Physiological and pathological regulation of calcium channel trafficking and function

Specialised nerve endings in the skin sense heat, cold, touch, pressure and chemical changes and send information to the spinal cord and brain where it is translated into touch, itch or pain sensation. These nerves can be damaged due to diabetes, some viral infections or after chemotherapy treatment for cancer and this alters the information transfer in the nerves, causing intense neuropathic pain. One effective treatment for neuropathic pain is gabapentin which interacts with a protein (alpha2delta-1) found in sensory nerves. Alpha2delta-1 forms a key part of N-type calcium channels that control pain signalling to the brain. The amount of alpha2delta-1 increases dramatically after nerve damage and although we know that gabapentin binds to alpha2delta-1, we don’t understand exactly how it dampens neuropathic pain.

We will study the function of N-type calcium-channels, including how they get to nerve terminals and how these actions are promoted by alpha2delta-1 protein. We have found that if we prevent alpha2delta-1 from being cut into its alpha2 and delta components by a protease enzyme, then we can block its action. Understanding this process could lead to the design of better drugs to treat neuropathic pain.