Transcript Slayt 1 - Cumhuriyet University

NADP+
NADPH
from phe, diet, or protein
breakdown
DHBR
BH4
BH2
1
Tyrosine
L-Dopa
Tyrosine hydroxylase
O2
(rate-determining step) H O
2
H2O
DPN OHase in neuroscretory granules
3
ascorbate
O2
Norepinephrine
Dopamine hydroxylase
PNMT
SAM from
metabolism of
Met
Epinephrine
4
SAM
SAH
2
PNMT specific to
adrenal medulla
CO2
Dopa
decarboxylase
pyridoxal
phosphate
Dopamine
Parkinson’s disease: local
deficiency of dopamine
synthesis; L-dopa boosts
production
Figure 1. Biosynthesis of catecholamines. BH2/BH4, dihydro/tetrahydrobiopterin;
DHBR, dihydrobiopterin reductase; PNMT, phenylethanolamine N-CH3 transferase;
SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine
Stress
Figure 2. Regulation of the release
of catecholamines and synthesis of
epinephrine in the adrenal medulla
chromaffin cell.
Chronic
regulation
Hypothalamus
ACTH
Cortisol
Tyrosine
L-Dopa
Acute
regulation
from adrenal
cortex via intraadrenal portal
system
DPN
induction
granule
Neuron
.....
..
.....
..
.
...
acetylcholine
Adrenal Medulla
Chromaffin Cell
DPN

NE
Ca2+
PNMT
NE

E E E
NE E
promotes
exocytosis
E
EEE
NE
E
E NE
EE
Epinephrine
neurosecretory
granules
Epinephrine
COMT + MAO
Vanillylmandelic acid
Norepinephrine
COMT + MAO
Dopamine
Homovanillic acid
Figure 3. Degradation of epinephrine, norepinephrine and dopamine via monoamine
oxidase (MAO) and catechol-O-methyl-transferase (COMT)
Table 1. Classification of Adrenergic Hormone Receptors
Receptor
Agonists
Second
Messenger
G protein
alpha1 (1)
E>NE
IP3/Ca2+; DAG
Gq
alpha2 (2)
NE>E
 cyclic AMP
Gi
beta1 (1)
E=NE
 cyclic AMP
Gs
beta2 (2)
E>>NE
 cyclic AMP
Gs
E = epinephrine; NE = norepinephrine
NH2
HOOC
Figure 4. Model for the structure of the 2-adrenergic receptor
Table 2. Metabolic and muscle contraction responses to catecholamine binding to
various adrenergic receptors. Responses in italics indicate decreases of the indicated
process (i.e., decreased flux through a pathway or muscle relaxation)
1-receptor
2receptor
1receptor
(IP3, DAG)
( cAMP)
( cAMP)
Process
2-receptor
( cAMP)
Carbohydrat
 liver
e
glycogenolysis
metabolism
No effect
No effect
liver/muscle
glycogenolysis;
 liver gluconeogenesis;
 glycogenesis
Fat
metabolism
No effect
 lipolysis
 lipolysis
No effect
Hormone
secretion
No effect
 insulin
secretion
No effect
 insulin and glucagon
secretion
Muscle
contraction
Smooth
muscle - blood
vessels,
genitourinary
tract
Smooth
muscle some
vascular;
GI tract
relaxation
Myocardial
- rate,
force
Smooth muscle
relaxation - bronchi,
blood vessels,
GI tract, genitourinary
tract
1 or 2
receptor
Gs
2 receptor
Gi
s 





GTP
GTP

inactive
adenylyl
cyclase

ACTIVE
adenylyl
cyclase
ATP


GTP
i
s
GTP
i
X
inactive
adenylyl
cyclase
cyclic AMP
Figure 5. Mechanisms of 1, 2, and 2 agonist effects on adenylyl cyclase activity
"FIGHT OR FLIGHT" RESPONSE
epinephrine/ norepinephrine major elements in the "fight or flight" response
acute, integrated adjustment of many complex processes in organs vital to the
response (e.g., brain, muscles, cardiopulmonary system, liver)
occurs at the expense of other organs less immediately involved (e.g., skin, GI).
epinephrine:
rapidly mobilizes fatty acids as the primary fuel for muscle action
increases muscle glycogenolysis
mobilizes glucose for the brain by  hepatic glycogenolysis/
gluconeogenesis
preserves glucose for CNS by  insulin release leading to reduced glucose
uptake by muscle/ adipose
increases cardiac output
norepinephrine elicits responses of the CV system -  blood flow and  insulin
secretion.
Figure 6. Mechanisms for terminating the signal generated by epinephrine
binding to a -adrenergic receptor
[1]
dissociation
epinephrine
[2]
degradation
to VMA
 GTP
AC


 GDP
[3]
[5]
GTPase
[6]
activated PKA
phosphorylates
enzymes
OH [7]
OP OP
phosphorylation
of -receptor by
-ARK decreases
activity even with
bound hormone
OH OH
ATP cAMP
AMP
phosphodiesterase
OP
[4]
OPOP
binding of -arrestin
further inactivates
receptor despite
bound hormone
insulin activation of protein
phosphatase to dephosphorylate
enzymes