This proposal is a request for a Mentored Research Scientist Development Award (K01). This research plan is designed to allow the candidate to develop neurobiological research skills while maintaining the candidate's productivity in the filed of ion channel regulation and mental illness. During the course of this training, the candidate will gain new technical expertise in molecular biology, protein biochemistry and immunocytochemistry. Successful completion of this proposal will further enhance the candidate's ability to become an independent investigator within the fields of mental health and neurobiological disease. The candidate holds an advanced degree (Ph.D) in the neurosciences and is well trained in a number of electrophysiological methods. The mentor of this project is Dr. Bill Catterall, a well-known researcher in the field of ion channel structure/function. The overall objectives of this proposal are to further elucidate the mechanisms by which voltage-gated sodium channels are regulated by neurotransmitters and to determine what role is played by these neuroregulatory mechanisms in neurodegenerative diseases such as Alzheimer's disease.
The specific aims to be addressed are as follows: 1) To complete the ongoing characterization of the molecular mechanisms underlying the voltage-dependent convergence of protein kinase C and cAMP-dependent protein kinase regulation of neuronal sodium current in hippocampal neurons. 2) To determine the role of the sodium channel beta1 and beta2 subunits in mediating phosphorylation dependent regulation of neuronal sodium channel alpha subunits by the neurotransmitters dopamine and acetylcholine. 3) To examine the neurotransmitter regulation of neuronal NaCh1 and NaCh6 sodium channels via PKA and PKC. 4) To elucidate the cellular and regional localization of NaCh1, NaCh2 and NaCh6 sodium channels in the hippocampus of transgenic and cellular models of Alzheimer's disease. 5) To study the neurotransmitter regulation of neuronal sodium channels in transgenic and cellular models of Alzheimer's disease and compare to the non-disease state. Further clarification of the neuromodulatory effects of neurotransmitters on the sodium conductance in the hippocampus may provide valuable information critical for the elucidation and treatment of a variety of cognitive and behavioral deficits observed in mental illnesses. Further, since signal transduction mechanisms are similar among various regions of the CNS, an understanding of the processes which play a role in Alzheimer's disease may become important in understanding other mental illnesses that involve neurotransmitter alterations.
| Cook, David G; Li, Xiaofan; Cherry, Sheree D et al. (2005) Presenilin 1 deficiency alters the activity of voltage-gated Ca2+ channels in cultured cortical neurons. J Neurophysiol 94:4421-9 |
| Chen, Yuan; Cantrell, Angela R; Messing, Robert O et al. (2005) Specific modulation of Na+ channels in hippocampal neurons by protein kinase C epsilon. J Neurosci 25:507-13 |
| Carr, David B; Day, Michelle; Cantrell, Angela R et al. (2003) Transmitter modulation of slow, activity-dependent alterations in sodium channel availability endows neurons with a novel form of cellular plasticity. Neuron 39:793-806 |
| Cantrell, Angela R; Tibbs, Victoria C; Yu, Frank H et al. (2002) Molecular mechanism of convergent regulation of brain Na(+) channels by protein kinase C and protein kinase A anchored to AKAP-15. Mol Cell Neurosci 21:63-80 |
