Abstract

The principal investigator will study human SH-SY-5Y neuroblastoma cells which possess m3 muscarinic cholinergic receptors linked to phospholipase C activation. These cells will be used to study molecular mechanisms by which cell surface receptors become internalized upon continuous agonist occupancy. He will focus upon the hypothesis that mAChRs are internalized via clathrin coated pits by an ATP-dependent mechanism. Three hypotheses are to be tested: 1) Muscarinic receptors are sequestered by a pathway that is common to that utilized by constitutively active receptors. Does sequestration involve a clathrin coated pit mechanism? To test this, procedures known to disrupt formation or budding of clathrin coated pits will be introduced. 2) Internalization of the muscarinic receptors requires ATP and cytosol and is regulated by G proteins. 3) Muscarinic receptors are sequestered into an environment deficient in the key components of the PPI signaling pathway and in substrate availability.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023831-11
Application #
2037234
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Baughman, Robert W
Project Start
1986-09-01
Project End
1998-11-30
Budget Start
1996-12-01
Budget End
1998-11-30
Support Year
11
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Psychiatry
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Fisher, Stephen K; Heacock, Anne M; Keep, Richard F et al. (2010) Receptor regulation of osmolyte homeostasis in neural cells. J Physiol 588:3355-64
Foster, Daniel J; Vitvitsky, Victor M; Banerjee, Ruma et al. (2009) Muscarinic receptor regulation of osmosensitive taurine transport in human SH-SY5Y neuroblastoma cells. J Neurochem 108:437-49
Fisher, Stephen K; Cheema, Tooba A; Foster, Daniel J et al. (2008) Volume-dependent osmolyte efflux from neural tissues: regulation by G-protein-coupled receptors. J Neurochem 106:1998-2014
Foster, Daniel J; Heacock, Anne M; Keep, Richard F et al. (2008) Activation of muscarinic cholinergic receptors on human SH-SY5Y neuroblastoma cells enhances both the influx and efflux of K+ under conditions of hypo-osmolarity. J Pharmacol Exp Ther 325:457-65
Cheema, Tooba A; Fisher, Stephen K (2008) Cholesterol regulates volume-sensitive osmolyte efflux from human SH-SY5Y neuroblastoma cells following receptor activation. J Pharmacol Exp Ther 324:648-57
Cheema, Tooba A; Pettigrew, Veryan A; Fisher, Stephen K (2007) Receptor regulation of the volume-sensitive efflux of taurine and iodide from human SH-SY5Y neuroblastoma cells: differential requirements for Ca(2+) and protein kinase C. J Pharmacol Exp Ther 320:1068-77
Heacock, Anne M; Foster, Daniel J; Fisher, Stephen K (2006) Prostanoid receptors regulate the volume-sensitive efflux of osmolytes from murine fibroblasts via a cyclic AMP-dependent mechanism. J Pharmacol Exp Ther 319:963-71
Heacock, Anne M; Dodd, Michael S; Fisher, Stephen K (2006) Regulation of volume-sensitive osmolyte efflux from human SH-SY5Y neuroblastoma cells following activation of lysophospholipid receptors. J Pharmacol Exp Ther 317:685-93
Cheema, Tooba A; Ward, Caroline E; Fisher, Stephen K (2005) Subnanomolar concentrations of thrombin enhance the volume-sensitive efflux of taurine from human 1321N1 astrocytoma cells. J Pharmacol Exp Ther 315:755-63
Heacock, Anne M; Kerley, Daniel; Gurda, Grzegorz T et al. (2004) Potentiation of the osmosensitive release of taurine and D-aspartate from SH-SY5Y neuroblastoma cells after activation of M3 muscarinic cholinergic receptors. J Pharmacol Exp Ther 311:1097-104

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