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

Yang Kevin XiangTupper Hall 2419c

ykxiang@ucdavis.edu

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 P

rize to

Brian K

obilka and R

obert Lefk

owitz

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

PDE4D3

P K A

PKA

P K A

P K A

PDE4D8

Arres

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

PDE4D3

P K A

PKA

P K A

P K A

PDE4D8

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

AMPA

AdaptativeGene 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

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10

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vel o

bje

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WT

β2-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

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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.