From G-protein coupled receptors to heart failure and Alzheimer ’ s disease Yang Kevin Xiang

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From G-protein coupled receptors to heart failure and Alzheimer s disease Yang Kevin Xiang Tupper Hall 2419c ykxiang@ucdavis.edu Department of Pharmacology UCD Medical School. Two diseases are explored in Xiang lab. Hypertrophy and Heart Failure (No: 1 Killer in the US) - PowerPoint PPT Presentation

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  • From G-protein coupled receptors to heart failure and Alzheimers disease

    Yang Kevin XiangTupper Hall 2419cykxiang@ucdavis.edu

    Department of PharmacologyUCD Medical School

  • Two diseases are explored in Xiang labHypertrophy and Heart Failure (No: 1 Killer in the US)

    Alzheimers Disease: a growing society burden (with aging babyboomers)

  • G-protein coupled Receptors (GPCRs)Adapted from Fredriksson et al MP 2003AmineMelatoninMECAGlycoproteinPurine Opioid ChemokineNeuropeptideTachykinin2012 Nobel Prize to Brian Kobilka and Robert Lefkowitz

  • AHeart rate, contractility, blood pressure, smooth muscle relaxation, fat and carbohydrate metabolism Memory, behaviorBlood pressure, analgesia, anesthesiaBlood pressureAdrenergic ReceptorsAR drugs are commonly used for asthma, hypertension, heart failure, and depression

  • Insights from molecules to mice Single molecule studiesReceptor /G protein couplingPosttranslational modificationReceptor dimerizationLigand efficacyIn vivo physiologyCardiac hypertrophy & heart failureMemory and learning in Alzheimers diseasesCellular studiesReceptor signaling transductionSignaling crosstalk among GPCRs and RTKsMyocyte contractionCardiac stem cell growth and differentiation

  • Receptor signaling crosstalk underlies cardiachypertrophy and apoptosis in heart failure

  • Intracellular adrenergic signaling in heartAdopted from Xiao, 2003

  • Signaling cross-talks during onset (early stage) of heart failureProstaglandin (chronic inflammation) directly impacts cardiac contractile

    Insulin (hyperinsulinemia) insults the heart directly.

    IGF and adrenergic regulation of cardiac stem cell proliferation and differentiation for cardiac repairing and regeneration under ischemia/heart failure

    The new idea: signaling alteration occursbefore structural/morphological changes in myocardium

  • Plasma membraneCytosolSarcoplasmic reticulumForskolinIsoproterenolLiu, PNAS, 2012Using FRET-based biosensors to study subcellular bAR signaling in diseased myocytes

  • Liu et al PNAS, 2012Soto et al Circ Res, 2009Cervantes, Circ Res, 2010PGE2 and Insulin impair adrenergic signaling in cardiac myocytes PGE2 activates PDE4D to block cAMP diffusion from the PM to the SR under bAR stimulationInsulin impairs adrenergic stimulation via enhanced Gi coupling

  • NSAIDs (such as Advil) or not?Inflammation is

    BAD during the early stage, NSAIDs prevent cardiovascular diseases

    GOOD in the late stage of heart diseases, NSAIDs kill patients.Many NSAIDs inhibit Cox-2, and reduce PGE2 for inflammatory responses in body

  • Alzheimers diseaseAdaptec from www.ahaf.org/alzdis/about/AmyloidPlaques.htm

  • The Amyloid hypothesis in Alzheimers diseaseAdaptec from www.ahaf.org/alzdis/about/AmyloidPlaques.htmAre there some specific cellulartargets for amyloid b peptide (Ab)?

  • AbbARcAMP/PKAAMPAAdaptativeGene transcriptionNEAbApoEAb interacts with CNS adrenergic system for Alzheimers disease AcuteChronicNeuronApopotosisWang et al FASEB, 2010Wang et al JBC, 2011Wang et all JBC, 2012, in press

  • Inhibition of 2AR ameliorates A toxicity:may provide a new therapy for AD

  • The TeamLee Cox (G.Gordavin), University of IllinoisTJ Ha (Ankur Jain), University of IllinoisJin Zhang, John Hopkins UniversityWen Chen, Temple UniversityDale Abel, University of UtahFundingNIHAmerican Heart AssociationAlzheimers associationUniversity of California at Davis

    Sungjin KimQin FuQian Shi

    Dippal ParikhRita Xu

    University of Illinois at Urbana

    Shu-Bai LiuDavid CervantesDagoberto SotoVania De ArcangelisRuijie LiuDayong WangYongyu Wang

    Antelope Canyon, AZ, 2009

  • Insights from MoleculesSignaling complexes under physiological and pathophysiological conditions

    Membrane protein oligomerization Receptors monomers or dimersChannels clustering, L-type Ca channels in diabetes

    Post-translational modification of receptors or channels under a specific neurohormonal stimulation or disease state

    The goal is to design biased drugs that selectively act on a specific pool of receptor in diseased conditions.

  • Flow Chart of SiMPullJain et al Nature 2011 &Nature Protocol 2012Receptor oligomersReceptor PTMsReceptor binding partners

    Under neurohormonal stimulation, drugs treatment, or in diseases

  • Hypertrophy and Heart FailureAdapted from Lutz et al Nature 1999

  • Schematic of SiMPullJain et al Nature 2011

  • A New Alzheimers Disease ModelAD modelTg6554 X b2AR-KO

    Reduced amyloid load in brain

    Reduced neuron loss over time

    Slow down decline of cognitive function

    A position on amyloid b induced b2AR signaling in neuron,and its implication in AD development, and potential therapeutic targets.

  • Studies of Single GPCR complex with SimPullThe similar signaling crosstalk may:

    Affect neuronal differentiation

    Enhance the memory

    Reduce the blood flow for cancer cell growth

    Immunoresponse

    A opening on study GPCR signaling cross-talk in both cardiac and neuronal cells.

    ***G protein coupled receptors are consisted of the largest Gene family in human and mouse genomes. It consists of more than 1000 individual genes.

    GPCRs are evolutionarily conserved genes. This picture highlights the classification of rhodopsin family in a recent study by Dr. Fredirksson. Rhodopsin family consists of over 300 genes, and many famous receptors are classified in this family, including my favorite adrenergic receptors, and opioid receptors which are heavily studied in this department. The rhodopsin family of GPCRs play very important roles in regulating a variety of physiological functions. Malfunction of these GPCRS leads to a wide range of diseases from brain dysfunction to cardiovascular diseases. Currently, more than 40% prescribed drugs in the US market are targeted on these GPCRS.******************