Acetylcholine, adrenalin, noradrenalin formation, effect, degradation Erzsébet Tóth 2014
Acetylcholine, adrenalin, noradrenalin formation, effect, degradation
Erzsébet Tóth
2014
Formation of acetylcholine in the nerve terminal in the cytoplasm
Choline acetyltransferase
Kolin-acetiltranszferáz
Cholinergic neuorotransmission
PC
Voltage-operated
High affinity choline-Na+ symporter
Acetylcholinesterase in synaptic cleft
active site: Ser, His, Glu
+δ
H+
Acetylcholinesterase inhibitors
Gyógyszerek = ideggázok = nerve gases,
medicines rovarölők = insectisides
Acetylcholine is an ancient signal transducing molecule:
found in bacteria, algae, protozoons, plants, animals, humans it has a regulatory role in: proliferation, migration, secretion, survival, apoptosis
Nicotinic receptor exist in the human cell, but do not produce acetylcholine: skeletal muscle: α1α1β1γδ neuromuscular junction macrophages, microglia: α7 pentamer (proliferation ↓, IL-6,12, TNF α secretion) astrocytes: α7 pentamer (brain function) blood vessel smooth muscle: α 2-5,7,10 pentamers (proliferation)
Acetylcholine is synthetized, secreted, has receptora, has ACE: lymphocytes: T-limph. proliferation, differentiation, selection, B-limf. growth, Ab secretion ↓ keratinocytes: proliferation, apoptosis, differentiation, adhesion, motility blood vessel endothel: α3,5,7,10 + β2,4 pentamer: angiogenesis, smooth muscle proliferation respiratory tract: many kind of cells, receptors and effect CNS = central nervous system: transmitter liberation, exitability, sleeping, neural integration, awakness, tiredness, pain, eating, cognitive functions α homopentamers and 2α3β heteropentamers
Ligand-operated
ion channel is a
pentamer nicotinic
receptor:
Na+ and Ca2+ channel
Each nicotinic receptor contains
5 subunits, it is a pentamer.
α-subunit have10 isotypes
β-subunit have 5 isotypes
In neurons there are
5 α-homopentamer, or
2 α and 3 db β heteropentamer
In skeletal muscle there is
(2α)βγδ heterotetramer
Ach always binds to α-subunit
The number of α-subunit equals the
No of bound Ach
One subunit has 4 transmembrane
segments, 4 α-helixes.
dohány
nicotine
tobacco
Skeletal muscle contraction
1.) action potential →
Na+ channels and VOOC open →
Ach vesicles’ endocytosis
2.) Ach binds to N-type Ach receptor
3.) Na+ enters through nicotinic rec.
→ postsynaptic potential →
voltage-operated Na+ chan. open →
action potential on sarcolemma →
T-tubules L-VOCC and
SER ryanodin receptors functional
interaction allows
Ca2+ release from SER (RR)→
Ca2+ binding to troponin C →
conformational change in
troponin I, T, tropomyosin →
F-actin binding site becomes free
to interact with myosin
Kerti susulyka
(Inocybe fastigata)
Every Inocybe species
is either poisonous or
not eatable
Inocybe lanuginella Clitocybe dealbata
Légyölő galóca
(Amanita muscaria)
Muscarin and muscarin
containing mushrooms
M3 receptor
Muscarinic receptors are heterotrimer G protein-coupled
7 transmembrane segment type receptors, 5 isotypes exist
INHIBITORY EFFECT OF ACETYLCHOLIN IN HEART – 1-2.
+ inotropic, chronotropic, dromotropic effect - chronotropic
hyperpolarization,
slower heart beat =
bradycardia =
lassabb szívverés
Contractory effect of acetylcholine in
gastrointestinal smooth muscle,
secretion in digesting glands, narrowing of pupil sphincters (opening of
Schlemm channels and
decreasing of inner pressure in eye)
Acetylcholine activates secretion of
digesting juice in digesting glands during
signal transduction of vagus nerve (X brain
nerve), Ach bind to M3 (muscarinic 3)
receptors
Smooth muscle contraction and relaxation
Ach
M3,5-rec
Gq
IP3
in SR
:adrenalin,
noradrenalin
GI=
gastrointestinal tract
longitudinal muscles,
pupilla sphincter
GI tract,
bronchi, genitourinal tract,
blood vessel smooth
muscle
AC
PKA
Figure 15-12a
Molecular Biology of the Cell
(© Garland Science 2008)
Ach
3 Muscarinic receptor
Myosin light chain kinase Myosin light chain
phosphatase
Ach
Rho dependent
kinase =
cyclic ADP-ribosylation
myosine light chain phosphorylated
protein kinase C
phospholipase C
cGMP activates protein kinase G. PKG phosphorylates and activates plasmamembrane Ca2+-ATPase and
Na+/Ca2+antiporter and SER Ca-ATP-ase, which remove Ca2+ from cell plasm. PKG phosphorylates
Rho-dependent kinase inhibitory protein, it stops inhibition, myosin light chain can work to dephosphorylate
MLC, so inactivates it, no contraction. Ca-2+ channel is anactivated, the ion do not enter.
PKG phosphorylates K+ channel, it opens, cell is hyperpolarized, Smooth muscle is relaxed.
and Erabutoxin
are blockers
in skeletal muscle,
κ-bungarotoxin inhibits
in neurons
Toxins of some
animals effect on
cholinergic signal
transduction
recep
tor
localization signal
transduction
effect agonist antagonist
M1 postsynapticneuron:
striatum, cortex, hippocampus
Gq, PLC +
Ca2+
transmitter
release
atropin
M2 heart, bronchus
presyn. parasymp.neur.
hypothalamus, brain
Gi, AC –
Gi, K-channel.
- chronotr. bronchoconstr.
transm.liberation inhib,
hypothermia, anelgesia
atropin
M3 GI tract longitud. muscle,
bronchus
digestive glands, brain,
pupilla sphincter,
Gq, PLC +,
Ca2+
contraction
secretio, anelgesia
pupilla narrowing
neostigmin
physostigmin
pilocarpin
atropin
M4 Striatum,hippocampus, cortex,
spinal cord pre -and postsyn.
Gi, AC –
Gi, K-channel.
DA liberation regul.
Anelgesia…
atropin
M5 dopaminergic neurons, basal
ganglions, blood vessels
Gq, PLC +
Ca2+
DA liberation regul.
brain arthery relax.
atropin
Nm skeletal muscle Na+-channel contraction tubocurarin,
cobrotoxin,
α-bungarotoxin
Nn nervous system,
ganglion, adrenal gland
Na+/Ca2+ -
channel
action potential Κ-bungarotoxin
Nn macrophage
astrocyte,
smooth muscle.
Na+/Ca2+ -
channel
prolif.↓,
brain function
prolif.↑
Κ-bungarotoxin
Nn limphocyte,
keratinocyte
endothel
respiratory tract
Na+/Ca2+ -
channel
prolif. diff. sel.
prolif. diff. adh
angiogenesis
different effects
Κ-bungarotoxin
Catecholamines,
adrenergic and noradrenergic signal transduction
= catechol
Synthesis of
catecholamines:
dopamine,
noradrenalin,
adrenalin
Neurotransmitter
in brain stem in
basal ganglions:
striatum,
substantia nigra
Role of
THB = tetrahydrobiopterin
in the synthesis of
Tyr, DOPA, serotonine, NO
most important
sympathetic
neurotransmitter
Mainly hormon in
adrenal medulla,
but neurotransmitter
in brain, too
Noradrenerg idegvégződés
Noradrenergic nerve terminal
Na+
Regulation of
synthesis of
stess hormons
and sympathetic
neurotransmitters
quickest, but
shortest action
(minutes)
slowest
Effect somewhere else
Effect somewhere else adrenal cortex
adrenal medulla
release
synthesis
MAO = monoaminoxidase
COMT = catechol
oximethyl transferase
and
either aldehyde-dehydrogenase
or aldehyde reductase
O2 + H2O
H2O2 + NH3
Catecholamines’ degradation
All adrenergic receptors are heterotrimeric G protein-coupled
7 transmembrane segment type receptors
BETA2-adrenerg receptor:
β1,2,3 receptors activate,
α2 receptors inhibit
adenylyl cyclase
α1-receptor increases [Ca2+]
D
Stimulatory effects of adrenalin/noradrenalin in cardiomyocytes, inhibitory effect of Ach
RyR = ryanodin receptor = Ca2+-csatorna
PLB = phospholamban = foszfolambán = Ca2+-ATP-áz reguláló fehérje
AKAP = A kinase anchoring protein = PKA-horgonyzó fehérje
VOCC = voltage-operated Ca2+ channel = feszültségfüggő Ca2+-csatorna
VOCC
Adrenalin activates gluconeogenesis and glycogenolysis,
it inhibits glycolysis and glycogen synthesis in liver
Adrenalin activates gluconeogenesis and glycogenolysis,
it inhibits glycolysis and glycogen synthesis in liver
Control of lypolysis (hormon sensitive lipase) in white adipocytes
ATGL
AC and PKA inhib. PDE act.
FFA-albumin
liver
Alfa1-adrenerg receptor
α1-receptors are found in arteriols,
blood vessels contract
by the effect of adrenalin and noradrenalin
to increase blood pressure,
so α1-receptor antagonist drugs
can decrease the blood pressure.
1.) In different organs different ARs are dominated, mainly only these are mentioned:
α 1: arteriols, GI and GU sphincters contract
liver glycogenolysis
kidney Na+ reabsorption, skin sweating
adipocyte lipolysis and glycogenolysis
α2: GI longitudinal muscles relax, sphincters contract,
pancreas insulin secretion↑, glucagon secretion↓
β1: in heart all function increase, (β1: β2 = 80:20, also β3 and α1)
adipocyte lipolysis, glycogenolysis
kidney renin secretion from juxtaglomerular cells,
stomach ghrelin secretion
β2 : bronchi, GI and GU smoothe muscles relax
liver: glycogenolysis, glyconeogenesis,
adipocyte lipolysis,
kidney renin secretion
β3: white adipocyte lipolysis ↑, brown adipocyte thermogenesis
2.) adrenerg receptor type in organs depends on species
e.g. human adipocytes β1 > β2 > β3 and also α1 and α2,
but rat β3 > β2 > β1 and also α1 and α2
3.) receptor types have different signal transduction and different effect
e.g. β 1,2,3 and α1 receptors activate, but α2 inhibit HSL
(hormon sensitive lipase) enzyme in adipocyte
4.) adrenerg receptor type depends on age, differentiation stage
e.g. in neonatal heart α1 receptors’ overproduction make growth,
heart hypertrophy
5.) altered metabolic state changes receptor types
e.g. in obesity α2/β1,2,3 ratio increases, consequently lipolysis decreases
e.g. in heart failure β1 receptor number ↓, while β2 and α1 receptors
non cAMP-dependent signal transduction↑
• speed of the synthesis e.g. testosteron, TNF-α → adipocyte β2-AR mRNA↑
• Desensitization happens because of repeated or continouos stimulus: a) AR-P (phosphorylated adrenerg receptor) → internalization → degradation translocation back e.g. β-AR → PKA → NA or A-bound AR-P → internalization α1-AR → PKC → NA or A- not bound AR-P → internalization b) AR mRNA and/or AR proteins are degraded
Quantity and sensitivity of adrenal receptors depends on:
Figure 15-51 Molecular Biology of the Cell
(© Garland Science 2008)
Localization and trafficking of
α2-adrenergic receptor subtypes
in cells and tissues (1999)
It depends on the target cell protein content, which proteins are phosphorylated, by this way the activity or amount of proteins are changed
PKA (cyclic AMP-dependent protein-kinase) substrates that are phosphorylated: adipocyta: HSL activated (perilipin also) TAG → 3 FA + glycerol → FFA ↑ heart muscle: L-VOCC open→ Ca2+↑ → + inotrop effect phospholamban SER-ben → Ca2+-pump act. → during relaxation Ca2+ enters to SER ↑ → faster reuptake of Ca2+ → faster haert beat = tachycardia PFK-2/FBP → F2,6P2 ↑ → PFK-1 act. → glycolysis ↑ smooth muscle: MLCK → Ca2+ sensitivity↓ → relaxation liver: GS inact. → glycogen synthesis ↓ PFK-2/FBP → F2,6P2 ↓ → PFK-1 not act. and F1,6P2-ase not inact. → gluconeogenesis ↑ and glycolysis ↓ CREBP → in nucleus induces: PC, PEPCK, F1,6P2-ase, G6P → gluconeogenesis ↑ PK inact. →glucose sparing PDHC inact. → from pyruvate AcCoA ↓ → glucose sparing ACC α inact. → malonyl-CoA ↓→ FA synthesis ↓ skeletal muscle: GPK act. → GP act. → glycogen degradation ↑ CREB → PGC -1α induction → mt. DNS replication ↑ → mt. number↑ → longer aerob metabolism during excercise
Figure 15-36 Molecular Biology of the Cell (© Garland Science 2008)
Genexpression effect