Ion Channels in Pain Pathways; VGSCs Flashcards
What mutations led to the ‘Human Pincushion’ phenomena?
- Mutations in Families 1 - 3 of the NaV 1.7 VGSC
- Via chromosome 2q24
- Point mutations in gene SCN9A (sodium channel 9A) rendered it inactive
What is the general structure of a VGSC?
- 2 subunits; α (large w/4 domains) and β (small; localisation of VGSCs)
- 4 domains w/6TM helices per domain
- Intracellular loops link helices and domains
- P (pore-forming) loop between 5 and 6 acted as selectivity filter for Na+
- 5 + 6 formed the pore whilst 1 - 4 faced the outside
How did people with the NaV 1.7 mutation (SCN9A) not have any other abnormalities?
NaV1.7 is largely localised in the PNS; few CNS side effects.
Which VGSCs share similar AA sequence and where are they localised?
- NaV1.1, 1.2, 1.3; CNS (+ PNS for 1.1)
- NaV1.5, 1.8, 1.9; Heart, DRG, DRG.
- NaV1.4; Skeletal muscle
- NaV1.6; CNS, PNS
- NaV1.7; PNS, Schwann cells
What is significant about Helix 4 of a VGSC?
- Voltage sensor
- Senses membrane potential + transduces a change in membrane potential by opening up channel/pore
What roles do the tetrodotoxin sensitive NaV1.1, 1.6 and 1.7 share and how does their localisation in tissue suggest this?
- Acute noxious mechanical sensation
- Localised in the CNS/PNS, “ “, and PNS/Schwann cells respectively
What roles do the tetrodotoxin insensitive NaV1.8 and 1.9 perform and how does their localisation suggest this?
- Highly expressed in nociceptors; both localised in the DRG
- Role in acute noxious mechanical sensation
What is significant about NaV1.8 and its relationship to temperature?
It is important in acute cold sensation; does not inactivate at low temperatures whereas all the other NaVs do.
Where is NaV1.7 primarily expressed?
- DRG and sympathetic ganglion neurons (PNS, Schwann cells)
What is the role of NaV1.7?
- Amplifies the generator potential in neurons expressing it (including nociceptors) - one of the first channels to pick up changes in membrane potential after receptor activation
- Threshold channel for firing action potentials
What is NaV1.7’s relationship with inflammation; can this be an analgesic target?
- Upregulated in inflammation
- Removal of NaV1.7 gene = no inflammatory pain but neuropathic pain still existing
Where is NaV1.8 primarily expressed?
- DRG and trigeminal ganglia (in the head)
What is the role of NaV1.8?
Contributes most of the sodium current underlying the action potential upstroke in neurons that express it
Can NaV1.8 be targeted for pain?
- Removal of NaV1.8 gene yielded inflammatory/cold pain relief, but not neuropathic
What is the modulated receptor hypothesis and how do VGSC inhibitors target it?
VGSC exists in several different states:
- Closed (pore closed h gate open)
- Open
- Inactivated (pore open but h gate closed)
