10/26/2012

1
Transmiterea i procesarea
semnalului n sistemul nervos
I.Transmiterea sinaptic
Transmiterea sinaptic chimic
II. Transmiterea nonsinaptic
T it h l
Transmiterea sinaptic electric
Transmiterea sinaptic chimic
Transmiterea efaptic
Transmiterea auto- paracrin
Transmiterea hormonal
Transmiterea sinaptic
chimic10/26/2012
2
I. Date generale
SNC - 10
11
neuroni;
Transmiterea i procesarea
semnalului n sistemul nervos
SNC - 10
11
neuroni;
- 1000 sinapse/neuron
lt i d i
- neuron=microprocesor ?
- alte mecanisme de comunicare
Transmiterea i procesarea
semnalului n sistemul nervos
Repere istorice
L Galvani electricitatea animal1797 L.Galvani- electricitatea animal
A.Volta-bateria electric 1800
1820 H C Oersted electromagnetism
1797
1820 H.C.Oersted-electromagnetism10/26/2012
3
Transmiterea i procesarea
semnalului n sistemul nervos
Repere istorice
Otto Loewi-1920- Ach
C l K S i C ti H 1939
Ch. Sherrington 1897, Sinapsa
Cole K. S i Curtis.H -1939
impedana electric, giant axon
Hodkin A.L. & Huxley A.F.1939,PA/Na
Sinapsa chimic
Segment
presinaptic
E
AGONITI
ANTAGONITI
Celul
Sinaps excitatorie
Sinaps inhibitorie
glial
Segment
postsinaptic10/26/2012
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Neurotransmitori cu molecul mic i enzimele lor de
biosintez
Neurot Neurotransmi ransmitor tor Enzime Enzime Activitate Activitate
ACETIL COLIN ACETIL COLIN Colin acetiltransferaz Colin acetiltransferaz Specific Specific
AMINE BIOGENE AMINE BIOGENE
D i D i Ti i hid il Ti i hid il S ifi S ifi Dopamin Dopamin Tirozin hidroxilaz Tirozin hidroxilaz Specific Specific
Epinefrin Epinefrin Tirozin hidroxilaz i Tirozin hidroxilaz i
dopamin b hidroxilaz dopamin b hidroxilaz
Norepinefrin Norepinefrin Tirozin hidroxilaz i Tirozin hidroxilaz i
dopamin b hidroxilaz dopamin b hidroxilaz
Specific Specific
Serotonin Serotonin Triptofan hidroxilaz Triptofan hidroxilaz Specific Specific
Histamin Histamin Histidin decarboxilaz Histidin decarboxilaz Specificitate incert Specificitate incert
AMINOACIZI AMINOACIZI
GABA GABA Glutamat decarboxilaz Glutamat decarboxilaz Specificitate probabil Specificitate probabil
Glutamat Glutamat Enzime din Enzime din
metabolismul general metabolismul general
Cale specific Cale specific
nedeterminat nedeterminat
Glicin Glicin Enzime din Enzime din
metabolismul general metabolismul general
Cale specific Cale specific
nedeterminat nedeterminat
Peptide cerebrale neuroactive
clasificate dup localizarea tisular
Categoria Categoria Peptide Peptide
HORMONI ELIBERATORI HORMONI ELIBERATORI
HIPOTALAMICI HIPOTALAMICI
TRH, GnRH, Somatostatin, CRH, GH TRH, GnRH, Somatostatin, CRH, GH- -RH RH
HORMONI NEUROHIPOFIZARI HORMONI NEUROHIPOFIZARI Vasopresin, Oxitocin Vasopresin, Oxitocin
PEPTIDE HIPOFIZARE PEPTIDE HIPOFIZARE
ACTH, B ACTH, B- -endorfin, A endorfin, A- -MSH, Prolactin, MSH, Prolactin,
LH, GH, TSH LH, GH, TSH
PEPTIDE GASTROINTESTINALE PEPTIDE GASTROINTESTINALE
VIP, CCK, Gastrin, Neurotensin, Met VIP, CCK, Gastrin, Neurotensin, Met- -
Enkefalin, Leu Enkefalin, Leu- -Enkefalin, SP, Enkefalin, SP,
Insulin, Glucagon, Bombezin, Insulin, Glucagon, Bombezin,
Secretin, SST, TRH, Motilin Secretin, SST, TRH, Motilin
PEPTIDE CARDIACE PEPTIDE CARDIACE PAN PAN
ALTELE ALTELE
Angiotensina II, Bradikinin, Angiotensina II, Bradikinin,
Calcitonin, CGRP, NPYY, Galanin, Calcitonin, CGRP, NPYY, Galanin,
Substana K (Neurokinina A), Peptide Substana K (Neurokinina A), Peptide
de somn de somn10/26/2012
5
Sinapsa colinergic
Receptori colinergici
.
Nicotinici
Ag.nicotina
Atg. d-tubocurarina
Muscarinici
Ag.muscarina, pilocarpina
Atg. atropina
Ag.oxotremorina
Atg. propilbenzilcolina
Nicotinici musculari
Ag.feniltrimetilamoniu
Atg. d-tubocurarina
Nicotinici neuronali
Ag.dimetilfenilpiperazina
citisina
Atg. trimetafan, bungarotoxin
embrionar
(
1
)
2
nicotinici
li
nicotinici
li
muscarinici
M
jonctional
(
1
)
2

neuronali

2-10
neuronali

2-5
M
1-510/26/2012
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R. MUSCARINICI
Muscarinici M1
pirenzepin
Muscarinici M2
metoctramin metoctramin
Muscarinici M3
hexahidrosiladifenidol
Muscarinici M4
himbacin
Muscarinici M5
?
I. Distribuia periferic
Distribuia receptorilor colinergici
- m.scheletic (N)
- s n v (N+M)
II. Distribuia central SNC (N+M)
III. Alte roluri
orgs. unicelulare
orgs. pluricelulare
dezvoltare
difereniere10/26/2012
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Receptorii nicotinici musculari embrionari
t t f fib i l
I.Distribuia receptorilor colinergici
- pe toat suprfaa fibrei musculare
neinervat sau denervat
- au o rat mare a turnoverlui
Receptorii nicotinici musculari joncionali Receptorii nicotinici musculari joncionali
- la nivelul jonciunii neuromusculare
- au o rat mic a turnoverlui
Receptorii nicotinici neuronali
I.Distribuia receptorilor colinergici
- sp.i psp.din creasta neural,
i i id i
Receptorii muscarinici neuronali
- gg. postsinp. sp.,psp. i MS.
au proprieti identice
- postgg psp - m n visceral miocard postgg.psp. m.n.visceral, miocard
glande secretorii
- postgg.sp.- piloerecie, sudoraie10/26/2012
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II.Distribuia receptorilor colinergici
-interneuronilor-corpul striat- controlul
motor extrapiramidal i memorie
-neuronilor de proiecie:
din nc.bazali,conectati cu hipocampusul
bulbul olfactiv i cortex.(Meynert- b. Alz.
- cel. Renshaw
-din tr.cerebral, conectati cu talamusul,
nc. interpeduncular,coliculii. sup
Sistemul Colinergic (Neurochemistry of Consciousness.
Neurotransmitters in mind by Elaine Perry,Heather Ashton, Allan
Young. John Benjamins BV. 2002)10/26/2012
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Transportor
de colina
Transportor
Transportor
vezicular de ACh
Muscarinici
carbachol
edrofoniu
Sinapsa Colinergica
Nicotinici musc.
suxametoniu
Muscarinici
atropina
ACh
h
vesamicol
ACh
Colina
ChAT
Nicotinici nn.
lobelina
suxametoniu
Nicotinici musc.
D-tubocurarina
M.Gravis ?...
ACh
fizostigmina
hemicolinium
ACh
Ach
AChE
Colina + Ac- Colina + Ac
-
AcCoA
Nicotinici nn.
hexametoniu
BNCh 188
PPSI poate fi mediat de DOPA i NA eliberate de
interneuroni sub aciunea Ach, i poate fi blocat de
antagoniti alfa adrenergici. PPSI poate avea
parametrii dinamici asemntori PPSE10/26/2012
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Trasportor de colina (ChT)
- 13 segmente transmembranare
- grad mare de conservare
filogenetic
- in neuron Na dependent situsuri de
- in alte esuturi, (K
m
=10-100 mol/L)
- in neuron, Na dependent, situsuri de
fosforilare, (K
m
= 1-5 mol/L)
- co-localizat n membr. vezicular
cu VAchT i n membrana sinaptic
Trasportor de colina (ChT)
- blocarea endocitozei colinei
- nr. i activitii ChT din
membrana sinaptic
- stimularea sintezei i elib. ACh
- nr. i activitii ChT din
membrana sinaptic
- captarea Ch = factor de control
al biosintezei i eliberrii ACh
- tratamentul cu hemicolin 10/26/2012
11
Transportor vezicular de
acetilcolina (VAChT)
- 12 segmente transmembranare
- gena localizat pe Cr.X in apropierea
genei de sinteza a ChAT
- este un antiporter H
+
/ ACh, ATP
depentent
- este inhibat selectiv de vesamicol
depentent
Acetilcolinesteraza (AChE)
-Este un important factor de control
al transmiterii sinaptice
- animale knock out prezinta un tremor
continuu, dezvoltare deficitar, disfuncii
neurologice
I hibit i AChE i l i -Inhibitori AChE: sarinul, compui
organofosforici induc fibrilaii
musculare, blocarea activitii musculare10/26/2012
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Acetilcolinesteraza (AChE)
-succinilcolina blocant muscular
competitiv - miorelaxant
i i - anticolinesteraze - tratament pentru
miastenia gravis, B.Alzhaimer
-inhibitori reversibili: edrofonium,
galamina galamina
sinapsa noradrenergic10/26/2012
13
Sinapsa noradrenergica
Subtipuri de receptori 1-adrenergici
1A 1B 1D
Aminoacizi 430-476 515 560
Cromosom 8 5 20
Cale efectoare Ca2+, PKC Ca2+, PKC Ca2+, PKC
Distributie inim ficat splin rinichi aorta Distributie inim, ficat, splin, rinichi, aorta,
cerebellum, creier fetal cortex cerebral
cortex cerebral, vase sang
vase sanguine10/26/2012
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Subtipuri de receptori 2-adrenergici

2A

2B

2C
Aminoacizi 450 450 461
Cromosom 10 2 4
Cale efectoare cAMP cAMP cAMP
Distribution pancreas, ficat, inim,plmn
intestin subire, talamus aorta, hipocampus
locus ceruleus bulb olfactiv,
hipocampus
Subtipuri de receptori -adrenergici
1 2 3
Aminoacizi 477 413 402/408
Cromosom 10 5 8
Cale efectoare cAMP cAMP cAMP
Distributie inim, rinichi, plmn,ficat creier,
cortex cerebral cerebellum esut adipos cortex cerebral, cerebellum, esut adipos
hipotalamus hipocampus,
cortex cerebral,
muschi neted,
bulb olfactiv10/26/2012
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Sistemul Noradrenergic (Neurochemistry of
Consciousness. Neurotransmitters in mind by Elaine
Perry,Heather Ashton, Allan Young. John Benjamins BV. 2002)
Caracteristici ale oarecilor knockout
pentru receptori catecolaminergici
Knockout Fenotip
Receptor adrenergic 1A Scderea presiunii arteriale
Receptor adrenergic 1B Scderea presiunii arteriale i a rspunsului la
stimulenii SNC
Receptor adrenergic 1D Scderea presiunii arteriale
Receptor adrenergic 2A Creterea activitii simpatice, tahicardie
Receptor adrenergic 2B Scderea rspunsului vasoconstrictor la
agonitii 2
R t d i 2C F f ti id t Receptor adrenergic 2C Fr un fenotip evident
Receptor adrenergic 1 Majoritatea mor prenatal
Receptor adrenergic 2 Modificri de tonus vascular i de metabolism
energetic n stres
Receptor adrenergic 3 Modificarea concentraiilor de leptin i insulin
dup tratamentul cu agoniti10/26/2012
16
Modularea chimic
Sistemul dopaminergic
Dopamine transporters in the cortex
are concentrated in cingulate and
medial
prefrontal regions.While cholinergic
and noradrenergic systems are said to and noradrenergic systems are said to
be involved in low level aspects of
attention (e.g. Attentional orienting),
the dopaminergic system contributes to
motivated behaviours and is said to be
associated with more executive
aspects of attention such as
attentional set-shifting or working
memory. It has recently been suggested
that dopamine rather than signalling 10/26/2012
17
Sistemul Dopaminergic (Neurochemistry of Consciousness.
Neurotransmitters in mind by Elaine Perry,Heather Ashton,
Allan Young. John Benjamins BV. 2002)
sinapsa glutamatergic10/26/2012
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Sinapsa glutamatergica
Transportori sinaptici10/26/2012
19
sinapsa GABAergic
Benzodiazepines
Nonbenzodiazepine
(Zolpidem)
Barbiturice
Methaqualone
Baclofen
Muscimol
Progabide
Tiagabine
Bicuculline
Metrazol
Flumazenil10/26/2012
20
Transmiterea i procesarea
semnalului n sistemul
nervos
II. Transmiterea nonsinaptic
Transmiterea hormonal
Transmiterea efaptic
Transmiterea auto- paracrin
Un model tridimensional
al sinapsei electrice:
A. Seciune prin sinaps.
Fiecare din cele dou
membrane conine cte
o jumtate din canalul
sinaptic.
B.Conformaia conexonului
variaz cu starea
nchis/deschis.10/26/2012
21
Transmitere efaptic
Myoclonus of peripheral origin: two case reports.
Tyvaert L, Krystkowiak P, Cassim F, Houdayer E, Kreisler A,
Deste A, Defebvre L. Mov Disord. 2009 Jan 30;24(2):2747
Bilateral processing in chemical synapses with electrical
'ephaptic' feedback: a theoretical model. Savtchenko LP.
Math Biosci. 2007 May;207(1):11337. Epub 2006 Oct 7.PMID:
17112549
Rhythmic neuronal discharge in the medulla and spinal cord
of fetal rats in the absence of synaptic transmission. Ren J,
MomoseSato Y, Sato K, Greer JJ. J Neurophysiol. 2006
Jan;95(1):52734. Epub 2005 Sep 710/26/2012
22
+
+
+
+
+
+
Axon
hillock
Neuron presinaptic
+
+
+
+
Neuron
presinaptic
Neuron postsinaptic
Modularea transmiterii
semnalului10/26/2012
23
Componenta t Componenta trigger rigger si de conducere si de conducere
Canale de Na
+
voltaj- dependente
Modularea activitii
Na
+
receptor RACK
Gk
PLC
PKC
activ
PKC
inactiv
P
Inhibarea C
Na
incetinirea inactivrii
Na1.8- PGE
2
AMPC,
efect opus
TTX rezistent
[Ca
2+
]
Ptdins(4,5)P
2
DAG
Dopamina,D
1
,AMPc,PKA
Ali modulatori
Muscarina Ach-PLC
Cocaina efectul DA
Fosfataza 1,2a
Calcineurina
Defosforilare