Proper brain function relies on the precise balance between excitation and inhibition. In some neurological disorders, such as epilepsy, this balance is shifted towards excitation leading to aberrant network discharges (i.e. seizures). Potassium channels have emerged as integral components in preventing excessive excitation, with their impairment leading to runaway activity. The slow afterhyperpolarization (sAHP) is a calcium-activated potassium current that follows a surge of neuronal activity, thereby limiting the number of action potentials fired, and consequently controlling neuronal excitability. To date, the molecular identity of the potassium channel and signaling pathways involved in the induction of the slow afterhyperpolarization are still unknown. The goal of the research proposed in this Pathway to Independence Award (k99/00) is to indentify and characterize the molecular components of the sAHP. The proposed studies are based on hypothesis driven experiments and a multi-disciplinary approach. During the mentored phase of this award I will be under the tutelage of Professor Roger A. Nicoll (UCSF), a leading neuroscientist that has successfully mentored many post-docs throughout his career.
The aim of the mentored phase (K99, two years) is two fold: First, to increase my knowledge in molecular and physiological techniques and second to complete my identification of the potassium channel(s) that mediate the sAHP as well as the neuronal calcium sensors that gate the sAHP. During the independent phase (ROD) of this award (three years), I plan to obtain a more detailed mechanistic insight into the generation of the sAHP. This proposal will be part of a broader research effort that focuses on understanding the mechanisms that regulate neuronal excitability under both physiological and pathophysiological conditions. Therefore, through the work described in this award, I intend to acquire a broad scientific and technical expertise along with preliminary data that could act as a foundation for my future career in science as an independent investigator in an academic institution. Relevance to public health: Results obtained from this project will unveil the identity of the sAHP potassium channel and its regulation by calcium activated proteins. This will constitute a substantial advancement in neuroscience research laying the foundation for the development of new treatments and diagnostic tests for neurological conditions like epilepsy and stroke.
| Kim, Kwang S; Kobayashi, Masaaki; Takamatsu, Ken et al. (2012) Hippocalcin and KCNQ channels contribute to the kinetics of the slow afterhyperpolarization. Biophys J 103:2446-54 |
| Andrade, Rodrigo; Foehring, Robert C; Tzingounis, Anastasios V (2012) The calcium-activated slow AHP: cutting through the Gordian knot. Front Cell Neurosci 6:47 |
| Soh, Heun; Tzingounis, Anastassios V (2010) The specific slow afterhyperpolarization inhibitor UCL2077 is a subtype-selective blocker of the epilepsy associated KCNQ channels. Mol Pharmacol 78:1088-95 |
| Tzingounis, Anastassios V; von Zastrow, Mark; Yudowski, Guillermo A (2010) {Beta}-blocker drugs mediate calcium signaling in native central nervous system neurons by {beta}-arrestin-biased agonism. Proc Natl Acad Sci U S A 107:21028-33 |
