L-type voltage activated calcium (Ca) channels are heteromultimeric proteins composed of a pore-forming alpha1 subunit and accessory subunits known as Beta, alpha2, delta, and gamma. Though electrophysiological studies have demonstrated that these accessory subunits are critical determinants of channel properties, the biochemical and molecular events underlying the interaction of these subunits is largely unknown. The proposed studies will address the hypothesis that multiple interactions are involved in the modulation of channel properties by accessory subunits. The two-hybrid system will be used to identify domains involved in protein-protein interactions. Subsequently, the functional significance of these interactions will be assessed in a mammalian cell expression system where a variety of immunological, pharmacological, and electrophysiological approaches can be used to evaluate channel properties and channel function. This multidisciplinary approach will lend further understanding into the mechanisms underlying Ca channel subunit associations, and consequently, channel function. Clinically, the elucidation of interacting domain will aid searches to identify novel pharmacological targets whereby Ca channels may be therapeutically manipulated, which would be extremely beneficial given the wide spectrum of disorders, particularly in the CNS, which are associated with changes in Ca homeostasis.
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