In neurons, electrical signaling and calcium signaling are localized events that depend upon the specific localization of ion channels and receptors. Elevations in intracellular ion concentrations can be highly localized to micron and submicron domains or propagated as intra- and intercellular waves over longer distances. Ion channels and receptors are important components of a variety of signal transduction pathways. It is therefore essential that channels and receptors are located in close proximity to the signaling molecules that modulate them. Thus, the subcellular localization of ion channels and receptors to discrete microdomains is critical for proper electrical signaling in neurons.
Neurons are highly polarized cells made up of a large dendritic tree, a soma and an axonal region. They have the ability to receive, process and transmit information due to the structural and molecular uniqueness of each of these compartments. The unique complement of ion channels in the somatodendritic and axonal regions is one of the important factors in determining the functioning of an individual neuron. Ion channels are proteins that reside in cellular membranes and contribute to intracellular communication. These proteins permit ions to flow into or out of cells and result in the generation of electrical signals that produce intracellular calcium transients. These intracellular calcium transients in turn control processing of information in the brain, secretion of hormones, and the processing of information from the brain to peripheral tissues.
My research has focused on the subcellular localization of voltage-gated ion channels and receptors in the central nervous system. Following the identification and cloning of voltage-gated sodium and calcium channels, our laboratory took advantage of known amino acid sequences and generated specific, anti-peptide antibodies to many of these ion channels. Prior to this time, in situ hybridization studies had been carried out to identify cells that contained the mRNA for many of these channels as well as physiological and pharmacological studies. Still lacking, however, was the precise subcellular localization of the protein for these channels. Specifically, my studies have used immunocytochemical studies and confocal microscopy to identify the subcellular localization of voltage-gated sodium channels and voltage-gated calcium channels in normal and diseased neuronal tissues. We have demonstrated that different voltage-gated sodium and calcium channels are localized to specific cellular compartments, suggesting specific functions. Secondly, we have demonstrated up-regulation and/or down-regulation of various voltage-gated sodium or calcium channels in various injury and disease models. Lastly, we have demonstrated altered levels of channels in various mouse models in which a specific protein was deleted. Collectively, these studies have provided a better understanding of the role of specific voltage-gated sodium and voltage-gated calcium channels in signal transduction.