Evidence suggests that the phospho-protein, phosducin, is a regulator of many G protein systems, including visual signal transduction in vertebrate photoreceptors. The long-term objective of this research is to understand the precise mechanism of phosducin regulation of G proteins in photoreceptors and other cells. Phosducin acts on the beta/gamma complex of G proteins to inhibit its function in the activation of G protein alpha subunits and effector proteins. When phosducin is phosphorylated, it does not affect these functions. This proposed mechanism of phosducin action has been termed the G beta/gamma sequestration model.
The specific aims of this proposal are designed to test this model by: (1) testing the predictions of the G beta/gamma sequestration model on the electrophysiological responses of intact rods to determine if the effects of phosducin on G beta/gamma observed in vitro are also functional in vivo; (2) determining structurally how phosducin is inactivated by phosphorylation and (3) characterizing the cellular factors that determine the phosphorylation state of phosducin. The methods to be employed to achieve these aims are multi-disciplinary. They include biochemical techniques for measuring phosphorylation-dependent changes in phosducin structure, site-directed mutagenesis of key phosducin residues, collaborative electrophysiological studies under conditions of high and low phosducin activity and biochemical measurements of the effect of dopamine on phosducin activity. Defects in G protein pathway components cause retinopathies and other non-retinal diseases. Therefore, it is imperative to understand how G protein signaling works in order to identify the causes of such diseases and develop treatments. These studies contribute to the understanding of G protein function by addressing the role of phosducin in G protein pathway regulation.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Visual Sciences C Study Section (VISC)
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Brigham Young University
Schools of Arts and Sciences
United States
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Lord, Nathan P; Plimpton, Rebecca L; Sharkey, Camilla R et al. (2016) A cure for the blues: opsin duplication and subfunctionalization for short-wavelength sensitivity in jewel beetles (Coleoptera: Buprestidae). BMC Evol Biol 16:107
Tracy, Christopher M; Kolesnikov, Alexander V; Blake, Devon R et al. (2015) Retinal cone photoreceptors require phosducin-like protein 1 for G protein complex assembly and signaling. PLoS One 10:e0117129
Xie, Keqiang; Masuho, Ikuo; Shih, Chien-Cheng et al. (2015) Stable G protein-effector complexes in striatal neurons: mechanism of assembly and role in neurotransmitter signaling. Elife 4:
Plimpton, Rebecca L; Cuéllar, Jorge; Lai, Chun Wan J et al. (2015) Structures of the G?-CCT and PhLP1-G?-CCT complexes reveal a mechanism for G-protein ?-subunit folding and G?? dimer assembly. Proc Natl Acad Sci U S A 112:2413-8
Tracy, Christopher M; Gray, Amy J; Cuéllar, Jorge et al. (2014) Programmed cell death protein 5 interacts with the cytosolic chaperonin containing tailless complex polypeptide 1 (CCT) to regulate ?-tubulin folding. J Biol Chem 289:4490-502
Lai, Chun Wan J; Kolesnikov, Alexander V; Frederick, Jeanne M et al. (2013) Phosducin-like protein 1 is essential for G-protein assembly and signaling in retinal rod photoreceptors. J Neurosci 33:7941-51
Zhou, Xueyuan; Shapiro, Leland; Fellingham, Gilbert et al. (2011) HIV replication in CD4+ T lymphocytes in the presence and absence of follicular dendritic cells: inhibition of replication mediated by ?-1-antitrypsin through altered I?B? ubiquitination. J Immunol 186:3148-55
Smrcka, Alan V; Kichik, Nessim; Tarragó, Teresa et al. (2010) NMR analysis of G-protein betagamma subunit complexes reveals a dynamic G(alpha)-Gbetagamma subunit interface and multiple protein recognition modes. Proc Natl Acad Sci U S A 107:639-44
Howlett, Alyson C; Gray, Amy J; Hunter, Jesse M et al. (2009) Role of molecular chaperones in G protein beta5/regulator of G protein signaling dimer assembly and G protein betagamma dimer specificity. J Biol Chem 284:16386-99
Willardson, Barry M; Howlett, Alyson C (2007) Function of phosducin-like proteins in G protein signaling and chaperone-assisted protein folding. Cell Signal 19:2417-27