Pumpopathies

Question 1

What are the basic characteristics of the sodium-potassium pump?

Answer 1

• It is an enzyme which uses ATP to drive ions across the membrane (ATPase)
• Has a transmembrane, extracellular and intracellular component

Question 2

How does the sodium-potassium pump work?

Answer 2

• Maintains the resting membrane potential of neurons (-65mV) by expelling 3xNa+ and bringing in 2xK+ ions
• Fueled by the breakdown of ATP to ADP

Question 3

What is responsible for the membrane potential?

Answer 3

Not pumps but the selective permeability of neurons to K+ due to leakage channels which are always open, there is a tendency for Na+ to leak in but much less

Question 4

What is the structure of the pump?

Answer 4

Two main subunits: Alpha which does the ion pumping and beta which is structural. There is also an auxiliary subunit called a fixit which may be involved with the modulation of pump activity through hormone or kinase pathways.

Question 5

What are the four isoforms of the alpha subunit and where are they expressed?

Answer 5

Alpha 1 - ubiquitously
Alpha 2 - glia
Alpha 3 - neurons
Alpha 4 - only in sperm

Question 6

Why is the alpha 1 subunit considered to be tonic?

Answer 6

Has a very high affinity for Na+ allowing the pump to be continuously active and contribute tonically to resting membrane potential ( low oubain affinity)

Question 7

Why is the alpha 3 subunit considered to be dynamic?

Answer 7

Has an extremely low affinity for intracellular Na+ and therefore these pumps are only active when there is a high firing frequency and consequently high Na+ levels, therefore they are active dynamically (high oubain activity)

Question 8

How might the alpha 3 subunits play a role in motor memory?

Answer 8

• At the end of a swimming episode there is an ultra-slow hyperpolarisation which lasts a minute where resting potential is -10mV lower, reducing the length of subsequent swimming episodes
• This is blocked by oubain and so potentially due to activation of alha-3 subunits due to high spiking frequency
• This hyperpolarisation de-inactivates A-type K+ channels, so that when the next excitation arrives there are shorter weaker episodes of fictive swimming

Question 9

What is the distribution of alpha 3 receptors in different neuron populations?

Answer 9

Motor neurons - 40%
Descending INs - almost none
Ascending INs - 50%

Question 10

Why do descending interneurons not express a ultra slow hyperpolarisation?

Answer 10

Are capable of it but this is masked by an Ih current, when this is blocked it is revealed

Question 11

What is the Ih current?

Answer 11

• Activated by hyperpolarisation and leads to depolarisation, if blocked causes the membrane potential to hyperpolarise adn also increases input resistance
• Counteracts the usAHP to maintain swimming rhythms even at higher intervals (escape), when blocked there is a failure os dINs to initiate swimming

Question 12

What are the unique properties of descending interneurons?

Answer 12

• Express a single broad spike
• Depolarised resting membrane potential
• Low input resistance due to Ih current channel which is always open

Question 13

Is the usAHP specific to tadpoles?

Answer 13

No! Phylogenetically conserved, seen in mice and drosophila

Question 14

What is the consequence of dysregulation of the usAHP?

Answer 14

• Uncontrolled firing and depolarisation
• High calcium entry and cellular damage
  This pump is encoded by ATP1A3 mutations in which have been associated with different diseases