Download Symp NS_WEB07

HuBio 543
September 25, 2007
Neil M. Nathanson
K-536A, HSB
3-9457
[email protected]
Introduction to the Sympathetic Nervous System
Catecholamines
HO
+
HO
Catechol Plus
HO
HO
OH
H
C
C
H
H
NH2
Amine
OH
H
HO
C
C
HO
H
H
NH
CH3
Epinephrine
Norepinephrine
H
H
HO
C
C
HO
H
H
Dopamine
NH
2
NH2
OH
H
HO
C
C
HO
H
H
Isoproterenol
CH3
NH
CH
CH3
Adrenergic Innervation of Vasculature
ADRENERGIC TRANSMISSION
Tyrosine
Tyrosine
TH
DOPA
DDC
MAO
Ca++
Dopamine
DA
Ca++
DßH
NE
NE
NE
Transp.
NE
COMT
AdR
SYNTHESIS OF EPINEPHRINE IN THE ADRENAL MEDULLA
TH
Tyrosine
DOPA
DDC
Ca++
Ca++
EPI
Dopamine
PMNT
NE
DA
DßH
NE
EPI
EPI
TERMINATION OF SYNAPTIC TRANSMISSION
Ch + AcCoA
ACh
CAT
ACh
ACh + CoA
ACh
ACh
NE
NE
NE
NE
NE
AChR
ACh
Ch +Ac
AChE
AdR
Re-Up
Metabolism of Catecholamines
OH
H
HO
C
C
HO
H
H
NH2
MAO
HO
HO
HO
H
C
C
H
H
Norepinephrine
O
C
C
H
H
OH
3,4- Dihydroxymandelic acid
Norepinephrine
OH
HO
OH
NH2
COMT
H3CO
HO
OH
H
C
C
H
H
Normetanephrine
NH2
ADRENERGIC TRANSMISSION
Tyrosine
Tyrosine
TH
DOPA
DDC
MAO
Ca++
Dopamine
DA
Ca++
DßH
NE
NE
NE
Transp.
NE
COMT
AdR
DRUGS ACTING ON
ADRENERGIC TERMINALS
Tyrosine
TH
Tyrosine
X
DOPA
DDC
-methyl
tyrosine
Dopamine
Reserpine
Ca++
X
DA
Ca++
DßH
NE
Bretylium
Guanethidine
X
NE
NE
Cocaine,
Tricyclic
AntiDepresants
X
NE
Amphetamine
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- -methyltyrosine
• Inhibit DDC activity- carbidopa
• Inhibit MAO activity- pargyline
• (Inhibit COMT activity- tolcapone)
Presynaptic Receptors Inhibit NE Release From Terminals
NE
NE ß1-
NE
NE
XX
2 NE
AdR
AdR
NE
The Subtypes of Adrenergic Receptors
: EPI > NOR >>ISO
ß: ISO > EPI > NE
Beta- Adrenergic Receptors Mediate Positive Chronotropic Effect
80
Isoproterenol
Norepinephrine
60
40
20
0
0.001 0. 01 0.1
1
10
100 Dose, µg/kg
Even More Subtypes of Adrenergic Receptors
: EPI > NOR >>ISO
ß: ISO > EPI > NE
1: contraction of smooth muscle (incl. VSM)
2: 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 cells
NOTE ON ß2: (1) mediate relaxation of skeletal muscle vasculature
(2) P’cologically administered NE is not effective
Specificity of Agonists at Targets and Receptors
E
Contraction of
VSM
(1-AdR)
I
Relaxation of
Airways
(ß2-AdR)
I
Increase in
HR (ß1-AdR)
NE
E
E
I
NE
NE
Concentration of Drug
 




Adenyl.
Cycl.
ATP
GTP
GTP
+
K
GDP
GDP
cAMP
Hormone/Transmitter

GDP
Receptors
9 adrenergic R
5 mAChR
G-Proteins
20 
5ß
12 
  Effector
GTP
BANG
Effectors
4 PLC-ß
10 AC
PDE (≥ 100?)
K channels (GIRK )
Na, Ca channels
IP3 Receptors
PI-3-kinases
Rho-GEF, Ras-GEF
Tyrosine Kinases (src)
EFFECTORS
NT
NT
GTP
R + 
R- 
R + 
NT
GTP
GDP
GDP
GDP
Regulator of
RGS G-protein
Signaling
R

GDP

GTP
GDP + Pi
The basic functions of G-proteins
s family: mediates stimulation of adenylyl cyclase (ß-AdR)
i family: mediates inhibition of adenylyl cyclase
activates GIRK (M2, M4 mAChR; 2-AdR)
q family: activate certain forms of PLC (M1, M3, M5
mAChR; 1-AdR)
(and others as well)
Beta-adrenergic receptors stimulate adenylyl cyclase
Norepinephrine
Adenylyl
Cyclase
G-protein
ATP
(Gs)
cAMP
cAMP-dependent protein kinase (PKA)
Increased phosphorylation
Regulation of Receptor Signaling by G-proteinCoupled Receptor Kinase (GRK) and ß-Arrestin
Iso
Iso
Ad.


Cyc.
P
ßARR


ßARR
GRK
Receptor is uncoupled from G-protein and targeted for
internalization and down-regulation
Ad.
Cyc.
Chronic Isoproterenol Decreases Cardiac Beta-AdR #
40
30
ß-Receptors
In Heart
20
10
0
Control
ISOTreated
ISO,
Withdrawn
Chronic Isoproterenol Decreases Cardiac Beta-AdR
Functional Responsiveness
Increase
In
Contractile
Force
Control
Isoproterenol,
Withdrawn
(OR)
Increase
In
Adenylyl
Cyclase
Isoproterenol
Treated
Concentration of Isoproterenol
Thyroid Hormones Increase Cardiac Beta-AdR #
200
ß-Receptors
In Heart
150
100
50
0
Control
T3Treated
T4Treated
Decreased number of cardiac ß-AdR in ventricles
of patients with heart failure
Controls
Heart Failure
(Receptor #)
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