Neuronal activity suppression of Kv1.1 channelmRNA translation in dendrites

Ion channels play crucial roles in a variety of cellular activities. A superfamily of ion channels known as voltage-gated ion channels is responsive to changes in the electrical potential across the cell membrane in which they reside. This property of voltage sensitivity allows voltage-gated ion channels to be major contributors to the electrical communication utilized by cells. The prominence of these channels in many biological processes has made them a popular drug target in hopes of treating a variety of pathologies. Chapter I is a broad overview of these voltage-gated ion channels with a particular emphasis on the pharmacology developed and discovered for these channels.; Voltage-gated ion channels play an integral role in neuronal signaling. A challenge for a neuron is managing the proper number and type of signaling proteins required for up to thousands of synaptic connections with other neurons. One strategy for neurons to deal with this problem is to translate the necessary proteins locally, near the required site for the protein to function optimally. Transcripts isolated from synaptosomes were quantified and the most abundant transcripts were considered to be candidate transcripts that are locally translated.; Chapter II explores how the local translation of one of the candidate transcripts, the voltage-gated potassium channel Kv 1.1 is regulated in neurons. Kv 1.1 mRNA was detected in neuronal dendrites and we developed a novel method to visualize the local translation of Kv 1.1 using Kaede, a photo-convertible fluorescent protein. Inhibiting NMDA glutamate receptors, PI3 kinase, or mTOR increased the local translation of Kaede-Kv 1.1 in dendrites. These findings suggest neuronal activity suppresses the local translation of Kv 1.1.; The appendix details other candidate transcripts that were further characterized. A particular focus is on 14-3-3 eta as a candidate transcript that is locally translated as well as the functional significance of the interaction between 14-3-3 and GABA-B receptors.