Vilardaga Lab

The Vilardaga laboratory carries an interdisciplinary research program aimed at elucidating molecular mechanisms of signal transduction mediated by G-protein coupled receptors in renal, skeletal and other cell systems.

Below displays the Research Details from the profile of each member of the lab.

Jean-Pierre Vilardaga, PhD

The Vilardaga Laboratory is directed at understanding molecular mechanisms of G protein-coupled receptor (GPCR) signaling and trafficking – two key processes in biological signaling in general and, more specifically, in pharmacology and drug research. Adrenergic and peptide receptors, which transmit signals, respectively for small neurotransmitters (such as noradrenaline and dopamine) and larger peptide hormones (vasopressin, parathyroid hormone, parathyroid hormone related peptide), are two well characterized distinct subtypes of GPCRs that serve as useful models for analyzing GPCR mechanisms. The objective of this line of research is to elucidate the general principles of signal transduction from the extracellular ligand binding event to intracellular signaling cascades, which are involved in systems as diverse as neurotransmitter and hormonal signaling.

Optical approaches (eg. FRET, TIRF microscopy) are used to monitor the activation/deactivation steps along the signaling cascades of GPCRs in live cells. This approach revealed fundamental mechanisms of GPCRs signaling and trafficking in live cells for neurotransmitter and peptide hormones such as the PTH, which were published in 2003-2007 in Nature Biotech, Nature Methods, Nature Chemical Biology, the Journal of Biological Chemistry and PNAS.

Recently Vilardaga laboratory also discovered the new concept that persistent cAMP production mediated by parathyroid hormone receptor endocytosis may mediate potent catabolic signaling actions via PTH (PNAS 2008, Nature Chem Biol 2009). This prolonged cAMP production from intracellular compartments further indicate that the traditional concept that cAMP production triggered by GPCRs originates exclusively at the cell membrane must be revised. The main focus of my current research aims at determining the origin of the prolonged signaling by GPCRs and its termination. These events and consequent signaling patterns are quite novel and important for cellular signaling.


Karina Pena, PhD
Research Instructor


Jean-Pierre Vilardaga, PhD
Professor

Jean-Pierre Vilardaga, PhD

Journal Articles

Chelocha RW, SH Gellman, JP Vilardaga and TJ Gardella. Signal transduction at type -1  parathyroid hormone receptor: Mechanistic studies provide insight into GPCR signaling and highlight therapeutic opportunities. Nature Review Endocrinology 11: 712-724, 2015. 
Gardella TJ and JP Vilardaga.  The parathyroid hormone receptors: Family B GPCRs.  Pharmacol Reviews 67: 310-337, 2015.
Vilardaga JP, FG Jean-Alphonse and TJ Gardella. Endosomal generation of cAMP in GPCR signaling. Nature Chemical Biology 10: 700-706, 2014.
Gidon A, MM Al-Bataineh, FG Jean-Alphonse, H Stevenson, T Watanabe, C Louet, A Khatri, G Calero, NM Pastor-Soler, TJ Gardella and JP Vilardaga. Endosomal GPCR signaling turned off by negative feedback actions of PKA and v-ATPase. Nature Chem Biol 10: 707-711, 2014.
Wehbi VL, H Stevenson, TN Feinstein, G Calero, G Romero and JP Vilardaga.  Non-canonical GPCR signaling arising from a PTH receptor-arrestin-Gßy complex.  Proc Natl Acad Sci USA 110:1530-1535, 2013.
Feinstein TN, N Yui, MJ Webber, VL Wehbi, HP Stevenson, J Darwin King, Jr., KR Hallows, D Brown, R Bouley and JP Vilardaga.  Noncanonical control of vasopressin receptor type 2 signaling by retromer and arrestin. J. Biol. Chem 288:27849-27860, 2013.
Vilardaga JP, TJ Gardella, VL Wehbi and TN Feinstein.  Non-canonical signaling of the PTH receptor.  Trends Pharmacol Sci 33:423-431, 2012.
Hanyu R, VL Wehbi, T Hayata, S Moriya, TN Feinstein, Y Yoichi Ezura, M Nagao, Y Saita, H Hemmi, T Notomi, T Nakamoto, E Schipani, S Takeda, K Kaneko, H Kurosawa, G Karsenty, KM Kronenberg, JP Vilardaga and M Noda.  Anabolic action of PTH regulated by the ß2-adrenergic receptor.  Proc Natl Acad Sci USA 109:7433-7438, 2012.
Feinstein TN, VL Wehbi, JA Ardura, DA Wheeler, S Ferrandon, TJ Gardella and JP Vilardaga.  Retromer terminates the generation of cAMP by internalized PTH-receptors.  Nature Chemical Biology 7:278-284,2011.
Ferrandon S, TN Feinstein, C Castro, B Wang R Bouley, JT Potts, TJ Gardella and JP Vilardaga.  Sustained cyclic AMP production by parathyroid hormone receptor endocytosis.  Nature Chemical Biology 5:734-742, 2009.
Okazaki M, S Ferrandon, JP Vilardaga, ML Bouxsein, JT Potts and TJ Gardella. Prolonged signaling at the parathyroid hormone receptor by peptide ligands targeted to a specific receptor conformation. Proc. Natl. Acad. Sci. USA 105:16525-16530, 2008.
Vilardaga JP, OV Nikolaev, K Lorenz, S Ferrandon, Z Zhuang and MR Lohse. Conformational cross-talk between a2A-adrenergic and m-opioid receptors control cell signaling. Nature Chemical Biology 4:126-131, 2008.
Rochais F, JP Vilardaga, VO Nikolaev, M Bünemann, MJ Lohse and S Engelhardt. Real-time optical recording of b1-adrenergic receptor activation reveals supersensitivity of the Arg389 variant to carvedilol. J. Clin. Invest. 117:229-235, 2007.
Vilardaga JP, M  Bünemann, C Krasel, M Castro and MJ Lohse.  Measurement of the millisecond activation switch of G protein-coupled receptors in living cells.  Nature Biotechnology 21:807-812, 2003.
 

Kunhong (Kevin) Xiao, MD, PhD

Journal Articles

Brady DC, Crowe MS, Turski ML, Hobbs GA, Yao XJ, Apirat C, Knapp S, Xiao K, Campbell SL, Thiele DJ and Counter CM. Copper is required for oncogenic BRAF signaling and tumorigenesis. Nature 509:492-496, 2014.
Shukla A, Westfield G, Xiao K, Reis RI, Huang LY, Tripathi-Shukla P, Qian J, Li S, Blanc A, Oleskie AN, Dosey AM, Su M, Liang CR, Gu LL, Shan JM, Chen X, Hanna R, Choi M, Yao XJ, Klink BU, Kahsai AW, Sidhu S, Koide S, Penczek PA, Kossiakoff AA, Woods V, Kobilka BK, Skiniotis G and Lefkowitz RJ. Visualization of arrestin recruitment by a G- protein-coupled receptor. Nature 512:218-22, 2014.

 
Kahsai AW, Rajagopal S, Sun J and Xiao K.  Monitoring protein conformational changes and dynamics using stable-isotope labeling and mass spectrometry. Nature Protocols 9:1301–1319, 2014.
Shukla A, Manglik A, Kruse A, Xiao K, Reis A, Tseng W, Staus D, Hilger D, Uysal S, Huang L, Paduch M, Tripathi-Shukla P, Koide A, Koide S, Weis W, Kossiakoff A, Kobilka B and Lefkowitz RJ. Structure of active β-arrestin1 bound to a G protein-coupled receptor phosphopeptide. Nature 497:137-141, 2013.
Kahsai AW, Xiao K, Rajagopal S, Ahn S, Shukla AK, Sun J, Oas TG and Lefkowitz RJ.   Multiple ligand-specific conformations of the β2-adrenergic receptor. Nature Chemical Biology 7:692-700, 2011.
Nobles KN, Xiao K, Ahn S, Shukla AK, Lam CL, Rajagopal S, Bressler EA, Hara RM, Shenoy SK, Gygi SP and Lefkowitz RJ.   Distinct GRK phosphorylation sites on the β2AR: A “bar code” which differentially encodes β-arrestin functions. Science Signaling 4:ra51, 2011.
Xiao K and Shenoy SK. β2AR lysosomal trafficking is regulated by ubiquitination of lysyl residues in two distinct receptor domains. Journal of Biological Chemistry 286: 12785-12795, 2011.