From G-protein coupled receptors to heart failure and Alzheimer’s disease
Yang Kevin XiangTupper Hall 2419c
Department of PharmacologyUCD 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)
Adapted from Fredriksson et al MP 2003
AmineMelatoninMECA
GlycoproteinPurine
Opioid Chemokine
NeuropeptideTachykinin
2012 Nobel Prize to
Brian Kobilka and Robert L
efkowitz
A
Heart rate, contractility, blood pressure, smooth muscle relaxation, fat and carbohydrate metabolism Memory, behavior
Blood pressure, analgesia, anesthesia
Blood pressure
Adrenergic Receptors
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
In vivo physiology•Cardiac hypertrophy &
heart failure•Memory and learning in Alzheimer’s diseases
Cellular studies•Receptor signaling transduction•Signaling crosstalk among GPCRs and RTKs•Myocyte contraction•Cardiac stem cell growth and differentiation
Receptor signaling crosstalk underlies cardiachypertrophy and apoptosis in heart failure
Intracellular adrenergic signaling in heart
Adopted from Xiao, 2003
Signaling cross-talks during onset (early stage) of heart failure
• 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
The new idea: signaling alteration occursbefore structural/morphological changes in myocardium
Plasma membrane Cytosol Sarcoplasmic reticulum
Gs
ISO
AKAP
A K A P
A K A P
A K A P
P D E 4 D 5
β A R
PD E4 D3
P K A
PKA
P K A
P K A
PD E4 D8Arres
tin2
10 M
AC
AR
AR
SERCA
RyR2
PLB
Gs
FSK
AKAP
A K A P
A K A P
A K A P
P D E 4 D 5
PD E4 D3
P K A
PKA
P K A
P K A
PD E4 D8
Arres
tin2
10 M
AC
AR
AR
SERCA
RyR2
PLB
P D E 4 D 5
Forskolin
Isoproterenol
Liu, PNAS, 2012
Using FRET-based biosensors to study subcellular AR signaling in diseased myocytes
Liu et al PNAS, 2012Soto et al Circ Res, 2009Cervantes, Circ Res, 2010
PGE2 and Insulin impair adrenergic signaling in cardiac myocytes
PDE
EP4-R AR
IsoPGE2
Cell death
PGE2 activates PDE4D to block cAMP diffusion from the PM to the SR under AR stimulation
Insulin 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
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 cellulartargets for amyloidpeptide (A)?
A
AR
cAMP/PKA
AMPAAdaptative
Gene transcription
NE
A
ApoE
A interacts with CNS adrenergic system for Alzheimer’s disease
AcuteChronic
NeuronApopotosis
Wang et al FASEB, 2010Wang et al JBC, 2011Wang et all JBC, 2012, in press
Inhibition of β2AR ameliorates Aβ toxicity:may provide a new therapy for AD
01020304050607080
Nov
el o
bjec
t pre
fere
nce
(%)
WTβ2-KO
PS1/APP
β2-KO/PS1/APP
**
The Team
•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•Alzheimer’s association
University 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 Molecules
• Signaling 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 SiMPull
Jain et al Nature 2011 &Nature Protocol 2012
• Receptor oligomers• Receptor PTMs• Receptor binding partners
Under neurohormonal stimulation, drugs treatment, or in diseases
Hypertrophy and Heart Failure
Adapted from Lutz et al Nature 1999
Schematic of SiMPull
0 5 10 150
200
400
600
800
Fluo
resc
ence
inte
nsity
(a.u
.)
Time (s)0 5 10 15
0
200
400
600
Fluo
resc
ence
inte
nsity
(a.u
.)
Time (s)
Jain et al Nature 2011
A New Alzheimer’s Disease Model
AD modelTg6554 X 2AR-KO
•Reduced amyloid load in brain
•Reduced neuron loss over time
•Slow down decline of cognitive function
A position on amyloid induced 2AR 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.