Abstract

Voltage-gated calcium channels, and their associated subunits, are major therapeutic targets in disease. In particular, CaV1 (L-type) channels, major targets in the cardiovascular system, have also been implicated as targets in CNS disorders such as Parkinson's disease, epilepsy and autism. CaV2.2 (N-type) channels are validated molecular targets of analgesics such as ziconotide. CaV3 (T-type) channels are, at least partially, targeted by ethosuximide in epilepsy. In addition, gabapentinoid drugs act via alpha2delta auxiliary calcium channel subunits to mediate anticonvulsant and anti-allodynic effects. Current drug discovery projects are focussing in particular on developing improved small molecule CaV2.2 or CaV3.2 blockers to treat neuropathic pain. More selective CaV3.1 blockers are also key targets in epilepsy. With particular relevance to targeting CaV3 channels, we have recently identified the calcium channel and chemotaxis receptor (cache) domain containing protein 1 (CACHD1) as a modulator of CaV3 calcium channel activity. CACHD1 has structural similarities to alpha2delta family proteins and acts to increase CaV3 cell surface expression and channel open probability. Our on-going work seeks to identify the function of structural motifs within CACHD1 and their effects on T-type calcium currents. Targeting modulatory proteins such as CACHD1 may provide an attractive alternative to agents that block the channel pore directly and provide potential for future therapeutic targeting.