Download - Seminar No. 8 - Chapter 22 -
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Receptors of
Hormones &
NeurotransmittersSeminar No. 8
- Chapter 22 -
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2
Q.
What are general features of signal molecule?
(see scheme on p. 130)
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Signal molecule (e.g. hormone)
• carries information into cell
• has extremely low concentration in blood (10-9 – 10-15 mol/l)
• specifically binds to receptor
• signal molecule is quickly inactivated
• agonist – (external) molecule which acts the same way as
physiological signal molecule
• antagonist – (external) molecule which blocks receptor
no biological response
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4
Q.
What is the amplification of signal?
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Amplification of signal
= to make it more powerful
1 molecule of hormone
~ 100-1000 molecules of second messenger
second messenger transfers information to other intracellular systems and then is quickly inactivated
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Two classes of hormones
Feature Lipophilic hormone Hydrophilic hormone
Chemical typesteroids, iodothyronines,
calcitriol, retinoids
aminoacid derivatives,
polypeptides, proteins
Water solubility
Transport protein*
Plasma half-time
Membrane penetration
Receptor
Second messenger
no
yes
long (hours, days)
yes
intracellular
hormone-receptor complex
yes
no
short (minutes)
no
in cell membrane**
cAMP, Ca2+ ....
* in blood ** hormone acts without entering the cell
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Concentration of hormone in blood
generally does not correlate with its
biological effects
More factors are involved (transport systems,
chemical modifications, activity of receptors etc.)
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feed back
metabolisminactivation
Hormone synthesis
Hormone storage
Hormone secretion
Transport in ECF
Receptor in target cell
Biological response
regulation effects
secretion impuls
excretioncell condition
Factors involved in biological action of hormones
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Two principal types of receptors
• membrane receptors
• intracellular receptors
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The main types of membrane receptors
Ligand gated ion channels
• in synapses, activated by neurotransmitters, very quick response
Receptors activating G-proteins
• stimulate or inhibit adenylate cyclase /phospholipase C
Receptors with guanylate cyclase activity
• atrial natriuretic factors
Receptors with tyrosine kinase activity
• insulin
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Nicotinic acetylcholine receptor
• transmembrane protein = channel for Na+ and K+
• heteropentamer (α2βγδ)
• α-subunits have two binding sites for acetylcholine (ACH)
• nicotine is agonist of this receptor
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Four events on postsynaptic membrane (see the scheme and the graph on p. 131)
1. ACH binds to receptor channel opens influx of Na+ and
efflux of K+
2. partial depolarization of membrane (-60 -40 mV) opens other
type of voltage-dependent Na+-channel further influx of Na+
depolarization of postsyn. membrane ( +20 mV)
3. this depolarization opens K+-channel (volt. dep.) efflux of K+
membrane potential returns to normal value (-60 mV) =
repolarization
4. Na+,K+-ATPase gets ion distribution to normal state
(Na+ OUT, K+ IN)
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Q.
Describe the formation of acetylcholine in the body.
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Acetylcholine
N
CH3
CH3
CH2CH2OHCH3 N
CH3
CH3
CH2CH2CH3 O C CH3
O
cholinacetylcholin
choline acetylcholine
food
acetyl-CoA
free choline or phosphatidylcholine
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GABA receptor
• channel for chloride ion (Cl-)
• has the binding site for GABA channel opens Cl- ions
get into cell hyperpolarization ( -80 mV) decrease
of excitability
• benzodiazepines and barbiturates (synthetic substances)
have similar effects like GABA, they are used as anxiolytics
and/or sedatives
• endozepines – endogenous peptides have opposite effects,
close the channel (are responsible for anxiety feelings)
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Q.
Describe the synthesis of GABA.
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GABA formation
COOHCHCH2
NH2
CH2HOOC
glutamát
CH2CH2
NH2
CH2HOOC
GABA gama-aminobutyric acid
CO2-
glutamate
the reaction requires:
enzyme (decarboxylase) + cofactor (pyridoxal phosphate)
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GABA inactivation
GABA succinate aldehyde
succinate
oxid. deamination
- NH3
CAC
oxidation
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Diazepine Benzo[f]diazepine
12a
bf
N
N
N
N4
diazepine is a seven-membered unsaturated heterocycle
with two nitrogen heteroatoms in the positions 1,4
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Benzodiazepines
N
NCl
OCH3
N
NO2N
OCH3
F
N
NCl
OCH3
diazepam
anxiolytic / sedative
flunitrazepam
hypnotic
tetrazepam
myorelaxant
structural modifications lead to different pharmacological effects
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Barbiturates
N
N
H
H
O
O
O
R2
R1
derivates of 2,4,6-trioxoperhydropyrimidine
allobarbital:
R1 = R2 = -CH2-CH=CH2
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G-Protein linked receptors (scheme, p. 132)
• extracellular part of receptor has a binding site for hormone
• intracellular part has a binding site for G-protein
• G-proteins are heterotrimers (αβγ)
• in resting state, α-unit has GDP attached
• after binding hormone (α-GDP)βγ makes complex with
receptor GDP is phosphorylated to GTP
• activated G-trimer dissociates: (α-GTP)βγ α-GTP + βγ
• α-GTP interacts with effector (enzyme) activated/inhibited
enzyme second messenger (↑ or ↓)
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Main types of G-proteins
• Gs (stimulatory)
• Gi (inhibitory)
• Gp (phospholipid)
• and other ...
• see table on p. 132 !!
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Q.
What reaction is catalyzed by adenylate cyclase?
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Adenylate cyclase reaction
O
OH
O
OH
AdeninP
O
O
OP
O
O
OP
O
O
OO
OH
Adenin
O
P OO
O
cAMP
ATP
- diphosphate
cAMP = cyclic 3’,5’-adenosine monophosphate
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Adenylate cyclase (AC)
• membrane bound receptor
• catalyzes reaction: ATP cAMP + PP (diphosphate)
• Gs protein stimulates AC conc. of cAMP ↑
• Gi protein inhibits AC conc. of cAMP ↓
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Q.
What is the function of cAMP?
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cAMP is the second messenger
• cAMP activates protein kinase A phosphorylation of cell proteins:
• Protein-OH + ATP Protein-O-P + ADP
-------------------------------------------------------------------------
• the second messenger cAMP is quickly inactivated
• cAMP is removed by hydrolysis, catalyzed by phosphodiesterase:
• cAMP + H2O AMP
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General scheme of phosphorylation
OH P
O
O
O O
O
O
P RibO
O
O
P O
Ade
+
ATP (4-)substrát
kinasa
++
fosforylovaný substrát (2-) ADP (3-)
P
O
O
O RibO
O
O
P O
Ade
HO P
O
O
O
protein kinase
substrate (protein)
phosphorylated protein (2-)
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30
Q.
Which aminoacids can be phosphorylated?
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A.
• AA with a hydroxyl group in a side chain
• serine
• threonine
• tyrosine
write the structural formulas
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Q.
What reaction is catalyzed by protein phosphatase?
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A.
Protein-O-P + H2O Protein-O-H + Pi
hydrolysis
(dephosphorylation)
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Phosphatidyl inositol system (p. 133)
• Gp protein activates phospholipase C (PL-C)
• PL-C catalyzes the hydrolysis of phosphatidyl inositol bis
phosphate (PIP2):
• PIP2 + H2O IP3 + DG
• both products (IP3, DG) are second messengers
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The structure of PIP2
OH
HOO
OOH
P
P
C
O
CH
CH2O
O
C
O
CH2 O P
O
O
O
describe the structure
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Q.
What is the source of inositol in human body?
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The origine of inositol
HO OH
OH
OHHO
HO
Exogenous source: food
Endogenous source: glucose-6-P (side path of metabolism)
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DG and IP3 as second messengers
• DG activates protein kinase C phosphorylation of
intracellular proteins
• IP3 opens calcium channel in ER Ca2+ concentration in
cytoplasm increases Ca2+ ions are associated with special
protein calmodulin (CM) Ca2+-CM complex activates
certain types of kinases biological response
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Insulin receptor
• has four subunits (α2β2)
• extracellular α-units bind insulin
• intracellular β-units have tyrosine kinase activity
phosphorylation of tyrosine phenolic hydroxyl of
intracellular proteins including insulin receptor itself
(autophosphorylation) cascade of further events
biological response
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Intracellular receptors:
- cytoplasmatic- nucleic
for steroids, iodothyronines, calcitriol, retinoids
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Intracellular receptors• make complex with hormone
• activate or repress the transcription of genes
hydrophobic hormone penetrates cell membrane
inactive receptor in cytoplasm in complex withhsp dimer and other proteins
active complex receptor-hormone
active complexes dimerize are translocated into nucleus
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Steroid and thyroid hormones
• insoluble in water in ECF are transported in complex with
transport proteins
• hormone themselves diffuse easily across cell membrane
• they are bound to cytoplasmatic or nuclear receptors
• in nucleus, the hormone-receptor complex binds to HRE
(hormone response element) in regulation sequence of DNA
• this leads to induction of mRNA synthesis = transcription of
gene
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Events on synapses
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Cholinergic synapses
• neurotransmitter: acetylcholine
• two types of receptors
• nicotinic rec. (ion channel) – e.g. neuromuscular junction
• muscarinic rec. (G-prot.) – e.g. smooth muscles
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Cholinergic receptors
Feature Nicotinic receptorMuscarinic receptors
M1, M3 M2
Receptor type
2nd messenger
Antagonist
Locations
Ion channel
∆ψ*
tubocurarine
neuromuscular juct.
Gp
DAG, IP3
atropine
brain
Gi
cAMP ↓
atropine
myocard
* the change of membrane potential
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Q.
How is acetylcholine released from presynaptic
terminal?
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A.
• influx of Ca2+ triggers the fusion of presynaptic vesicles
(contaning acetylcholine) with cell membrane and
exocytosis of acetylcholine
• acetylcholine is liberated into synapse
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Q.
What reaction is catalyzed by acetylcholinesterase?
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A.
acetylcholine + H2O choline + acetic acid
hydrolysis of ester
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Q.
What is nicotine?
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Nicotine is the main alkaloid of tobacco (Nicotiana tabacum)
N
N
CH3
3-(1-methylpyrrolidine-2-yl)pyridine
more basic
pKB = 6.2
less basic
pKB = 11
1
2
3
1
2
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52
Q.
Why nicotine triggers the release of adrenaline?
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Main effects of nicotine
• nicotine binds to acetylcholine nicotinic receptors in brain and
other tissues including cells of adrenal medula
• stimulates the secretion of adrenaline – because it binds to
receptors in adrenal medula (p. 135 !) - silent stress
other effects:
• increases the secretion of saliva and gastric juice
• increase intestinal peristalsis
• vasoconstriction
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Q.
What is muscarine?
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Muscarine is an alkaloid in some mushrooms
OH3C
HO CH2 N
CH3
CH3
CH3 CH2 N
CH3
CH3
CH3CH2HO
muskarin kandicin
Amanita muscaria (fly agaric)
muscarine
tetrahydro-4-hydroxy-N,N,N,5-
tetramethyl-2-furanmethanammonium
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Inhibitors of acetylcholinesterase
• Reversible – carbamates (N-substituted esters of carbamic acid), e.g. fysostigmine, neostigmine
• they are used to improve muscle tone in people with myasthenia gravis and routinely in anesthesia at the end of an operation to reverse the effects of non-depolarising muscle relaxants. It can also be used for urinary retention resulting from general anaesthetia
• Irreversible – organophosphates, very toxic compounds
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Carbamates – General formulas
OHCH2N
O
OCH2N
O
R OCN
O
R
R
R
carbamic acid
(hypothetic compound)
alkyl carbamate
(ester)
N-disubstituted
alkyl carbamate
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Organophosphates
P
S
OH
OHHO P
O
OH
FHO P
O
OH
CNHO
P
O
OH
CH3HO P
O
F
CH3HO P
O
F
CH3O
H3C
H3C
thiophosphoric acid fluorophosphoric acid cyanophosphoric acid
kys. methylfosfonová kys. methylfluorofosfonová sarin methylphosphonic acid methylfluorophosphonic acid sarin
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Adrenergic synapses
• neurotransmitter: noradrenaline
• four types of receptors: α1, α2, β1, β2
• all of them are G-protein linked receptors
• occur in various cells and tissues
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Adrenergic receptors
Feature α1 α2 β1 β2
G-protein
2nd messenger
Occurence*
Gp
DG, IP3
smooth muscle
Gi
cAMP
brain
Gs
cAMP
myocard
Gs
cAMP
smooth m.
* Example of occurence
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61
Q.
Describe the synthesis of noradrenaline.
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The formation of DOPA and dopamine
COOH
CHH2N
CH2
OH
COOH
CHH2N
CH2
OH
OH
hydroxylace
O2, BH4
tyrosin DOPA(3,4-dihydroxyfenylalanin)
dekarboxylace
- CO2
CH2
CH2
OH
OH
NH2
dopamin(katecholamin)
hydroxylation decarboxylation
tyrosine DOPA
3,4-dihydroxyphenylalanine dopamine
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Noradrenaline and adrenaline
CH2
CH2
OH
OH
NH2
hydroxylace na C-2
O2, askorbát
CH2
CH
OH
OH
NH2
OH
dopamin noradrenalin
N-methylace
SAM
CH2
CH
OH
OH
NH
OH
CH3
adrenalin
Cu2+
prefix nor- means N-demethyl
hydroxylation at C2 N-methylation
dopamine noradrenaline adrenaline
O2, ascorbate
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The next seminar
April 24, 2006
Chapter 21 - I. part