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)
Alzheimer’s Disease: a growing society burden
(with aging babyboomers)
G-protein coupled Receptors (GPCRs)
Neuropeptide
Tachykinin
Opioid
Chemokine
Amine
Melatonin
MECA
Glycoprotein
Purine
Adapted from Fredriksson et al MP 2003
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
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
Alzheimer’s diseases
Receptor signaling crosstalk underlies cardiac
hypertrophy and apoptosis in heart failure
Intracellular adrenergic signaling in heart
Adopted from Xiao, 2003
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
Using FRET-based biosensors to study subcellular
bAR signaling in diseased myocytes
Plasma membrane
Cytosol
Sarcoplasmic reticulum
Forskolin
10 mM
FSK
A
K
A
P
PD
E4
D3
P
K
A
A
K
PD A
E4 P
D8
G
s
P
K
A
bAR
PLB
SERCA
Arres
tin2
P
D
E
4
D
5
bAR
A
K
A
P
P
D
E
4
D
5
RyR2
A
K
A
P
P
K
A
P
K
A
AC
Isoproterenol
10 mM
ISO
P
K
A
A
K
A
P
SERCA
PLB
G
s
P
K
A
bAR
A
K
A
P
Arres
tin2
PD
E4
D3
β
A
R
PD
E4 P
D8 D
E
4
D
5
bAR
A
K
A
P
RyR2
P
K
A
Liu, PNAS, 2012
A
K
A
P
P
K
A
AC
PGE2 and Insulin impair adrenergic signaling in
cardiac myocytes
PGE2
Iso
bAR
EP4-R
PDE
Cell death
PGE2 activates PDE4D to block cAMP
diffusion from the PM to the SR under bAR
stimulation
Insulin impairs adrenergic stimulation via
enhanced Gi coupling
Liu et al PNAS, 2012
Soto et al Circ Res, 2009
Cervantes, Circ Res, 2010
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.
Alzheimer’s disease
Adaptec from www.ahaf.org/alzdis/about/AmyloidPlaques.htm
The Amyloid hypothesis in Alzheimer’s disease
Adaptec from www.ahaf.org/alzdis/about/AmyloidPlaques.htm
Are there some specific cellular
targets for amyloid b peptide (Ab)?
Ab interacts with CNS adrenergic system
for Alzheimer’s disease
NE
Ab
Wang et al FASEB, 2010
Wang et al JBC, 2011
Wang et all JBC, 2012, in press
bAR
cAMP/PKA
Acute
AMPA
Chronic
Adaptative
Gene transcription
Ab
Neuron
Apopotosis
ApoE
Inhibition of β2AR ameliorates Aβ toxicity:
may provide a new therapy for AD
A
β2-KO
Novel object preference (%)
WT
PS1/APP
80
70
60
50
40
30
20
10
0
**
β2-KO/PS1/APP
The Team
University of California at Davis
University of Illinois at Urbana
Sungjin Kim
Qin Fu
Qian Shi
Shu-Bai Liu
David Cervantes
Dagoberto Soto
Vania De Arcangelis
Ruijie Liu
Dayong Wang
Yongyu Wang
Dippal Parikh
Rita Xu
Funding
•NIH
•American Heart Association
•Alzheimer’s association
•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
Antelope Canyon, AZ, 2009
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.
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
Hypertrophy and Heart Failure
Adapted from Lutz et al Nature 1999
Schematic of SiMPull
600
Fluorescence intensity (a.u.)
Fluorescence intensity (a.u.)
800
600
400
200
0
0
5
Time (s) 10
Jain et al Nature 2011
400
200
0
15
0
5
10
Time (s)
15
A New Alzheimer’s 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.
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.