hubio 543 september 25, 2007

HuBio 543September 25, 2007

Neil M. NathansonK-536A, [email protected]

Introduction to the Sympathetic Nervous System

HO

HO

Catechol Plus Amine

NH2+

Catecholamines

OH

HO

HO

C

H H

C

H

NH2

Norepinephrine Epinephrine

HO

HO

C

H H

C

H

3CH

OH

NH

IsoproterenolDopamine

HO

HO

C

H H

C

H

NH2

H

HO

HO

C

H H

C

H

CH

OH

NH

3CH

3CH

Adrenergic Innervation of Vasculature

ADRENERGIC TRANSMISSION

DOPA

Dopamine

Tyrosine

Ca++

AdR

TyrosineTH

DDC

DA

NE

DßH

NE

MAO

NE

Transp.

NECa++

COMT

SYNTHESIS OF EPINEPHRINE IN THE ADRENAL MEDULLA

DOPA

Dopamine

TyrosineTH

DDC

NEDßH

EPI

Ca++Ca++

NEEPIPMNT

EPI

DA

Ch + AcCoA ACh + CoACAT

ACh

ACh

ACh NE

NE

NE

AChEACh Ch +Ac

Re-UpNE

AChRAdR

ACh

NE

TERMINATION OF SYNAPTIC TRANSMISSION

OH

HO

HO

C

H H

C

H

NH2

Norepinephrine

OH

H3CO

HO

C

H H

C

H

NH2

Normetanephrine

COMT

OH

HO

HO

C

H H

C

H

NH2

Norepinephrine

MAOOH

HO

HO

C

H H

C

O

OH

3,4- Dihydroxymandelic acid

Metabolism of Catecholamines

ADRENERGIC TRANSMISSION

DOPA

Dopamine

Tyrosine

Ca++

AdR

TyrosineTH

DDC

DA

NE

DßH

NE

MAO

NE

Transp.

NECa++

COMT

ADRENERGIC TERMINALS

DOPA

Dopamine

Tyrosine

Ca++

TyrosineTH

DDC

DA

NE

DßH

NE

NE

Ca++

Reserpine X

Cocaine,TricyclicAntiDepr-esants

X

Bretylium XGuane-thidine

Amphet-amineNE

α-methyltyrosine

X

DRUGS ACTING ON

Drugs that act on adrenergic terminals

• Inhibit reuptake of NE into terminal- cocaine, tricyclic antidepressants

• Induce release of NE from terminal- amphetamine, tyramine

• Inhibit uptake of DA & NE into vesicle- reserpine• Block release of NE- bretylium• Displace NE from vesicle- guanethidine• Inhibit TH activity- α-methyltyrosine• Inhibit DDC activity- carbidopa• Inhibit MAO activity- pargyline• (Inhibit COMT activity- tolcapone)

NE

NE

α-AdR

NE

X

ß-AdR

XNE

Presynaptic Receptors Inhibit NE Release From Terminals

NE

NE

The Subtypes of Adrenergic Receptors

α: EPI > NOR >>ISO

ß: ISO > EPI > NE

Change in HR. BPM Isoprotere

nol Norepinephrine

0.001

0.1 10 Dose, µg/kg0. 01

1 100

80

60

40

20

0

Beta- Adrenergic Receptors Mediate Positive Chronotropic Effect

Even More Subtypes of Adrenergic Receptors

α: EPI > NOR >>ISOß: ISO > EPI > NE

α1: contraction of smooth muscle (incl. VSM)α2: presynaptic receptors ( decrease NE release)ß1: in heart and juxtaglomerular cells (and some fat cells)ß2: relaxation of smooth muscle (and in heart)ß3: some fat cellsNOTE ON ß2: (1) mediate relaxation of skeletal muscle vasculature

(2) P’cologically administered NE is not effective

I ENE

IE NE

IE NEContraction of VSM

(α1-AdR)

Relaxation of Airways(ß2-AdR)

Increase in HR (ß1-AdR)

Specificity of Agonists at Targets and Receptors

Concentration of Drug

αγγ β

ATP

cAMP

Adenyl.Cycl.

GTP

GDP

β

K+

GTP

GDP

α

γβ Effector

GTPGDP

α

BANG

Hormone/Transmitter

Receptors G-Proteins Effectors 9 adrenergic R 20 α 4 PLC-ß 5 mAChR 5 ß 10 AC 12 γ PDE (≥ 100?) K channels (GIRK )

Na, Ca channelsIP3 Receptors

PI-3-kinases Rho-GEF, Ras-GEF Tyrosine Kinases (src)

R + αβγGDP

NT

R- αβγ

GDP

NTGTP

GDP

R + α + βγNT

GTP

EFFECTORS

α + βγαβγ

GTP

RGS

GDP + PiGDP

R Regulator of G-protein Signaling

The basic functions of G-proteins

αs family: mediates stimulation of adenylyl

cyclase (ß-AdR)

αi family: mediates inhibition of adenylyl

cyclase

activates GIRK (M2, M4 mAChR; α2-

AdR)

αq family: activate certain forms of PLC (M1,

M3, M5

mAChR; α1-AdR)

(and others as well)

ATP

cAMP

Norepinephrine

AdenylylCyclase

G-protein

cAMP-dependent protein kinase (PKA)

Increased phosphorylation

Beta-adrenergic receptors stimulate adenylyl cyclase

(Gs)

Iso

γβα

ß- ARR

GRK

Ad.

Cyc.

Regulation of Receptor Signaling by G-protein- Coupled Receptor Kinase (GRK) and ß-Arrestin

Iso

P

γβα

ß-ARR

Ad.

Cyc.

Receptor is uncoupled from G-protein and targeted for internalization and down-regulation

0

10

20

30

40

Control ISO-Treate

d

ISO,Withdrawn

ß-ReceptorsIn Heart

Chronic Isoproterenol Decreases Cardiac Beta-AdR #

Control Isoproterenol,

Withdrawn

IsoproterenolTreated

Chronic Isoproterenol Decreases Cardiac Beta-AdR Functional Responsiveness

Concentration of Isoproterenol

IncreaseIn

ContractileForce

IncreaseIn

AdenylylCyclase

(OR)

Thyroid Hormones Increase Cardiac Beta-AdR #

0

50

100

150

200

Control T3-Treate

d

T4-Treate

d

ß-ReceptorsIn Heart

Decreased number of cardiac ß-AdR in ventricles of patients with heart failure

(Receptor #)

Controls

Heart Failure

Decreased function of cardiac ß-AdR in ventricles

of patients with heart failure

Differential coupling of ß1 and ß2- AdR

• ß1-AdR only couple to the stimulatory G-protein Gs

• ß2-AdR can couple to both Gs & the inhibitory G-protein Gi

• In heart failure, levels of ß1-AdR decrease and levels of Gi increase

• Therefore, ß2-AdR has less stimulatory and more inhibitory effects in a failing heart than in a non-failing heart

• Failing heart has increased expression and activity of GRK, which increases ß1 desensitization and degradation and also increases coupling of ß2 to Gi

• The decreased level of ß1-AdR and increased ß2-AdR coupling to Gi both contribute to decreased ß-adrenergic stimulation of contractility in failing heart

hubio 543 september 25, 2007

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