Neurotransmitter modulation of voltae-gated Ca2+ channel activity leads to the regulation of cellular processes such as neurotransmitter release, processing of electrical information in dendrites and gene expression. In CNS neurons, neither the biophysical nor the biochemical mechanisms of modulation are completely understood. The model system employed in the proposed research is comprised of somatostatin receptor type 4 (SSTR4) coexpressed with the pore- forming alpha and the auxiliary alpha 2 and beta subunits of Ca2+ channels in Xenopus oocytes. This sytem serves as a tool for reconstituting a modulatory pathway which allows me to study channel biophysics as well as structure-function relationships. We have previously demonstrated in this system that bath application of 1 upsilonM somatostatin (SST) inhibited peak Ba 2+ current; the magnitude of inhibition in cells expressing alpha1A, alpha2 but no beta was approximately three times that in cells expressing alpha1A, alpha2 and beta. This research plan is designed to determine the role of the Ca2+ channel beta subunit in the modulation of Ca2+ channel current by (1) determining the biophysical mechanism of modualtion and (2) identifying the structural elements of channel subunits required for modulation. The results of this research are anticipated to help answer the question: what is a modulated Ca2+ channel? Since voltage-gated Ca2+ channels are essential components in the processes of neurotransmitter release and information processing in dendrites, the mechanisms of their regulation are relevant to diseases of the central nervous system such as epilepsy.
