Download - HuBio 543 September 25, 2007
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HuBio 543September 25, 2007
Neil M. NathansonK-536A, [email protected]
Introduction to the Sympathetic Nervous System
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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
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Adrenergic Innervation of Vasculature
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ADRENERGIC TRANSMISSION
DOPA
Dopamine
Tyrosine
Ca++
AdR
TyrosineTH
DDC
DA
NE
DßH
NE
MAO
NE
Transp.
NECa++
COMT
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SYNTHESIS OF EPINEPHRINE IN THE ADRENAL MEDULLA
DOPA
Dopamine
TyrosineTH
DDC
NEDßH
EPI
Ca++Ca++
NEEPIPMNT
EPI
DA
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Ch + AcCoA ACh + CoACAT
ACh
ACh
ACh NE
NE
NE
AChEACh Ch +Ac
Re-UpNE
AChRAdR
ACh
NE
TERMINATION OF SYNAPTIC TRANSMISSION
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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
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ADRENERGIC TRANSMISSION
DOPA
Dopamine
Tyrosine
Ca++
AdR
TyrosineTH
DDC
DA
NE
DßH
NE
MAO
NE
Transp.
NECa++
COMT
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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
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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)
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NE
NE
α-AdR
NE
X
ß-AdR
XNE
Presynaptic Receptors Inhibit NE Release From Terminals
NE
NE
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The Subtypes of Adrenergic Receptors
α: EPI > NOR >>ISO
ß: ISO > EPI > NE
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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
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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
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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
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αγγ β
ATP
cAMP
Adenyl.Cycl.
GTP
GDP
β
K+
GTP
GDP
α
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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)
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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
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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)
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ATP
cAMP
Norepinephrine
AdenylylCyclase
G-protein
cAMP-dependent protein kinase (PKA)
Increased phosphorylation
Beta-adrenergic receptors stimulate adenylyl cyclase
(Gs)
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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
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0
10
20
30
40
Control ISO-Treate
d
ISO,Withdrawn
ß-ReceptorsIn Heart
Chronic Isoproterenol Decreases Cardiac Beta-AdR #
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Control Isoproterenol,
Withdrawn
IsoproterenolTreated
Chronic Isoproterenol Decreases Cardiac Beta-AdR Functional Responsiveness
Concentration of Isoproterenol
IncreaseIn
ContractileForce
IncreaseIn
AdenylylCyclase
(OR)
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Thyroid Hormones Increase Cardiac Beta-AdR #
0
50
100
150
200
Control T3-Treate
d
T4-Treate
d
ß-ReceptorsIn Heart
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Decreased number of cardiac ß-AdR in ventricles of patients with heart failure
(Receptor #)
Controls
Heart Failure
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Decreased function of cardiac ß-AdR in ventricles
of patients with heart failure
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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