G protein signaling in neurons was originally described as a linear sequence in which agonist bound to a specific receptor. which in turn activated a single species of G protein. That G protein then went on to activate or inhibit intracellular effectors such as adenylyl cyclase, phospholipase or various ion channels. Over the past several years, it has become clear that G protein signaling is a complex process. Some of this complexity involves direct regulation of receptors and G proteins by a variety of molecules that bind to or phosphorylate receptors (arrestins and receptor kinases) or increase GTPase activity of G proteins (RGS proteins). A more subtle form of regulation appears to be from a series of proteins and lipids that alter the positioning of the molecules of the G protein cascade on the membrane. Some of these are passive positioning molecules, but others, such as microtubules, offer dynamic interactions that both position and activate G proteins. The interface between G proteins and microtubules is bidirectional, as certain fty subunits stabilize microtubules, while a subunits promote rapid microtubule depolymerization. G proteins are highly concentrated at the post-synaptic density and it is hypothesized that their activation leads to cytoskeletal rearrangement and rapid synaptic shape change. It is in this framework, that research is proposed to explore the relationship of structure and function within the context of G protein signaling. Several imaging tools for both G proteins and microtubules will be used in experiments designed to discover the interplay between these systems. These techniques will be combined with the enzyme assays and the photoaffinity labeling we have used successfully to probe the activation of G proteins and the functional activity of fluorescent (normal and mutant) G proteins in cells and in mice. G protein coupled receptors and their downstream effects are favorite targets of current neuropharmacology. By developing a better understanding of the relationship of those receptors and G proteins to the neuronal microenvironment, new therapeutic strategies for the diseases of brain and mind are likely to be forthcoming.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH039595-19
Application #
6986169
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Asanuma, Chiiko
Project Start
1984-12-01
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2007-11-30
Support Year
19
Fiscal Year
2006
Total Cost
$379,093
Indirect Cost
Name
University of Illinois at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Cocchi, Massimo; Bernroider, G; Rasenick, Mark et al. (2017) Document of Trapani on animal consciousness and quantum brain function: A hypothesis. J Integr Neurosci 16:S99-S103
Schappi, Jeffrey M; Krbanjevic, Aleksandar; Rasenick, Mark M (2014) Tubulin, actin and heterotrimeric G proteins: coordination of signaling and structure. Biochim Biophys Acta 1838:674-81
Saengsawang, Witchuda; Rasenick, Mark M (2013) Heterotrimeric G proteins and microtubules. Methods Cell Biol 115:173-89
Davé, Rahul H; Saengsawang, Witchuda; Lopus, Manu et al. (2011) A molecular and structural mechanism for G protein-mediated microtubule destabilization. J Biol Chem 286:4319-28
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Allen, John A; Yu, Jiang Z; Dave, Rahul H et al. (2009) Caveolin-1 and lipid microdomains regulate Gs trafficking and attenuate Gs/adenylyl cyclase signaling. Mol Pharmacol 76:1082-93
Dave, Rahul H; Saengsawang, Witchuda; Yu, Jiang-Zhou et al. (2009) Heterotrimeric G-proteins interact directly with cytoskeletal components to modify microtubule-dependent cellular processes. Neurosignals 17:100-8
Donati, Robert J; Dwivedi, Yogesh; Roberts, Rosalinda C et al. (2008) Postmortem brain tissue of depressed suicides reveals increased Gs alpha localization in lipid raft domains where it is less likely to activate adenylyl cyclase. J Neurosci 28:3042-50
Layden, Brian T; Saengsawang, Witchuda; Donati, Robert J et al. (2008) Structural model of a complex between the heterotrimeric G protein, Gsalpha, and tubulin. Biochim Biophys Acta 1783:964-73
Roychowdhury, Sukla; Rasenick, Mark M (2008) Submembraneous microtubule cytoskeleton: regulation of microtubule assembly by heterotrimeric Gproteins. FEBS J 275:4654-63

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