Lecture 9 - Linking Structure to Function & Implications for Disease

Question 1

What models of voltage gating are there?

Answer 1

• Helical screw model
• Paddle model

Question 2

Ball and chain mechanism

Answer 2

Gating inactivation - physical blockage of the channel

Defects in inactivation may cause disease

Question 3

Channelopathies: what are they and where can they be caused?

Answer 3

Arise as a consequence of defects

• In the coding region of ion channel genes
• Outside the coding region (introns, promoter regions, etc)
• In genes encoding for auxiliary proteins
• Antibodies to ion channel proteins
• Ion channel recycling/trafficking

Question 4

CFTR: what is it, what mutation classes are there, what defects are caused by which mutation class, and what examples of these mutations are there?

Answer 4

Hereditary disease

I - Deficient synthesis - G542X
II - Deficient traffic - F508del
III - Impaired gating - G551D
IV- Decreased conductance - R334W
V - Less protein - 3272-26A>G
VI - Reduced half-life - rF508del

Question 5

Piezo 1/2

Answer 5

Loss-of-function mutations in the human PIEZO genes cause autosomal recessive congenital lymphatic dysplasia (Piezo 1) autosomal recessive syndrome of muscular atrophy with perinatal respiratory distress, arthrogryposis and scoliosis (Piezo 2)

b) Gain-of-function mutations in the human PIEZO genes cause the autosomal dominant haemolytic anaemia, hereditary stomatocytosis (Piezo 1) and three clinical types of autosomal dominant distal arthrogryposis (Piezo 2)

Mechanosensitive channels - In hereditary stomatocytosis red blood cells show
increased cation permeability, causing erythrocyte dehydration leading to hemolytic
anemia, with PIEZO1 mutations linked to the disease. Mechanotransduction
properties show altered properties, including slower inactivation kinetics to
mechanical stimulation, which could lead to increased cation flux.

Correct functioning - slower inactivation, more ions pass through, damage causes

Question 6

Voltage-gated sodium channels (NaVChs) – Inherited disorders
a) Muscle: Hypercalemic paralysis, Myasthenic syndrome, painful congenital
myotonia
b) Cardiac: Long QT syndrome, Sudden infant death syndrome, dilated
cardiomyopathy
c) Brain: Epilepsy with seizures

Answer 6

• Muscle: Hyperkalemic paralysis, Myasthenic syndrome, painful congenital myotonia
• Cardiac: Long QT syndrome, Sudden infant death syndrome, dilated cardiomyopathy
• Brain: Epilepsy with seizures

Sodium channels - Disturbances in the function of NaVChs channel affect the
ability of skeletal muscle to contract or relax. Periodic paralysis is characterized by
episodic weakness or paralysis of voluntary muscles. Mutations associated with
hyperkalemic periodic paralysis exhibit incomplete inactivation leading to a small
level of persistent Na+ current causing sustained muscle fibre depolarization.
Depolarization will cause the majority of NaVChs to become inactivated, leading to
conduction failure and electrical inexcitability during periodic paralysis.

Question 7

Potassium channels: what syndromes are caused by defects in these channels and what is the process behind these issues?

Answer 7

• Long QT syndrome
• Arrhythmias
• Epilepsy
• Ataxia
• Neuromyotonia
• Type 2
• Diabetes mellitus
• Cardiac hypertrophy
• Hereditary deafness syndromes

TREK-1 potassium channel is expressed in the heart and is related to abnormal heart rhythms causing arrhythmias, with the most common type being atrial fibrillation (AF)

AF is perpetuated by the imbalanced electrical properties of cardiomyocytes, leading to atrial repolarization and a decrease in electrical conduction velocity

TREK-1 is activated by a drop in the pH and ATP levels, which leads to electrophysiological disturbances in the ventricle wall, resulting in a high risk of arrhythmias

Downregulation of TREK-1 results in cardiac refractoriness and shortening of action potential duration

Question 8

LQT syndrome: what is it, what does it cause, and what is it caused by?

Answer 8

The abnormally long delay between electrical excitation and relaxation of the ventricles

• Arrhythmias
• Syncope on with exercise or excitement
• Ventricular fibrillation
• Death
• LQT3/10 are caused by defects in different components of VGNaCs, resulting in impaired channel inactivation - depolarisation problems
• LQT8 caused by VGCaCs, prolonging the depolarisation current - plateau phase issues
• LQT2/6 and LQT1/5 caused by VGKCs, causing impaired channel inactivation of the HERG channel - fast repolarisation and terminal repolarisation issues
• LQT7 and LQT13 are caused by defective Kir, altering the background current values - resting phase issues

Question 9

Insulin release

Answer 9

beta cells

Potassium channel voltage raised (stimulated by ATP/ADP), calcium ion influx, release of insulin

Question 10

Uncontrolled insulin release

Answer 10

Defects in ABCC8/KCNJ11, causing congenital hyperinsulinism in infancy (CHI)

Loss of functional Katp associaye with a spontaneous depolarised membrane potential and uncontrolled CA2+ influx through VGCaCs

Profound hypoglycaemia caused - resulting in neonatal irreversible brain damage and potentially lethal