Ion Channels in Pain Pathways; VGCCs

Question 1

What are the structural differences betweens VGCCs and VGSCs?

Answer 1

• Both have a subunit with 4 domains of 6TM helices that form the pore
• VGCC has more sub-units though; α2, β, and γ.

Question 2

Which VGCC subtype is expressed at the nociceptor terminal?

Answer 2

• CaV2.2; Ca2+ influx after AP arrival (then Glu released into cleft etc)

Question 3

What is the association of CaV2.2 (N-type VGCC) and neuropathic pain?

Answer 3

• CaV2.2 and α2 subunits upregulated in neuropathic pain; target for analgesia

Question 4

How have CaV2.2 blockers been developed into clinical use for neuropathic pain? How must it be delivered?

Answer 4

• MVIIA toxin from C. magnus slug isolated; inhibits neuropathic pain when delivered intrathecally

Question 5

What is Ziconotide and why does it have to be delivered intrathecally?

Answer 5

• Synthetic version of OG MVIIA toxin (targeting CaV2.2)

- It is a peptide thus would get broken down in gut etc.

Question 6

What are gabapentin and pregabalin used for OG?

Answer 6

Epilepsy; anticonvulsant drugs

Question 7

How are gabapentin and pregabalin effective in treating neuropathic pain?

Answer 7

They bind to the α2 subunit; upregulated in neuropathic pain.

Question 8

What VGCC blocker of the same vain as Ziconotide has been developed?

Answer 8

TROX-1; a small molecule CaV2.2 blocker.