Acetylcholine, adrenalin, noradrenalin formation, effect ...

44
Acetylcholine, adrenalin, noradrenalin formation, effect, degradation Erzsébet Tóth 2014

Transcript of Acetylcholine, adrenalin, noradrenalin formation, effect ...

Page 1: Acetylcholine, adrenalin, noradrenalin formation, effect ...

Acetylcholine, adrenalin, noradrenalin formation, effect, degradation

Erzsébet Tóth

2014

Page 2: Acetylcholine, adrenalin, noradrenalin formation, effect ...
Page 3: Acetylcholine, adrenalin, noradrenalin formation, effect ...
Page 4: Acetylcholine, adrenalin, noradrenalin formation, effect ...
Page 5: Acetylcholine, adrenalin, noradrenalin formation, effect ...

Formation of acetylcholine in the nerve terminal in the cytoplasm

Choline acetyltransferase

Kolin-acetiltranszferáz

Cholinergic neuorotransmission

Page 6: Acetylcholine, adrenalin, noradrenalin formation, effect ...
Page 7: Acetylcholine, adrenalin, noradrenalin formation, effect ...

PC

Voltage-operated

High affinity choline-Na+ symporter

Page 8: Acetylcholine, adrenalin, noradrenalin formation, effect ...

Acetylcholinesterase in synaptic cleft

active site: Ser, His, Glu

H+

Page 9: Acetylcholine, adrenalin, noradrenalin formation, effect ...

Acetylcholinesterase inhibitors

Gyógyszerek = ideggázok = nerve gases,

medicines rovarölők = insectisides

Page 10: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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

Page 11: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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.

Page 12: Acetylcholine, adrenalin, noradrenalin formation, effect ...

dohány

nicotine

tobacco

Page 13: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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

Page 14: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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

Page 15: Acetylcholine, adrenalin, noradrenalin formation, effect ...

M3 receptor

Muscarinic receptors are heterotrimer G protein-coupled

7 transmembrane segment type receptors, 5 isotypes exist

Page 16: Acetylcholine, adrenalin, noradrenalin formation, effect ...

INHIBITORY EFFECT OF ACETYLCHOLIN IN HEART – 1-2.

+ inotropic, chronotropic, dromotropic effect - chronotropic

hyperpolarization,

slower heart beat =

bradycardia =

lassabb szívverés

Page 17: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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

Page 18: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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)

Page 19: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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

Page 20: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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.

Page 21: Acetylcholine, adrenalin, noradrenalin formation, effect ...

and Erabutoxin

are blockers

in skeletal muscle,

κ-bungarotoxin inhibits

in neurons

Toxins of some

animals effect on

cholinergic signal

transduction

Page 22: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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

Page 23: Acetylcholine, adrenalin, noradrenalin formation, effect ...

Catecholamines,

adrenergic and noradrenergic signal transduction

= catechol

Page 24: Acetylcholine, adrenalin, noradrenalin formation, effect ...

Synthesis of

catecholamines:

dopamine,

noradrenalin,

adrenalin

Neurotransmitter

in brain stem in

basal ganglions:

striatum,

substantia nigra

Page 25: Acetylcholine, adrenalin, noradrenalin formation, effect ...

Role of

THB = tetrahydrobiopterin

in the synthesis of

Tyr, DOPA, serotonine, NO

Page 26: Acetylcholine, adrenalin, noradrenalin formation, effect ...

most important

sympathetic

neurotransmitter

Mainly hormon in

adrenal medulla,

but neurotransmitter

in brain, too

Page 27: Acetylcholine, adrenalin, noradrenalin formation, effect ...

Noradrenerg idegvégződés

Noradrenergic nerve terminal

Na+

Page 28: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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

Page 29: Acetylcholine, adrenalin, noradrenalin formation, effect ...

MAO = monoaminoxidase

COMT = catechol

oximethyl transferase

and

either aldehyde-dehydrogenase

or aldehyde reductase

O2 + H2O

H2O2 + NH3

Catecholamines’ degradation

Page 30: Acetylcholine, adrenalin, noradrenalin formation, effect ...
Page 31: Acetylcholine, adrenalin, noradrenalin formation, effect ...

All adrenergic receptors are heterotrimeric G protein-coupled

7 transmembrane segment type receptors

BETA2-adrenerg receptor:

Page 32: Acetylcholine, adrenalin, noradrenalin formation, effect ...

β1,2,3 receptors activate,

α2 receptors inhibit

adenylyl cyclase

α1-receptor increases [Ca2+]

Page 33: Acetylcholine, adrenalin, noradrenalin formation, effect ...

D

Page 34: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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

Page 35: Acetylcholine, adrenalin, noradrenalin formation, effect ...

Adrenalin activates gluconeogenesis and glycogenolysis,

it inhibits glycolysis and glycogen synthesis in liver

Page 36: Acetylcholine, adrenalin, noradrenalin formation, effect ...

Adrenalin activates gluconeogenesis and glycogenolysis,

it inhibits glycolysis and glycogen synthesis in liver

Page 37: Acetylcholine, adrenalin, noradrenalin formation, effect ...

Control of lypolysis (hormon sensitive lipase) in white adipocytes

ATGL

AC and PKA inhib. PDE act.

FFA-albumin

liver

Page 38: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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.

Page 39: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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

Page 40: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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↑

Page 41: Acetylcholine, adrenalin, noradrenalin formation, effect ...
Page 42: Acetylcholine, adrenalin, noradrenalin formation, effect ...

• 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)

Page 43: Acetylcholine, adrenalin, noradrenalin formation, effect ...

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

Page 44: Acetylcholine, adrenalin, noradrenalin formation, effect ...

Figure 15-36 Molecular Biology of the Cell (© Garland Science 2008)

Genexpression effect