The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

Research in my lab focuses on the signaling transduction of adrenergic receptors, a family of G-protein coupled receptor (GPCRs) in two diseases, heart failure and Alzheimer’s disease. The goals are to identify novel therapeutic strategies and targets for drug screen and for treatment of the diseases.

GPCRs are nature's most versatile biological sensors. They conduct the majority of transmembrane responses to extracellular stimulation of hormones and neurotransmitters, as well as pressure, sight, smell, and taste, regulate physiological responses in both peripheral tissues and central nerve system. Dysfunction of the receptor signaling pathways have been linked a variety of diseases including both Alzheimer's disease and heart failure. We are using integrated approaches including single molecule study, living-cell imaging study, and transgenic animals to understand the fundamentals of GPCR signaling transduction and their functions in tissues, as well as pathogenesis of heart failure and Alzheimer’s diseases.

Our current research focuses on the following areas:

1. Adrenergic receptor signaling in Alzheimer's disease (AD). We have identified b2 adrenergic receptors as a receptor for amyloid peptide Ab in vitro and on cell cultures (FASEB J 2010). We are examining the functional implication of the receptor signaling induced by amyloid Ab peptide in both glia and cortical and hippocampal neurons. Current advance shows that the b2 adrenergic signaling has broad implication, including contributing to AMPAR hyperactivation, Tau phosphorylation in vivo and in vitro. Transgenic approach shows that deficiency in b2 gene attenuates the symptoms in AD transgenic mice. We will further determine the role of the receptor signaling involved the etiology of disease.

2. Diabetic cardiomyopathy (DCM). Diabetes is one of the most prevalent health issues in the world. DCM is a consequence of chronic diabetic condition, which eventually leads to heart failure. We have uncovered a novel signaling network between insulin receptor and beta adrenergic receptor through analyzing subcellular signaling dynamics in cardiac muscle cells. This discovery will help us to unveil the puzzling disease without obvious causes.

3. Heart Failure. Heart failure is resulted from a sequence of complicated adaption and remodeling in myocardium after initial insults (such as acute ischemia or chronic hypertension and inflammation). Both myocytes and fibroblasts undergo extensive changes including hypertrophic growth, proliferation, and myocyte apoptosis. We aim to understand how the insults lead to signaling alteration in these cells by focusing cross-communication with adrenergic receptor signaling. In one direction, we observed a crossing talk between b and a1 adrenergic receptors for cardiac hypertrophy (Circulation Research, 2010). In another direction, we observed a crosstalk between prostagladin-induced inflammatory response and adrenergic signaling in myocytes, leading impaired cardiac function. We will explore these mechanisms to understand heart failure development, and potential therapeutic approaches to intervene the diseases.

4. Signaling Dynamics (FRET). In this direction, we employ highly sensitive FRET approach to analyze the intracellular dynamics of second messenger cAMP and Calcium, and try to understand how the small cAMP molecules evade the degradation enzyme "barriers" to reach specific compartments inside cells, such as ER/SR for calcium cycling in muscle cells and nucleus for activation CREB and other transcription factors. This study leads to unexpect observation such as receptor internalization is ciritical for diffusion of cAMP from the plasma membrane (Circulation research, 2009 et al). Explorng these mechanism will facilitate our understanding of neurohormonal regulation in general in physiological responses.

5. High resolution imaging of single receptor activation (SimPull). Working together with Dr. TJ Ha in Physics, we developed a single molecule approachSimPull to analyze a single protein complex (such as GPCR complex. Nature, 2011). This novel technology allows us to adventure into the single molecule demension to understand the fundamentals of GPCR signaling.

6. Functional adrenergic synapses between SGN and myocyte or ES-derived myocytes. Adrenergic synaptic regulation of b1 and b2 adrenergic receptor cellular and signaling properties within the model system of co-culturing sympathetic ganglia neurons and cardiac myocytes (J.Cell Biology 2007). We will try to understand formation of neuron/muscular synaptic formation, and its influence on the adrenergic receptor function. In parallel, we are also trying to co-culture of sympathetic ganglia neurons and human ES derived cardiac myocytes to study the signaling network controlling myogenesis.

Representative Publications

Chakir K, Depry C, Dimaano VL, Zhu WZ, Vanderheyden M, Bartunek J, Abraham TP, Tomaselli GF, Liu SB, Xiang YK, Zhang M, Takimoto E, Dulin N, Xiao RP, Zhang J, Kass DA (2011) Gas-Biased b2-Adrenergic Signaling from Restoring Synchronous Contraction in the Failing Heart. Science Translational Medicine (in press, Sept 14)

Xiang YK. (2011) Spatiotemporal regulation of beta adrenergic signals in cardiomyocytes. Circulation Research 109(2):231-44

Jain A, Liu R, Ramani B, Arauz E, Ishitsuka Y, Ragunathan K, Park J, Chen J, Xiang YK*, and Ha J*. (2011) Probing Cellular Protein Complexes via Single Molecule Pull-down. Nature 473(7348):484-8, * corresponding authors.

He Y, Kapoor A, Cook S, Liu S, Xiang YK, Rao CV, Kenis P, and Wang F. (2011) The non-receptor tyrosine kinase Lyn controls neutrophil adhesion by recruiting the CrkL/C3G complex to and activating Rap1 at the leading edge. J Cell Sci 124(Pt 13):2153-64.

Liu S, Zhang J, Xiang YK. (2011) FRET-based direct detection of dynamic protein kinase A activity on the sarcoplasmic reticulum in cardiomyocytes. Biochem Biophys Res Commun. 14;404(2):581-6

Yum K, Yu MF, Wang N, Xiang YK. (2011) Biofunctionalized nanoneedles for the direct and site-selective delivery of probes into living cells. Biochim Biophys Acta 1810(3):330-8.

Wang D, De Arcangelis V, Ruijie Liu, Xiang YK. (2011) Amyloid β dimer induces β2 adrenergic receptor internalization and desensitization J. Biol. Chem. (revision)

Sellers ZM, De Arcangelis V, Xiang YK, and Best PM. (2010) Cardiomyocytes with disrupted CFTR function require CaMKII and Ca2+-activated Cl- channel activity to maintain contraction rate. J. Physiology. 588(Pt 13):2417-29

De Arcangelis V, Liu SB, Zhang D, Soto D, and Xiang YK. (2010) Equilibrium between adenylyl cyclase and phosphodiesterase patterns adrenergic agonist dose-dependent spatiotemporal cAMP/PKA activities in cardiomyocytes. Mol Pharmacol 78(3):340-9

Wang D, Govindaiah, Liu R, Skarpiak B, De Arcangelis V, Cox CL, Xiang YK. (2010) Amyloid β dimer activates β2 adrenergic receptor and induces PKA dependent AMPA receptor hyperactivity. FASEB J 24(9):3511-21

Cervantes D, Crosby C, Xiang YK. (2010) Arrestin orchestrates cross-talk between GPCRs to modulate the spatiotemporal activation of ERK MAPK Circulation Research. 106(1):79-88 (Faculty of 1000 recommended paper)

Complete Publications List