From G-protein coupled receptors to

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From G-protein coupled receptors to heart
failure and Alzheimers disease Yang Kevin
Xiang Tupper Hall 2419c ykxiang_at_ucdavis.edu Depar
tment of Pharmacology UCD Medical School
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Two diseases are explored in Xiang lab
Hypertrophy and Heart Failure (No 1 Killer in
the US) Alzheimers Disease a growing society
burden (with aging babyboomers)
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G-protein coupled Receptors (GPCRs)
Neuropeptide Tachykinin
Opioid Chemokine
2012 Nobel Prize to Brian Kobilka and Robert
Lefkowitz
Amine Melatonin MECA
Glycoprotein Purine
Adapted from Fredriksson et al MP 2003
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Adrenergic Receptors
A
Heart rate, contractility, blood pressure, smooth
muscle relaxation, fat and carbohydrate
metabolism Memory, behavior
Blood pressure, analgesia, anesthesia
Blood pressure
AR drugs are commonly used for asthma,
hypertension, heart failure, and depression
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Insights from molecules to mice

• Single molecule studies
• Receptor /G protein coupling
• Posttranslational modification
• Receptor dimerization
• Ligand efficacy

• Cellular studies
• Receptor signaling transduction
• Signaling crosstalk among
• GPCRs and RTKs
• Myocyte contraction
• Cardiac stem cell growth
• and differentiation

• In vivo physiology
• Cardiac hypertrophy
• heart failure
• Memory and learning in
• Alzheimers diseases

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Receptor signaling crosstalk underlies
cardiac hypertrophy and apoptosis in heart
failure
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Intracellular adrenergic signaling in heart
Adopted from Xiao, 2003
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Signaling cross-talks during onset (early stage)
of heart failure
The new idea signaling alteration occurs before
structural/morphological changes in myocardium

• Prostaglandin (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

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Using FRET-based biosensors to study subcellular
bAR signaling in diseased myocytes
Plasma membrane
Cytosol
Sarcoplasmic reticulum
Forskolin
Isoproterenol
Liu, PNAS, 2012
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PGE2 and Insulin impair adrenergic signaling in
cardiac myocytes
Insulin impairs adrenergic stimulation via
enhanced Gi coupling
PGE2 activates PDE4D to block cAMP diffusion from
the PM to the SR under bAR stimulation
Liu et al PNAS, 2012 Soto et al Circ Res,
2009 Cervantes, Circ Res, 2010
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NSAIDs (such as Advil) or not?
Many NSAIDs inhibit Cox-2, and reduce PGE2 for
inflammatory responses in body
Inflammation is BAD during the early stage,
NSAIDs prevent cardiovascular diseases GOOD in
the late stage of heart diseases, NSAIDs kill
patients.
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Alzheimers disease
Adaptec from www.ahaf.org/alzdis/about/AmyloidPlaq
ues.htm
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The Amyloid hypothesis in Alzheimers disease
Are there some specific cellular targets for
amyloid b peptide (Ab)?
Adaptec from www.ahaf.org/alzdis/about/AmyloidPlaq
ues.htm
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Ab interacts with CNS adrenergic system for
Alzheimers disease
NE
Ab
Wang et al FASEB, 2010 Wang et al JBC, 2011 Wang
et all JBC, 2012, in press
bAR
cAMP/PKA
Chronic
Acute
Adaptative Gene transcription
AMPA
Ab
Neuron Apopotosis
ApoE
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Inhibition of ß2AR ameliorates Aß toxicity may
provide a new therapy for AD
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The Team
University of California at Davis Sungjin
Kim Qin Fu Qian Shi Dippal Parikh Rita Xu
University of Illinois at Urbana Shu-Bai
Liu David Cervantes Dagoberto Soto Vania De
Arcangelis Ruijie Liu Dayong Wang Yongyu Wang

• Lee Cox (G.Gordavin), University of Illinois
• TJ Ha (Ankur Jain), University of Illinois
• Jin Zhang, John Hopkins University
• Wen Chen, Temple University
• Dale Abel, University of Utah

• Funding
• NIH
• American Heart Association
• Alzheimers association

Antelope Canyon, AZ, 2009
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Insights from Molecules

• Signaling complexes under physiological and
  pathophysiological conditions
• Membrane protein oligomerization
• Receptors monomers or dimers
• Channels 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.

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Flow Chart of SiMPull

• Receptor oligomers
• Receptor PTMs
• Receptor binding partners
• Under neurohormonal stimulation,
• drugs treatment, or in diseases

Jain et al Nature 2011 Nature Protocol 2012
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Hypertrophy and Heart Failure
Adapted from Lutz et al Nature 1999
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Schematic of SiMPull
Jain et al Nature 2011
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A New Alzheimers Disease Model

• AD 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.
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Studies of Single GPCR complex with SimPull

• The 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.