Deciphering mechanisms of nervous system function is a major focus of current neuroscience research. Elaborating the details by which the nervous system is fine-tuned to sense and respond to specific stimuli is of critical importance for understanding mechanisms of sensory perception, information integration and cognition. Invertebrate model systems are making a significant contribution to this effort since many details of basic neuronal function are remarkably conserved. This is particularly actual with the nematode C. elegans whose comparative simplicity invites a comprehensive description of the development, structure and function of the entire nervous system. Recently, we have cloned and expressed functionally a voltage-gated potassium channel, KVS that mediates basic neuronal excitability in C. elegans nervous system. In addition we cloned mps-1, the first C. elegans MiRP. MinK Related Peptides (MiRPs) are small transmembrane proteins that associate with K+ channels to alter their function. MPS- 1 which shares significant homology with cardiac human MiRP1 and MiRP3 (further underscoring the importance of C. elegans as model system to understand our own biological processes), partners with KVS in sensory neurons to produce the neuronal potassium current IK. The recent discovery of this channel complex poses several questions of genetic, physiological and functional relevance. The broad aim of this proposal is to study KVS and MPS-1 function. This project will elucidate the role of potassium channels in determining C. elegans neuronal excitability and will improve our understanding of basic neuronal processes. Our 4 specific aims are:
1 Aim : To generate kvs-1 and mps-1 knockout worms through mutational germline gene inactivation.
2 Aim : To investigate kvs and mps processing, trafficking and subcellular localization.
3 Aim : To characterize chemosensory neuron physiology in culture and in vivo and to define how KVS and MPS-1 proteins influence amphid neuron basic function.
4 Aim : To establish the superfamily of C. elegans MiRPs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068581-04
Application #
7070031
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Tompkins, Laurie
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$292,852
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Physiology
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Cai, Shi-Qing; Wang, Yi; Park, Ki Ho et al. (2009) Auto-phosphorylation of a voltage-gated K+ channel controls non-associative learning. EMBO J 28:1601-11
Cai, Shi-Qing; Sesti, Federico (2009) Oxidation of a potassium channel causes progressive sensory function loss during aging. Nat Neurosci 12:611-7
Wang, Yi; Sesti, Federico (2007) Molecular mechanisms underlying KVS-1-MPS-1 complex assembly. Biophys J 93:3083-91
Cai, Shi-Qing; Li, Wenchao; Sesti, Federico (2007) Multiple modes of a-type potassium current regulation. Curr Pharm Des 13:3178-84
Park, Ki Ho; Sesti, Federico (2007) An arrhythmia susceptibility gene in Caenorhabditis elegans. J Biol Chem 282:19799-807
Hernandez, Leonardo; Park, Ki Ho; Cai, Shi-Qing et al. (2007) The antiproliferative role of ERG K+ channels in rat osteoblastic cells. Cell Biochem Biophys 47:199-208
Cai, Shi-Qing; Sesti, Federico (2007) A new mode of regulation of N-type inactivation in a Caenorhabditis elegans voltage-gated potassium channel. J Biol Chem 282:18597-601
Cai, Shi-Qing; Park, Ki Ho; Sesti, Federico (2006) An evolutionarily conserved family of accessory subunits of K+ channels. Cell Biochem Biophys 46:91-9
Park, Ki Ho; Hernandez, Leonardo; Cai, Shi-Qing et al. (2005) A family of K+ channel ancillary subunits regulate taste sensitivity in Caenorhabditis elegans. J Biol Chem 280:21893-9
Cai, Shi-Qing; Hernandez, Leonardo; Wang, Yi et al. (2005) MPS-1 is a K+ channel beta-subunit and a serine/threonine kinase. Nat Neurosci 8:1503-9

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