Transmiterea i procesarea semnalului n sistemul nervos

I.Transmiterea sinaptic Transmiterea sinaptic chimic Transmiterea sinaptic electric II. Transmiterea nonsinaptic Transmiterea T it h hormonal l Transmiterea auto- paracrin Transmiterea efaptic

Transmiterea sinaptic chimic

I. Date generale SNC - 1011 neuroni;

Transmiterea i procesarea semnalului n sistemul nervos

- 1000 sinapse/neuron - neuron=microprocesor ? - alte lt mecanisme i de d comunicare i

Transmiterea i procesarea semnalului n sistemul nervos

Repere istorice L Galvani electricitatea animal 1797 L.GalvaniA.Volta-bateria electric 1800 H C Oersted electromagnetism 1820 H.C.Oersted-electromagnetism

Transmiterea i procesarea semnalului n sistemul nervos

Repere istorice Ch. Sherrington 1897, Sinapsa Otto Loewi-1920- Ach Cole C l K. K S i Curtis.H C ti H -1939 1939 impedana electric, giant axon Hodkin A.L. & Huxley A.F.1939,PA/Na

Sinapsa chimic
Segment presinaptic
AGONITI

E
Celul glial

ANTAGONITI

Sinaps excitatorie Sinaps inhibitorie

Segment postsinaptic

Neurotransmitori cu molecul mic i enzimele lor de biosintez

Neurotransmi Neurot ransmitor ACETIL COLIN AMINE BIOGENE D Dopamin i Epinefrin Norepinefrin Serotonin Histamin AMINOACIZI GABA Glutamat Glicin Glutamat decarboxilaz Specificitate probabil Enzime din metabolismul general Enzime din metabolismul general Cale specific nedeterminat Cale specific nedeterminat Ti Tirozin i hid hidroxilaz il Tirozin hidroxilaz i dopamin b hidroxilaz Tirozin hidroxilaz i dopamin b hidroxilaz Triptofan hidroxilaz Histidin decarboxilaz Specific Specific Specificitate incert Specific S ifi Enzime Colin acetiltransferaz Activitate Specific

Peptide cerebrale neuroactive clasificate dup localizarea tisular

Categoria HORMONI ELIBERATORI HIPOTALAMICI HORMONI NEUROHIPOFIZARI PEPTIDE HIPOFIZARE Peptide TRH, GnRH, Somatostatin, CRH, GHGH-RH Vasopresin, Oxitocin ACTH, BB-endorfin, A A-MSH, Prolactin, LH, GH, TSH VIP, CCK, Gastrin, Neurotensin, MetMetEnkefalin, LeuLeu-Enkefalin, SP, Insulin, Glucagon, Bombezin, Secretin, SST, TRH, Motilin PAN Angiotensina II, Bradikinin, Calcitonin, CGRP, NPYY, Galanin, Substana K (Neurokinina A), Peptide de somn

PEPTIDE GASTROINTESTINALE

PEPTIDE CARDIACE

ALTELE

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 embrionar (1)2 jonctional (1)2

Nicotinici neuronali Ag.dimetilfenilpiperazina citisina Atg. trimetafan, bungarotoxin nicotinici neuronali li 2-5 nicotinici neuronali li 2-10

muscarinici M1-5

R. MUSCARINICI

Muscarinici M1 pirenzepin Muscarinici M2 metoctramin Muscarinici M3 hexahidrosiladifenidol Muscarinici M4 himbacin Muscarinici M5 ?

Distribuia receptorilor colinergici I. Distribuia periferic - m.scheletic (N) - s n v (N+M) II. Distribuia central SNC (N+M) III. Alte roluri orgs. unicelulare orgs. pluricelulare dezvoltare difereniere

I.Distribuia receptorilor colinergici Receptorii nicotinici musculari embrionari - pe toat t t suprfa f a fibrei fib i musculare l neinervat sau denervat - au o rat mare a turnoverlui Receptorii nicotinici musculari joncionali - la nivelul jonciunii neuromusculare - au o rat mic a turnoverlui

I.Distribuia receptorilor colinergici Receptorii nicotinici neuronali - sp.i psp.din creasta neural, au propriet i i identice id i - gg. postsinp. sp.,psp. i MS. Receptorii muscarinici neuronali postgg psp - m.n.visceral, m n visceral miocard - postgg.psp. glande secretorii - postgg.sp.- piloerecie, sudoraie

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. -din tr.cerebral, conectati cu talamusul, nc. interpeduncular,coliculii. sup - cel. Renshaw

Sistemul Colinergic (Neurochemistry of Consciousness. Neurotransmitters in mind by Elaine Perry,Heather Ashton, Allan Young. John Benjamins BV. 2002)

Sinapsa Colinergica
Transportor Transportor vezicular de ACh Transportor de colina

Muscarinici carbachol edrofoniu Nicotinici musc. suxametoniu Nicotinici nn. lobelina Muscarinici atropina Nicotinici musc. D-tubocurarina Nicotinici nn. hexametoniu

ACh

vesamicol
ACh ChAT ACh

Colina AcCoA hemicolinium Colina + Ac Colina + Ac-

AChE
ACh Ach

M.Gravis ?...
BNCh 188

fizostigmina

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 PPSE

Trasportor de colina (ChT)

- 13 segmente transmembranare - grad mare de conservare filogenetic - in alte esuturi, (Km=10-100 mol/L) - in neuron neuron, Na dependent, dependent situsuri de fosforilare, (Km= 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

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

Acetilcolinesteraza (AChE)
-Este un important factor de control al transmiterii sinaptice - animale knock out prezinta un tremor continuu, dezvoltare deficitar, disfuncii neurologice -Inhibitori I hibit i AChE AChE: sarinul, i l compui organofosforici induc fibrilaii musculare, blocarea activitii musculare

Acetilcolinesteraza (AChE)
-succinilcolina blocant muscular competitiv - miorelaxant - anticolinesteraze i i - tratament pentru miastenia gravis, B.Alzhaimer -inhibitori reversibili: edrofonium, galamina

sinapsa noradrenergic

Sinapsa noradrenergica

Subtipuri de receptori 1-adrenergici 1A Aminoacizi 430-476 Cromosom 8 Cale efectoare Ca2+, PKC Distributie inim, ficat, ficat cerebellum, cortex cerebral, vase sanguine 1B 515 5 Ca2+, PKC 1D 560 20 Ca2+, PKC

splin, rinichi, rinichi aorta, aorta creier fetal cortex cerebral vase sang

Subtipuri de receptori 2-adrenergici 2A 2B 2C 461 4 cAMP inim,plmn aorta, hipocampus bulb olfactiv,

Aminoacizi 450 450 Cromosom 10 2 Cale efectoare cAMP cAMP Distribution pancreas, ficat, intestin subire, talamus locus ceruleus hipocampus

Subtipuri de receptori -adrenergici 1 Aminoacizi Cromosom Cale efectoare Distributie 477 10 cAMP 2 413 5 cAMP 3 402/408 8 cAMP

inim, rinichi, plmn,ficat creier, cortex cerebral, cerebral cerebellum, cerebellum esut adipos hipotalamus hipocampus, cortex cerebral, muschi neted, bulb olfactiv

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
Receptor adrenergic 1A Receptor adrenergic 1B Receptor adrenergic 1D Receptor adrenergic 2A Receptor adrenergic 2B R Receptor t adrenergic d i 2C Receptor adrenergic 1 Receptor adrenergic 2 Receptor adrenergic 3

Fenotip
Scderea presiunii arteriale Scderea presiunii arteriale i a rspunsului la stimulenii SNC Scderea presiunii arteriale Creterea activitii simpatice, tahicardie Scderea rspunsului vasoconstrictor la agonitii 2 Fr un fenotip f ti evident id t Majoritatea mor prenatal Modificri de tonus vascular i de metabolism energetic n stres Modificarea concentraiilor de leptin i insulin dup tratamentul cu agoniti

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 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

Sistemul Dopaminergic (Neurochemistry of Consciousness. Neurotransmitters in mind by Elaine Perry,Heather Ashton, Allan Young. John Benjamins BV. 2002)

sinapsa glutamatergic

Sinapsa glutamatergica

Transportori sinaptici

sinapsa GABAergic

Benzodiazepines Nonbenzodiazepine (Zolpidem) Barbiturice Methaqualone Baclofen Muscimol Progabide Tiagabine Bicuculline Metrazol Flumazenil

Transmiterea i procesarea semnalului n sistemul nervos

II. Transmiterea nonsinaptic Transmiterea hormonal Transmiterea auto- paracrin Transmiterea efaptic

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.

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 7

Neuron presinaptic Axon hillock

+ + + + + + + +

Neuron presinaptic

Neuron postsinaptic

Modularea transmiterii semnalului

Componenta trigger trigger si de conducere

Canale de Na+ voltaj- dependente

Modularea activitii
receptor RACK Na+

Gk PLC

PKC activ PKC inactiv

Inhibarea C Na incetinirea inactivrii

Na1.8- PGE2 AMPC, efect opus TTX rezistent

Ali modulatori

DAG

Ptdins(4,5)P2

[Ca2+]

Muscarina Ach-PLC Dopamina,D1,AMPc,PKA Cocaina efectul DA Defosforilare Fosfataza 1,2a Calcineurina