PhD, The Pennsylvania State University, College of Medicine, 1983
Postdoctoral Training, University of Texas Health Science Center of Dallas, 1983-1986
Cellular Regulation, Signal Transduction, G protein-Coupled Receptor Signaling, Neurosciences, Epilepsy
Heterotrimeric G Proteins, Gene Diversity, Functional Genomic Approaches
G protein-coupled receptor (GPCR) signaling pathways are therapeutic targets for more than 50% of drugs currently on the market. Particularly abundant in the brain, GPCR signaling pathways must integrate many cellular functions to produce a coordinated neurological response. To allow the design of more selective drugs, it is necessary to sort out the individual contributions of the various GPCRs, G proteins, and effectors that specify these cellular responses. The long-term goal of research in my laboratory has been to understand how this specificity is encoded in the abg subunit structure of the G protein. Beginning with our cloning of diverse a, b, g subunits, our research has run the gamut from determining their expression and subcellular localizations; to purifying and characterizing their potential interactions in reconstitution systems; to ascertaining their signaling roles in the developmental and physiological settings of zebrafish and mice; to identifying their genetic variations in neurologic and psychiatric diseases; to modeling these genetic variations in mice to create humanized, mouse models of disease that can be used to explore the defective mechanisms underlying diseases and to test new investigational drugs (Figure 1).
The use of this comprehensive approach has provided the first conclusive evidence that the gamma subtypes are major determinants of signaling specificity by stabilizing and directing the hierarchical assembly of functionally distinct G alphabetagamma heterotrimers that operate downstream of receptors in cell type specific contexts, paving the way for the design of more selective drugs to treat a range of neurologic and psychiatric disorders. Moreover, it should come as no surprise that variations in the expression or structure of the genes encoding the gamma subtypes are increasingly being identified in human disease cohorts.
Moon AM, Stauffer AM, Schwindinger WF, Sheridan K, Firment A, Robishaw JD.
Disruption of G-Protein y5 Subtype Causes Embryonic Lethality in Mice.
J Am Soc Nephrol
Schwindinger WF, Mirshahi UL, Baylor KA, Sheridan KM, Stauffer AM, Usefof S, Stecker MM, Mirshahi T, Robishaw JD. (2012, Mar). Synergistic roles for G-protein ?3 and ?7 subtypes in seizure susceptibility as revealed in double knock-out mice. J Biol Chem , 287(10), 7121-33.
Schwindinger WF, Mihalcik LJ, Giger KE, Betz KS, Stauffer AM, Linden J, Herve D, Robishaw JD. (2010, Sep). Adenosine A2A receptor signaling and golf assembly show a specific requirement for the gamma7 subtype in the striatum. J Biol Chem , 285(39), 29787-96.
Schwindinger WF, Borrell BM, Waldman LC, Robishaw JD. (2009, Nov). Mice lacking the G protein gamma3-subunit show resistance to opioids and diet induced obesity.. Am J Physiol Regul Integr Comp Physiol. , 297(5),r1494-502.
Leung T, Humbert JE, Stauffer AM, Giger KE, Chen H, Tsai HJ, Wang C, Mirshahi T, Robishaw JD. (2008, Nov). The orphan G protein-coupled receptor 161 is required for left-right patterning. Dev Biol , 323(1), 31-40.