1. HuBio 543 September 25, 2007 Neil M. Nathanson K-536A, HSB 3-9457
Introduction to the Sympathetic Nervous System

2. Catecholamines + HO Catechol Plus Amine NH 2 OH C H Norepinephrine3 CH
Isoproterenol
Dopamine

5. Adrenergic Innervation of Vasculature

6. ADRENERGIC TRANSMISSION
DOPA
Dopamine
Tyrosine Ca ++
AdR TH
DDC DA NE
DßH
MAO
Transp.
COMT

7. SYNTHESIS OF EPINEPHRINE IN THE ADRENAL MEDULLA
Tyrosine
DOPA
DDC Ca ++
Dopamine
PMNT DA NE
EPI
DßH NE
EPI
EPI

8. TERMINATION OF SYNAPTIC TRANSMISSION
Ch + AcCoA
ACh + CoA
CAT NE NE
ACh NE
ACh
ACh NE
ACh
Re-Up NE
ACh
Ch +Ac
AdR
AChR
AChE

9. Metabolism of CatecholaminesOH HO C H NH 2
Norepinephrine
H3CO
Normetanephrine
COMT
MAO O
3,4- Dihydroxymandelic acid
Metabolism of Catecholamines

10. ADRENERGIC TRANSMISSION
DOPA
Dopamine
Tyrosine Ca ++
AdR TH
DDC DA NE
DßH
MAO
Transp.
COMT

12. 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- a-methyltyrosine
Inhibit DDC activity- carbidopa
Inhibit MAO activity- pargyline
(Inhibit COMT activity- tolcapone)

13. Presynaptic Receptors Inhibit NE Release From Terminals
ß1-
AdR NE X X NE NE
a2-
AdR NE

14. The Subtypes of Adrenergic Receptors
a: EPI > NOR >>ISO
ß: ISO > EPI > NE

15. Beta- Adrenergic Receptors Mediate Positive Chronotropic Effect80
Isoproterenol
Norepinephrine 60
Change in HR. BPM 40 20
Dose, µg/kg
0.001
0. 01
0.1 1 10
100

16. Even More Subtypes of Adrenergic Receptors
a: EPI > NOR >>ISO
ß: ISO > EPI > NE
a1: contraction of smooth muscle (incl. VSM)
a2: 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

17. Specificity of Agonists at Targets and ReceptorsNE I
Contraction of
VSM
(a1-AdR) I
Relaxation of
Airways
(ß2-AdR) E NE I E NE
Increase in
HR (ß1-AdR)
Concentration of Drug

19. Hormone/Transmitter Effector BANG Receptors G-Proteins Effectors
GTP
BANG
GDP
Receptors G-Proteins Effectors
9 adrenergic R 20 a 4 PLC-ß
5 mAChR 5 ß AC
12 g PDE (≥ 100?)
K channels (GIRK )
Na, Ca channels
IP3 Receptors
PI-3-kinases
Rho-GEF, Ras-GEF
Tyrosine Kinases (src)

20. Regulator of G-protein Signaling

21. The basic functions of G-proteins
as family: mediates stimulation of adenylyl cyclase (ß-AdR)
ai family: mediates inhibition of adenylyl cyclase
activates GIRK (M2, M4 mAChR; 2-AdR)
aq family: activate certain forms of PLC (M1, M3, M5
mAChR; 1-AdR)
(and others as well)

22. Beta-adrenergic receptors stimulate adenylyl cyclase
Norepinephrine
Adenylyl
Cyclase
G-protein
ATP
(Gs)
cAMP
cAMP-dependent protein kinase (PKA)
Increased phosphorylation

23. Regulation of Receptor Signaling by G-protein-
Coupled Receptor Kinase (GRK) and ß-Arrestin
Iso g b a ß-
ARR
GRK
Ad.
Cyc.
Iso P g b a ß-
ARR
Ad.
Cyc.
Receptor is uncoupled from G-protein and targeted for internalization and down-regulation

24. Chronic Isoproterenol Decreases Cardiac Beta-AdR #10 20 30 40
Control
ISO-
Treated
ISO,
Withdrawn
ß-Receptors
In Heart

25. 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

26. Thyroid Hormones Increase Cardiac Beta-AdR #50
100
150
200
Control
T3-
Treated
T4-
ß-Receptors
In Heart

27. Decreased number of cardiac ß-AdR in ventricles
of patients with heart failure
Controls
Heart Failure
(Receptor #)

28. Decreased function of cardiac ß-AdR in ventricles
of patients with heart failure

29. 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