Physiological and pathological regulation of calcium-channel and other ion-channel functions by alpha2delta-subunits and their interacting proteins. (360G-Wellcome-098360_Z_12_Z)

The alpha2delta proteins are voltage-gated calcium-channel auxiliary subunits. We have made very important contributions to the understanding of the properties and mechanism of action of these proteins, which are the therapeutic targets of the gabapentinoid drugs. There are a number of key open questions regarding their function, which form the two main Aims of this research. Firstly, how do alpha2delta-subunits facilitate calcium-channel trafficking, and what are their cellular binding par tners in these processes? Secondly, do alpha2delta-subunits influence other proteins, including ion-channels, evidence for which has recently emerged from our own preliminary studies? We have recently uncovered an interaction between alpha2delta-subunits and the multifunctional trafficking protein, low-density lipoprotein-receptor-related protein (LRP1). In Aim1 our goal is to examine how interaction with LRP1 controls trafficking of alpha2deltas and their associated calcium-channels. We wi ll investigate whether gabapentin disrupts this interaction, as this could be very important for future drug discovery, since alpha2delta-1 is a validated drug target. We will also examine whether interaction with LRP1 can bridge identified associations between alpha2delta-1 with both thrombospondins and prion protein. With respect to Aim 2, we have recently found disruption of specific sensory modalities in alpha2delta-1 knockout mice, and a marked inhibition of action-potential duration fol lowing alpha2delta-1 over-expression in dorsal root ganglion neurons. Both results point to alpha2delta interactions with other ion-channels; association with specific candidate channels will be investigated in Aim 2. My goal is to develop a comprehensive picture of alpha2delta-subunit function, in terms both of calcium-channels, and of other proteins mediating calcium-channel-independent functions.