Ion channels are the major determinant for excitability changes of neurons. Our long-term objective is to elucidate the mechanism by which slow excitation and slow inhibition of brain neurons take place. These events occur on time scales of tens of seconds to a few minutes, and are mostly mediated by G proteins. Our immediate research will focus on clarifying the signal transduction mechanism by which G-protein-coupled inward rectifier Kv (GIRK) channels are modulated by substance P (SP), an excitatory peptide neurotransmitter. Native cultured noradrenergic neurons in the locus coeruleus (LC) from newborn rats and mice, as well ascloned GIRKs expressed in HEK293 cells will be used. Electrophysiological and molecular biological techniques will be employed for the investigation. The LC contains neurons that innervate and supply norepinephrine to a wide area of the brain, and plays a vital role in arousal and alertness. Furthermore, LC neurons often degenerate in Alzheimer's disease. LC neurons are dually regulated by opposing signals: inhibitory transmitters, such as somatostatin, activate GIRK channels, whereas excitatory transmitters, such as SP, inhibit the GIRK activity that is activated by somatostatin. The mechanism of the GIRK inhibition, however, is controversial and yet to be determined. The goal of the proposed project is to elucidate the signal transduction mechanism of the SP-induced GIRK channel inhibition. Three possible signal transduction pathways could be responsible for the SP-induced GIRK channel inhibition: the phosphatidyl inositol 4,5-bisphosphate (PIP2) pathway, the protein kinase C pathway, and a new pathway, which we designate as the """"""""quick pathway."""""""" The existence of the quick pathway is hypothesized because the inhibition is too rapid to be accounted for by the other pathways. We intend to elucidate the mechanism of this pathway. We also intend to investigate the possible synergistic relation between the quick and the PIP2 pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG006093-31
Application #
6847748
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Wise, Bradley C
Project Start
1988-03-01
Project End
2008-01-31
Budget Start
2005-02-15
Budget End
2006-01-31
Support Year
31
Fiscal Year
2005
Total Cost
$311,740
Indirect Cost
Name
University of Illinois at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Nakajima, Yasuko; Nakajima, Shigehiro (2010) Measurement of orexin (hypocretin) and substance P effects on constitutively active inward rectifier K(+) channels in brain neurons. Methods Enzymol 484:613-30
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Kawano, Takeharu; Zhao, Peng; Nakajima, Shigehiro et al. (2004) Single-cell RT-PCR analysis of GIRK channels expressed in rat locus coeruleus and nucleus basalis neurons. Neurosci Lett 358:63-7
Zhao, Qi; Kawano, Takeharu; Nakata, Hiroko et al. (2003) Interaction of G protein beta subunit with inward rectifier K(+) channel Kir3. Mol Pharmacol 64:1085-91
Hoang, Q V; Bajic, D; Yanagisawa, M et al. (2003) Effects of orexin (hypocretin) on GIRK channels. J Neurophysiol 90:693-702
Stanfield, Peter R; Nakajima, Shigehiro; Nakajima, Yasuko (2002) Constitutively active and G-protein coupled inward rectifier K+ channels: Kir2.0 and Kir3.0. Rev Physiol Biochem Pharmacol 145:47-179
Bajic, D; Koike, M; Albsoul-Younes, A M et al. (2002) Two different inward rectifier K+ channels are effectors for transmitter-induced slow excitation in brain neurons. Proc Natl Acad Sci U S A 99:14494-9
Albsoul-Younes, A M; Sternweis, P M; Zhao, P et al. (2001) Interaction sites of the G protein beta subunit with brain G protein-coupled inward rectifier K+ channel. J Biol Chem 276:12712-7

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