GSBS Dissertations and Theses

Approval Date

6-13-2013

Document Type

Doctoral Dissertation

Academic Program

Neuroscience

Department

Psychiatry

First Thesis Advisor

Haley Melikian, PhD

Keywords

Potassium Channels, Carrier Proteins, Cell Membrane, Dopamine Plasma Membrane Transport Proteins, Dynamins, Membrane Proteins, Neurons, Neurotransmitter Transport Proteins, Tandem Pore Domain Potassium Channels, Protein Kinase C

Subjects

Dissertations, UMMS; Potassium Channels; Carrier Proteins; Cell Membrane; Dopamine Plasma Membrane Transport Proteins; Dynamins; Membrane Proteins; Neurons; Neurotransmitter Transport Proteins; Potassium Channels, Tandem Pore Domain; Protein Kinase C

Abstract

Endocytic trafficking dynamically regulates neuronal plasma membrane protein presentation and activity, and plays a central role in excitability and plasticity. Over the course of my dissertation research I investigated endocytic mechanisms regulating two neuronal membrane proteins: the anesthetic-activated potassium leak channel, KCNK3, as well as the psychostimulant-sensitive dopamine transporter (DAT). My results indicate that KCNK3 internalizes in response to Protein Kinase C (PKC) activation, using a novel pathway that requires the phosphoserine binding protein, 14-3-3β, and demonstrates for the first time regulated KCNK3 channel trafficking in neurons. Additionally, PKC-mediated KCNK3 trafficking requires a non-canonical endocytic motif, which is shared exclusively between KCNK3 and sodium-dependent neurotransmitter transporters, such as DAT. DAT trafficking studies in intact ex vivo adult striatal slices indicate that DAT endocytic trafficking has both dynamin-dependent and –independent components. Moreover, DAT segregates into two populations at the neuronal plasma membrane: trafficking-competent and -incompetent. Taken together, these results demonstrate that novel, non-classical endocytic mechanisms dynamically control the plasma membrane presentation of these two important neuronal proteins.

DOI

10.13028/M22K5H

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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