Excitable Cells

Question 1

What are excitable cells?

Answer 1

Definition - ability of cells to be electrically excited resulting in the generation of action potentials

Examples - Neurons, muscle cells (skeletal, cardiac, and smooth), and some endocrine cells (e.g., insulin-releasing pancreatic β cells)

Question 2

What is an electrical signal?

Answer 2

Electrical - Electrical Synapses facilitate communication between neural cells
Direct flow of ions from one neurone to another, hence direct influence of electric current from one to another
= Gap junction
Electrical synapses are in the minority

Excitable cells use these specialized channels that open in response to a signal and permit rapid ion movement across the cell membrane
Opening of just a single ion channel can alter the electrical charge on both sides of the membrane - due to fluctuation of ionic concentrations

Question 3

What is a chemical signal?

Answer 3

Chemical - At a Chemical Synapse chemicals known as neurotransmitters diffuse across the synaptic cleft from one neurone to another
Chemical Synapses constitute the vast majority of synapses
e.g. acetylcholine

Question 4

How do ions move across the membrane?

Answer 4

Ion pump: The ion binds and then the ion is pumped across the membrane
This can actively move ions against its concentration gradient using ATP

Ion channel: The ions diffuse through a water filled passageway allowing ions across the phospholipid bilayer, down concentration gradients
They are selective, and have a permeability to ions

Question 5

How do ion channels work?

Answer 5

They are integral membrane proteins
Span the membrane - often more than once
Generate water filled pores
Water molecules stabilize the ions as they pass through the channel

Must shed the water molecules to pass through the selectivity filter
They are typically selective for specific ions
Selectivity filter: narrowest part of the conduction pathway
Discriminates between the different ionic species in a cell

Question 6

How do we categorise ion channels?

Answer 6

By ion selectivity:

K+ channels, Na2+ channels etc…

Question 7

What are some types of channels?

Answer 7

Most channels are gated - open/close in response to a stimulus

Ligand gated - chemicals
Voltage gated - voltage change
Mechanically - stretch activated

Opening of gated channels alters the ionic balance and thus membrane potential

Question 8

What are some concentrations of ions at resting potential?

Answer 8

Na+ - has more extracellular than intracellular

K+ has less extracellular than intracellular

Question 9

What are the 4 main factors involved with action potentials? and the other contributing factor?

Answer 9

The Na+/K+ pump: moves 3 Na+ out for every 2 K+ in
The leakage channel: allows K+ to diffuse out of the axon
Na+ channel
K+ channel

The other factor is charge intracellular proteins - Large negatively charged intracellular proteins cannot cross the membrane and leave the cell interior and so contribute to its negativity

Question 10

What is resting potential?

Answer 10

No impulse is being passed along
More positive ions outside the axon
-65 mV

Question 11

Describe resting potential in terms of ions?

Answer 11

Na+/K+ actively transports 3Na+ out of the axon for every 2K+ in
The leakage channel is open and facillitated diffusion of K+ out of the axon down it’s conc gradient takes place
Na+ ion channel is closed
K+ ion channel is closed

-65 mV

Question 12

What are the stages of an action potential?

Answer 12

Resting potential
Depolarisation (overshoot)
Repolarisation
Hyperpolarisation (undershoot)

Question 13

Describe depolarisation in terms of ions?

Answer 13

Na+/K+ actively transports 3Na+ out of the axon for every 2K+ in
The leakage channel is open and facillitated diffusion of K+ out of the axon down it’s conc gradient takes place
Na+ ion channel opens - Na+ facillitated diffuese into axon down electrochemical gradient
K+ ion channel is closed

-65 mV to +40 mV

Question 14

Describe repolarisation in terms of ions?

Answer 14

Na+/K+ actively transports 3Na+ out of the axon for every 2K+ in
The leakage channel is open and facillitated diffusion of K+ out of the axon down it’s conc gradient takes place
Na+ ion channel closes
K+ ion channel opens - K+ facillitated diffuses out of axon down conc gradient and electrochemical gradient

+40 mV to -65mV

Question 15

Describe hyperpolarisation in terms of ions?

Answer 15

Na+/K+ actively transports 3Na+ out of the axon for every 2K+ in
The leakage channel is open and facillitated diffusion of K+ out of the axon down it’s conc gradient takes place
Na+ ion channel is closed
K+ ion channel is open - too many +ions have diffused out (temporary overshot of the electrochemical gradient)
The Na+/K+ pump, pump K+ ions back into the axon to restore resting potential

Question 16

What is the principal of action potentials?

Answer 16

All or nothing

There is an action potential or not at all
It needs to exceed threshold of -55 mV

Question 17

What are the refractory periods?

Answer 17

Absolute - no further action potentials can be produced to ensure the propagation of the action potential is unidirectional (within de and repolarisation)

Relative - an action potential is inhibited but not impossible if a large stimulus is given (within hyperpolarisation)

Question 18

What are the 3 purposes of the refractory period?

Answer 18

Ensures the action potential moves in only one direction

Produces discrete impulses

Limits the numner of action potentials

Question 19

What features dictate action potential propagation?

Answer 19

Action potentials only form at the Nodes of Ranvier (gaps in the myelin sheath - as myelin acts as an electrical insulator)
Due to localised current, only sections of the whole axon have to be depolarised
The action potential jumps from node to node - called saltatory conduction

Question 20

What is a disease linked with myelin?

Answer 20

Multiple Sclerosis
Breach of the blood brain barrier
Leukocytes enter the brain’s blood supply
T-cell attack of antigenic myelin - as the leukocytes have recognised the myelin as non-self
Loss of myelination: slower AP propagation

Question 21

What are channelopathies in excitable cells?

Answer 21

When ion channel activity is disrupted – disease states often occur
Diseases caused by disturbed function of ion channel subunits or the proteins that regulate them

Types:
Acquired - autoimmune attack, drug effect, toxin on an ion channel
Congenital - genetic which results from a mutation or mutations in the encoding genes

Question 22

What are the types of acquired channelopathies?

Answer 22

Blocks action potentials in nerves by binding to the voltage-gated, fast Na+ channels in nerve cells
Cardiac arrhythmias may precede complete respiratory failure and cardiovascular collapse
Example: tetrodotoxin - from a pufferfish

OR

Blocks voltage-gated K+ channels in neuronal tissue
Voltage-gated K+ channels control excitability of nerves and muscle
Controls the resting membrane potential and repolarises the membrane following an action potential
Example: Mamba snake venom - dendrotoxin K

Question 23

Describe the mechanism of action for tetrodotoxin and dendrotoxin K

Answer 23

Tetrodotoxin
It binds to channel preventing the flow of Na+

Dendrotoxin K
It prolongs action potential duration
Increases acetylcholine release at the neuromuscular junction
Results in muscle hyperexcitability and convulsive symptoms

Question 24

What is an example of an acquired channelopathy drug that was unknown?

Answer 24

Terfenadine
Was marketed as an anti-histamine to treat allergic rhinitis
There was evidence of ventricular arrhythmias 5 years later
Eventually the FDA removed the terfenadine-containing drugs

Question 25

What is the mechanism of action for Terfenadine?

Answer 25

Prolonged ventricular repolarization and an increased risk of ventricular arrhythmia
In drug development, early recognition of blocking HERG channels is now a requirement

K+ channels play a critical role in cardiac action potential repolarization
HERG encodes a voltage-gated potassium channel (Kv11.1)
Suppression of HERG current - action potential prolongation and cardiac arrhythmias

Question 26

Describe congenital channelopathies?

Answer 26

Mutations in the human ether-a-go-go-related gene (HERG) – over 30 identified
Many ‘healthy’ people who have a heart attack under stress is often due to a mutation in HERG
Drug companies now how to screen for affects on HERG - for impacting cardiac disease

Question 27

What is an example of a congential channelopathy?

Answer 27

Insulin disorders
ATP-sensitive potassium channels
Channels are composed of Kir6.x-type subunits and sulphonylurea receptor (SUR) subunits
In pancreatic beta cells, which are sustained primarily by ATP, the ATP/ADP ratio determines KATP channel activity

KATP links metabolic state to membrane potential in pancreatic β-cells
Normal conditions, KATP - active
K+ flows out the cell at resting membrane

Increased glucose metabolism = increased levels of ATP
KATP channels close (inhibited)
Membrane potential depolarizes
Promotes insulin release (Ca2+ influx)

Question 28

Describe neonatal diabetes?

Answer 28

This happens due to KATP channel mutations (many identified) that reduce the ability of the channels to be inhibited by ATP
Channels are therefore overactive

Question 29

What is an avenue for a new drug for insulin disorders?

Answer 29

Ion channels are a major target
Glibenclamide (glyburide) inhibits KATP channels through binding to SUR1
Causes membrane depolarization leading to the opening of voltage-gated Ca2+ channels.
Stimulates insulin release

Question 30

What could be used as a therapeutic agent?

Answer 30

Venom
Ziconotide a synthetic peptide of a conotoxin from Cone snail (Conus magus) venom
Ziconotide - blocks voltage gated Ca2+ channels of the spinal cord
Reduces pronociceptive neurotransmitter release in the dorsal horn of the spinal cord
Results in an inhibition of pain signal transmission