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Voltage-gated potassium ion channels such as Kv1.3 have a role in altering excitability of neurons. The neuron has to have a sophisticated mechanism to regulate the modulation, expression, turnover and distribution of ion channels. Ion channels, like Kv1.3, become crucial in affording the neuron one of a symphony of players that can strategically play their part in transmitting electrical and chemical signals into meaning. This dissertation uses electrophysiology and biochemistry to investigate how brain-derived neurotrophic factor (BDNF) and TrkB utilize a very simple aspect of the biochemistry of Kv1.3 to specifically modulate the biophysical properties, expression and turnover of Kv1.3. Acute BDNF application suppresses Kv1.3 current and results in phosphorylation of tyrosine residues 111-113, 137 and 449. There is a delicate balance of other downstream cellular components; N-Shc, Grb10 and PSD95 that disrupt this BDNF induced current suppression. N-Shc disrupts a post-phosphorylation event that usually leads to BDNF-evoked Kv1.3 current suppression, and N-Shc causes phosphorylated Kv1.3 to be retained in the membrane. Grb10 and PSD95 left-shift the voltage at half-activation of Kv1.3 and this effect may not be phosphorylation-dependent. Grb10 also reduces Kv1.3 expression and causes redistribution of membrane inserted Kv1.3. The presence of BDNF activated tropomyosin-related kinase B (TrkB) increases the phosphorylation of Kv1.3 tyrosine residues and increases Kv1.3 expression by two fold. TrkB also increases the half-life of Kv1.3 and this can account for the increase in protein expression. Kv1.5 is another member of the Shaker family but TrkB decreases the expression of Kv1.5. The insulin receptor (IR) is also a tyrosine kinase like TrkB however, IR decreases Kv1.3 expression and has no effect on Kv1.5 expression. These effects demonstrate that the TrkB and IR mediated regulation of Kv1.3 expression is not a promiscuous interaction of Shaker channels with receptor tyrosine kinases. Given the prominence of Kv1.3 in the olfactory bulb, one can hypothesize that the above interactions can play a part in modulating the function of Kv1.3 during development, learning and injury in the olfactory bulb. The neuron can utilize these interactions to regulate Kv1.3 and change how Kv1.3 contributes to shaping the neuron's response.
Olfactory Bulb, Kv1.3 Protein Expression, N-Shc, PSD95, Grb10, IR, Kv1.5, TrkB, BDNF, Kv1.3, Kv1.3 Distribution, Kv1.3 Electrophysiology
Date of Defense
March 27, 2006.
A Dissertation submitted to the Department of Biological Science in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Includes bibliographical references.
Debra Ann Fadool, Professor Directing Dissertation; Timothy M. Logan, Outside Committee Member; Marc E. Freeman, Committee Member; Cathy W. Levenson, Committee Member; Mohamed Kabbaj, Committee Member; Richard L. Hyson, Committee Member.
Florida State University
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