medical physiology- w.f nfz c 1... · medical physiology- w.f.boron target audience. we wrote...
TRANSCRIPT
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Medical Physiology- W.F.Boron
Target Audience. We wrote Medical Physiology primarily as an introductory text for medical students, although it should also be valuable for students in the allied health professions...
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Neurofiziologie -cursMecanisme celulare ale excitabilităţii
Generarea, transmiterea şi procesarea semnalului in sistemul nervos
Fiziologia senzorială
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Noţiuni introductive
Organizarea morfofuncţională a SN
Macroscopică
Microscopică
Funcţională
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Organizare morfofuncţională a SN
Macroscopică
-sistem nervos central
-sistem nervos periferic
Microscopică
-celule: neuroni
-celule: celule glialesinapse
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Organizare funcţională a SN
Sistem nervos vegetativ
Sistem nervos somatic
Creierul holistic
Suportul genetic al SN
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Excitabilitate
Excitabilitate - capacitatea
(condiţia) unui sistem viu de a
capta semnale specifice, ca
formă de actualizare a
informaţiei, necesară
organizării lui întru
adaptabilitate şi continuitate
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Mecanisme celulare şi
moleculare ale
excitabilităţii
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The phenomenon of “animal electricity” is central to the understanding of physiological processes. Throughout this book, we will describe many basic functions of tissues and organs in terms of electrical signals mediated by cell membranes. Whereas electrical currents in a metal wire are conducted by the flow of electrons, electrical currents across cell membranes are carried by the major inorganic ions of physiological fluids: Ca2+,
Na+, K+, Cl−, and HCO3− . Boron and Boulpaep. Medical Physiology. 2012
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La nivelul cel mai
elementar, noi nu
suntem o reacţie
chimică ci o sarcină electrică...
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Câmpul electromagnetic este realitatea fizică cu care suntem în contact permanent şi nemijlocit, deşi nu avem simţuri pentru a o percepe. În odaia în care stăm, în parcurile în care ne plimbăm, în noi înşine, totul este plin de câmp electromagnetic, în fiecare moment, datorită câmpului electromagnetic, fiecare cută a fiinţei noastre este pătrunsă de toate melodiile care se cântă pe Pământ, ba şi de şoapte din afara lui, rostite poate cu miliarde de ani în urmă.
A.Ţugulea- Câmpul electromagnetic? Ed. Agir, 2011
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Hans Berger
de la telepatie la EEG -1926
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Interacţiunea
stimul - receptor - răspuns
chimic
fizic
stimul
R e
c e
p t
o r
P r
o c
e s
o r
?răspuns
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…Due to its ability to give rise to
spontaneous activity, the brain does
not simply process information but
also generates information.
György Buzsáki
...spontaneous neuron activity, far
from being mere noise, is actually the
source of cognitive abilities.
...the source of spontaneous neuron
activity (noise), has never been
identified and has been assumed to
result from brain’s imperfections.
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Citation
ReportAuthor: Buzsaki G
Results found (no. of papers): 274
Sum of the Times Cited: 27. 404
Average Citations per paper : 100
h-index (Hirsch index): 86
ISI Web of Science®
Published Items in Each Eear Citations in Each Year
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Interrelaţiile dintre propietăţile membranei celulare
şi principalele dimensiuni ale existenţei
sistemelor biologice
identitate
excitabilitate
adaptabilitate
evoluţie
Premise
permeabilitate
selectivă
membranară
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Molecule
hidrofobe Subst.
steroidice
O2
CO2N2
Apă
Glicerol
Uree
ZaharozăGlucoză
Na+, H+, K+
Ca2+, Mg2+
HCO3-, Cl-
Molecule
mici
nepolare
Molecule
mari
nepolare
Ioni
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Halobacterium salinarium
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- Canale ionice
- Pompe ionice
- Transportori ionici
Sistemul de transport ionic
membranar (STIM)
- Mecanisme ale
transportului ionic
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Bacteriorodopsina (Alberts
B. 2008)
Extracelular
Citosol
Bistrat
lipidic
(3nm)
Retinal
legat de
lizina
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transport pasiv
transport membranar
difuzie
simpla
mediată
de canalemediată de
transportori
mediată de
pompe
transport activ
bistrat
lipidic
canal
proteic transportori
Gradient de
concentraţie
adaptat după MOLECULAR BIOLOGY OF THE CELL. 2008
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- difuzie
- difuzie facilitată
- transport activ
- Mecanisme ale
transportului ionic
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- DIFUZIE
- prin canalele ionice
- prin spațiile intermoleculare
Mecanisme ale
transportului ionic
Rol
- p. osmotică, vol. celular
- excitabilitate
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- DIFUZIE FACILITATĂ
- prin cotransportori
- prin schimbători ionici
Mecanisme ale
transportului ionic
Rol - reglare metabolică
- cuplare metab.-excitabilitate
- metab. neurotransmițători
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Canale ionice
- controlate fizic
- controlate chimic:
- mecanic
Canale ionice controlate (gated)
Canale ionice fără poartă necontrolate (nongated)
- termic TRP
- de voltaj
- neurotransmiţători- ioni, H+- produşi metabolici ş.a
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Canale ionice fără poartă (de repaus)
-fluxul ionic de cca. 1000 de ori mai redus decât cel prin canale ionice controlate (cu poartă)
-asigură menţinerea potenţialului de repaus prin transportul ionic pasiv, în echilibru cu transportul activ primar şi secundar
Clasificare: K+, Na+, Ca2+, Cl-
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Canale ionice cu poartă
Particularităţi:-permit un flux controlat mai rapid...
-participă la generarea, transmiterea sau modularea potenţialului de acţiune
-au fost descoperite primele
-prezintă o diversitate mai mare
-reprezintă principala ţintă terapeutică
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Canale ionice controlate de voltaj
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Canale de Na+ voltaj- dependente
Structura canal de Na voltaj dependent
identificat 1970
PP
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Curent de poarta
_ _ SCTXTTX
+ +
+ +
+ +
+
+ +
+ +
+ +
+
__ __
LA
Senzor de voltaj
Bis
trat
lip
idic
BTX
Poarta
Po
r
Extracelular_ _ SCTXSCTXTTXTTX
+ +
+ +
+ +
++
+ +
++
+ +
+ +
+ +
+ +
+
__ __
LALA
Senzor de voltaj
Bis
trat
lip
idic
BTXBTX
Poarta
Po
r
Extracelular
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poartă de
inactivare
poartă de
activare
extracelular
membrană
celulară+
Canale de Na+ voltaj- dependente
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REPAUS (închis)
+
INACTIVAT (închis)
ACTIVAT (deschis)
+
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Permeabilitatea membranei
celulare depinde de:
-interacţiunea ionilor cu apa
-bistratul lipidic membranar
-canale ionice
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K+ansă de selecţiefiltru de selecţie
OO
O OO
O
Filtrul de selecţie
vestibul
por
citosol
ΦNa = 0,095 nm
ΦK = 0,133 nm
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Canale voltaj-dependente- Canale pentru Na+
- distribuţie – 30-10000/µm²- 10 gene pt. Na V
-subunitatea α - (α1- α9/ Nav 1- 9)
-subunitatea β
-1800-2000 aa- formează porul canalului
- controlează transportul ionic- ancorează canalul în membrana
celulară
- structură
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Canale de Na+ voltaj- dependente
- transport - 107 ioni/sec./canal
- rol
- faza depolarizare a PA- conducerea PA in fibrele nervoase
-canalopatie-paralizie periodică hiperkaliemică –inactivarea întârziată a Na V muscular
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Distribuţie, rol
Canale de Na+ voltaj- dependente
Nav 1-3, Nav 6-9 – în SNP, SNC cu rol in durere – pot fi mai multe tipuri pe acceaşi celulă nervoasă
Nav 4-5 – în m. scheletic şi miocard
Nav1.6 – în celule imune, microglia şimacrofage
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Canale pentru K+
voltaj-dependente
- diversitate genetică - 200 gene (peste 78 la om)
- rectificare
- modularea excitabilităţii celulare prin re-/hiperpola-rizarea membranei
- controlul duratei p. a.
- rol:
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Canale pentru K+ voltaj-dependente- clasificare
-cn.K tip M - Ach
- cn.K+ dependente de vol. cel.
-cn.K dependente de Ca – cel βpancreatice
-cn.K dependente de ATP- cel.β-pancreatice- ATP închiderea cn. K depolarizare -miocardice- ATP/ADP
activarea cn K hiperpolarizare
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Saxitoxină
Novocaina
TEA
TTX
Variaţia PA indusă de blocanti
Mordecai P. Blaustein. Cell. Physiol.and Neurophysio. Ed. Elsevier 2012
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Canale pentru Calciu voltaj-dependente- distribuţie - 100/µm²- transport - 180000 ioni/sec./cn -tipuri: - activat la potenţial înalt pozitiv
- modulat - AMP c
- blocanţi: - dihidropiridine: nimodipin, nifedipin, nicardipine;
L
- fenilalchilamine: verapamil, gallopamil;- benzotiazepine :
diltiazem
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Canale pentru Calciu voltaj-dependente
Canalopatii legate de canale de tip L
-cecitate congenitală diurnă - hemeralopie
-cecitate congenitală nocturnă- nictalopie
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Canale de Calciu voltaj-dependente
-Tipuri:
P/Q:
T:- conductanţă mică
- rol -pacemaker
- activat la voltaj intermediar
- activat la potential negativ
N: - blocant - ω-conotoxină
P-cel.Purkinje; blocant- ω-agatoxină Q- cel granulare; ω - agatoxină
- blocant- mibefradil
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Canale ionice controlate mecanic
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membrană
celulară
poartăproteină
fibrilară
situs de
ancorareextrcelular
intracelular
Când celula este alungită, proteina fibrilară
fixată pe situsul de ancorare deschide
poarta canalelor ionice
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membrană
celulară
extrcelular
intracelular
membrană celulară
intracelularsitus de ancorare
proteină fibrilară
Când distanța dintre două celule învecinate
crește, proteina fibrilară fixată pe situsul de
ancorare dintr-o celulă, deschide poarta
canalelor ionice din celula învecinată
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Canale ionice controlate termic (vezi superfamilia TRP)
TRPV1 - temperatura >430C
TRPM8 – temperatura 8-28 0C, mentol
TRPA1 – usturoi, mustar
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Tranzient Receptor Potenţial TRP superfamily ion channels
(Superfamilia canalelor ionice cu potenţial tranzitoriu de receptor) -sunt activate de diferiţi factori: -fizici: lumină, variaţii de
temperatură; -chimici: Vaniloizi , Melastatină, Policistină, Mucolipină şi Anicrină-permit transportul cationilor, în special Ca şi Na
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TRP superfamily ion channels
TRPC (canonical): TRPC1, TRPC2, TRPC3/6/7, TRPC4/5
-sunt canale pentru Ca şi/sau Na
-sunt activate de PLC activată prin: a)cuplarea receptorilor de către liganzi =receptor operated channels -DAG- TRPC3, TRPC6- vasoconstricţie
b)Ca din depozitele celulare = store-operated channels
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Canale controlate chimic
- ionotrope- NT-se cuplează cu
receptorul canal
- metabotrope- NT-se cuplează cu
receptorul postsinaptic care declanșează mesagerul secud ce controlează canalul ionic
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Canale ionice – Ach
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Schema generala a receptorului de NMDA
N-metil-D-aspartat; PCP- fenciclidina; MK-801 - dizocilpina
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Ka
ina
t
20
0 n
M,
CA
3
CONTROL CRIZĂ CRIZĂ EVOCATĂ SPONTANĂ
Bic
ucu
lin
ă
20
M
, C
A3
B
A
Relația agonist-antagonist
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Legenda pt. relația agonist-antagonist
A. Administrarea de Kainat (agonist glutamat-
ergic) induce după cca. 10 min activitate
electrică epileptiformă (aee), inițial, după
stimulare electrică, ulterior, în mod spontan.
B. Administrarea de Bicuculină (antagonist
GABAergic), induce după cca. 10 min activitate
electrică epileptiformă (aee), inițial, după
stimulare electrică, ulterior, în mod spontan.
Inregistrările aee au fost realizate pe secțiuni de
creier animal, perfuzate cu lichid cefalorahidian
artificial, in care au fost administrate kainat și
bicuculină.
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particularităţi funcţionale
POMPE IONICE
- transport activ-ioni, mol. organice
- implică reacţii enzimatice
- rată mică de transport
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POMPE IONICEtip P
- Pompa Na-K
- Schatzmann 1953 glicozide cardiace
- Skou, 1957 ATP-aza activata de Na şi K
1977, PN
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Pompa Na-K
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NNN
CCC
SSSiiitttuuusss dddeee llleeegggaaarrreee aaa CCCaaa222+++
EEExxxtttrrraaaccceeelll
IIInnntttrrraaaccceeelll...
SSSiiitttuuusssuuulll AAATTTPPP---aaazzzeeeiii
CCCaaalllmmmoooddduuullliiinnnăăă
AAA
SSSiiitttuuusssuuulll dddeee llleeegggaaarrreee aaa AAATTTPPP
Pompa de Ca
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- Na/H
Transportori ionici
- Cl/HCO3 -
- Na/K/2Cl
- K/Cl
- Na/Ca
- Na/ aa, Na/G
- Na/HCO3
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S
2
S
6
S
4
S
3S
5
S
1
Etapele transportului unui solvit (S) prin intermediului transportorului membranar
Boron and Boulpaep. Medical Physiology. 2012
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3Na+
Ca2+
Cl-
K+
H+
H+
Ca2+
K+
Cl-
Cl-
AA
Na+
POMPE
CANALE
K+
Componentele sistemului de transport ionic membranar.
TRANSPORTORI
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Transport ionic membranarConcluzii
Interrelaţii excitabilitate-metabolism
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Distribuţia sarcinilor electrice
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Concentraţia intra- extracelulară a
principalilor ioni în celula mamiferelor
(mMol)
Ion Extracelular Intracelular
Na+ 145 12
K+ 4 155
Ca2+ 1.8 0.001(rep)– 0.1(activ.)
Cl– 123 4.2
Mg2+ 1.5 0.8
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Potenţial de acţiune
50
0
m
V PA
Na+
K+
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timp (ms)
+20
- 60
Pm
(m
V)
Variaţia potenţialului de membrană în raport cu
activitatea celulei nervoase
repolarizaredepolarizare
hiperpolarizare
depolarizare
repolarizare
Nerst
Vm = lnzXF
RT [X]i
[X]o
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