical models
• Wisedchaisri et al. (2019): Resting-state structure and gating mechanism of a voltage-gated sodium channel

What is Nav1.5?

• The cardiac sodium channel is composed of α and β subunits
• Nav1.5 is the pore-forming subunit of the voltage-gated sodium channel, found in the human myocardium
• Nav1.5 function drives sodium current (I_Na) in the human heart

Nav1.5 Gating

• The resting state, activated state, and inactivated state are key to the gating mechanism of Nav1.5
• Depolarization activates the channel
• Repolarization inactivates the channel

SCN5A

• Nav1.5 is encoded by the SCN5A gene
• Structural components of SCN5A are detailed (TBX5, NF-кB, GATA4, etc. are associated with transcription/translation/assembly and anchoring)
• Polymorphisms may impact drug action and cardiac conditions.

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 gain-of-function mutations identified
• Mutations prolong action potential duration (APD), thus increasing QT interval

Brugada Syndrome

• BrS type 1 is caused by loss-of-function mutations in SCN5A
• Characteristic ECG changes can be spontaneous or unmasked by sodium-channel blockers
• MAPRE2 has been identified as a contributing gene

Optical Mapping for Cardiac Electrophysiology

• Fluorescence-based technique using potentiometric dyes in whole tissues or hearts to measure changes in electrophysiology
• Enables quantification of regional/global changes in electrophysiology in paced specimens

Major Adverse Events with "Pill-in-Pocket" Approach

• At therapeutic doses, flecainide and propafenone can cause adverse effects
• QRS prolongation, Brugada syndrome, and cardiogenic shock are possible complications
• These complications may be related to SCN5A polymorphisms and biophysical properties, impacting drug effects

Polymorphisms in SCN5A

• Propafenone can induce Brugada syndrome ECG patterns in patients with SCN5A polymorphisms
• Example: R1193Q polymorphism may increase sensitivity to propafenone

Point Mutations in SCN5A

• Mutations in the C-terminus of the α subunit, like M1875T, reduce sensitivity to flecainide
• Heterozygous M1875T mutations associated with familial atrial fibrillation

Biophysical Diversity in SCN5A

• Left ventricular and left atrial cardiomyocytes show natural biophysical differences in SCN5A properties
• These differences may relate to distinct sodium channel subunit protein expression.