The objective of this proposal is to understand the cellular and subcellular mechanisms by which various neuropeptides modulate the activity of brain neurons. Particularly, these studies attempt to elucidate the function and structure of brain neurons that are correlated with Alzheimer's disease. It was for this purpose that the principal investigator (P.I.) developed a unique method of culturing cholinergic neurons from the basal forebrain nuclei including the nucleus basalis as well as the noradrenergic neurons from the locus careless. Neurons in these nuclei have been shown to degenerate in Alzheimer's disease. Cultured cholinergic neurons and noradrenergic neurons were identified using immunocytochemical and histochemical methods. The P.I. plans to study the signal transduction process involved in the effects of neuropeptides on these primary cultures with particular emphasis on the mechanism by which second messengers modulate potassium channels. There are three major projects: The first project deals with the modulation of the inwardly rectifying K- channels by substance P and somatostatin in nucleus basalis and locus careless neurons. The P.I.'s previous work has demonstrated that substance P excites neurons by suppressing an inwardly rectifying K-conductance, whereas somatostatin inhibits them by inducing a similar conductance. This work will be extended at the single channel level to include a detailed analysis of the properties of these potassium channels. The second project is to identify the second messengers. The P.I. has found that two different GTP-binding proteins seem to be the second messengers for the substance P- and somatostatin-induced modulations of potassium conductance. In this project,the P.I. proposes to examine the role that arachidonic acid metabolites play in somatostatin- and substance P-induced modulation of potassium channels. The third project is to study the ionic and second messenger mechanisms involved in the effects of galanin and neurotensin on cultured nucleus basalis and locus careless neurons using the whole-cell clamp and single- channel recording. Preliminary results from the pilot study suggest that galanin inhibits locus careless neurons, whereas both galanin and neurotensin excite nucleus basalis neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG006093-20
Application #
3116893
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1988-03-01
Project End
1996-01-31
Budget Start
1992-02-01
Budget End
1993-01-31
Support Year
20
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Schools of Medicine
DUNS #
121911077
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
Zhao, Qi; Albsoul-Younes, Abla M; Zhao, Peng et al. (2006) Dominant negative effects of a Gbeta mutant on G-protein coupled inward rectifier K+ channel. FEBS Lett 580:3879-82
Koike-Tani, Maki; Collins, John M; Kawano, Takeharu et al. (2005) Signal transduction pathway for the substance P-induced inhibition of rat Kir3 (GIRK) channel. J Physiol 564:489-500
Tesmer, Valerie M; Kawano, Takeharu; Shankaranarayanan, Aruna et al. (2005) Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complex. Science 310:1686-90
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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