Differential roles in Kv1 and Kv3 channels in regulating neuronal excitability

Question 1

What are the 4 Kv families and their properties?

Answer 1

1.) Kv1 – LOW voltage-activated.
Raise AP threshold, reduces excitability and firing Fq.
Expressed very widely in the brain

2.) Kv2 – Most widely expressed delayed rectifier in heart, brain.
Kv2.1 is highly expressed in neocortex/hippocampus
Kv2.2 is highly expressed in the MNTB

3.) Kv3 – HIGH voltage-activated
Speeds AP repolarization - Fast-spiking interneurones

4.) Kv4 – (IA) Very rapidly inactivates – the classic A-current.
Requires hyperpolarization to remove resting inactivation
Assists in rhythmic AP firing and involved in plasticity.

Question 2

What are the 4 methods to identify and characterise K+ currents?

Answer 2

1.) Electrophysiology: a neuron is voltage-clamped and other voltage-gated currents blocked:
– Na+ channels with Tetrodotoxin
– Ca2+ with Dihydropyridine  blocks L type Ca2+ channel

2. ) Specific pharmacological agents are used as tools to distinguish between different Kv channels/families.
3. ) Immunohistochemistry used to identify presence of Kv1 subunit protein in the membrane.  uses antibodies
4. ) PCR measures specific mRNA of K+ channels

Question 3

Describe and explain the native Kv function in the brainstem auditory pathway (include what Forsythe et al, 2010 found)

Answer 3

• Involved in localisation of sound source.
• This requires very accurate timing of APs & comparison of information from both ears.
• Information is relayed across the brainstem by fast conducting axons and a giant synapse.
• This occurs in the medial nucleus of the trapezoid body (MNTB) which expresses both Kv1 & Kv3.
• MNTB – computes inter-aural level differences
• LSO/MSO – computes inter-aural timing differences
• The MNTB never fires more than a single AP for each presynaptic input. This is due to low voltage activated channels formed from Kv1.1 and kv1.2 subunits
• MNTB neurons give inhibitory projections to the MSO, LSO, SPN (Superior Paraolivary Nucleus) and the NLL (Nuclei of the Lateral Lemniscus) (Forsythe et al, 2010)

Question 4

What is the implication of Kv1 channels being at the nodes of Ranvier?

Answer 4

The Kv1 channels are under the myelin, so they have little influence during normal AP’s  but they cause AP failure when exposed during demyelinating diseases such as multiple sclerosis

Question 5

What did Yeh Jan and Nung Jan, 2012 find about Kv1.1 mRNA?

Answer 5

Kv1.1 mRNA is localised to dendrites where its local translation is under the regulation of glutamate receptors of the NMDA subtype, and the downstream cascade of PI3 kinase and MTOR Kinase (mammalian target of rapamycin) (Yeh Jan and Nung Jan, 2012)

Question 6

Describe and explain High voltage-activated currents: Kv3 (include what Yeh Jan and Nung Jan,2012 said)

Answer 6

• HVA – only open when depolarised to near 0mV (i.e. during an AP)
• Shorten APs by accelerating repolarisation
• Blocked by low 1-3mM TEA
• Kv3 currents make short APs
• 4 Kv3 genes, 12 sliced variants:
• 4 genes encoding 12 alternatively spliced proteins ranging in size from 511 to 889 amino acids
• Two alternatively spliced N-terminal effect N-terminal inactivation by shifting translation between one or two start methionine initiation sites  cells can “choose” which channels can be inactivated
• C-terminal variants have no direct impact on channel kinetics but changed tissue expression and regulatory phosphorylation
• Increasing Kv3.1 enhancing AP following is due to the axonal targeting and AIS localisation of Kv3.1b (Yeh Jan and Nung Jan, 2012)