'w' conotoxin

Question 1

what does ‘w’ conotoxin bind to

Answer 1

N-type (neuronal) voltage-gated calcium channel; found concentrated in the spinal region which conveys nociceptive messages to CNS

Question 2

structure of the target

Answer 2

4 homologous domains; alpha core associated with auxillary beta subunits; pore forming alpha 1 subunit that co-assembles with diff beta and alpha2 delta subunits

Question 3

w conotoxin -
Where does the binding occur

Answer 3

Through alanine replacement studies, Tyr13 - single most impt residue, with the hydroxyl moiety being the key binding determinant.
As for the CaV channel, extracellular linker region between the P-region and S5 in domain III (the pore of CaV2.2 is said to be the area where toxins bind

Question 3

Chemistry and function of ‘w’ conotoxin

Answer 3

24-29 amino acid residue length; disulfide bonds between 6 cysteines; 2º structure is a pattern of cys-residues (6 cys-residues arranged to give 4 loop cys framework (c-c-cc-c-c) +3 disulfide bonds; highly conserved)

Question 4

MOA

Answer 4

• ω-conotoxins physically block channel pore; selective, poorly reversible inhibitor; long tern inhibition
• Prevent entry of Ca2+
• Interfere with release of Ach-containing vesicles

Question 5

Use of toxin

Answer 5

Treatment of chronic and neuropathic pain (pain relief). Prevents neuronal cell death following ischaemic brain injury

○ CONFIRMED AND APPROVED W-CONOTOXIN: ω-MVIIA
–> inhibit the nociceptive message = interception of the pain signal = clinical pain relief
–> selective to N-type CaV channels = neuroprotective and analgesic properties

As research tool: Investigate role of Cav channel in neurotransmitter release