Na+ channels, structural & functional basis, pharmacology and disease

Question 1

How are Na channels distributed along the neuron?

Answer 1

Unevenly

Question 2

Where would you find most Na channels on a neuron?

Answer 2

In the axon hillock

Question 3

What is the role of Ankyrin G in the neuron? What is a consequence of its presence and what happens in its absence?

Answer 3

PSD-95/Gephyrin analogue for Na channels

Keeps then presenting on cell membrane, allows for clustering of channels which leads to action potentials

Without ankyrin/clustering, you would get depolarization of the cell but no AP

Question 4

Why would you find GABARs near the axon hillock?

Answer 4

To prevent the AP from firing down the axon

Question 5

How does saltatory conduction keep the signal strength better than unmyelinated axons?

Answer 5

Clusters of Na channels allow for the signal to be “reset” to keep signal shape

Question 6

Where do action potentials propagate when the soma of a cell is depolarized? How do their signals differ?

Answer 6

Down the axon and also back into the dendrites

Axon has basically the same characteristic shape (due to saltatory conduction)

Dendrits have a delayed, dampened signal (no myelination)

Question 7

What are the three states of a sodium channel?

Answer 7

open, closed, inactivated

Question 8

How can you map open probability of a voltage gated ion channel?

Answer 8

Using conductance/potential graph

Question 9

Define the Window current

Answer 9

Range of potential where the activation and inactivation curves overlap (indicates steady-state activation level)

Question 10

What are the 4 NaV channels found in the CNS?

Answer 10

1.1, 1.2, 1.3, and 1.6

Question 11

How do NaVs differ from GABAR and IGluRs in terms of structure?

Answer 11

NaVs are one gene, not a polypeptide

“Subunits” are called Domains

Question 12

Describe the structural functionality of NaVs

Answer 12

Subunits 1-4 detect voltage (4 has many positive charges that are repelled by strong membrane potential)

S5-6 form the pore which opens when S1-4 hikes up due to depolarization

Eventually, the lid domain comes in and inactivates the pore

Question 13

What are the two classes of drugs that affect the NaV and what are their effects on depolarization?

Answer 13

Drugs that bind the voltage sensor (Causes it to open/close at voltages it shouldn’t)

Drugs that bind the top/bottom of pore region (change de/repolarization rates)

Question 14

How can NaV1.1 mutation be mapped in terms of diseases?

Answer 14

Mild missense causes Febrile seizures

Moderate missense causes GEFS+

Severe missense or Truncation (loss of function) leads to Dravet Syndrome

Question 15

What was found in Ms Dravet?

Answer 15

Truncated Nav1.1 channel, caused it to be degraded similar to a total knockout

Host of terrible symptoms, labelled Dravet syndrome