Na + 117 A - 0 K + 3 Cl - 120
description
Transcript of Na + 117 A - 0 K + 3 Cl - 120
Na+ 117A- 0K+ 3Cl- 120
Model cell
Extracellular Intracellular
30116904
Nernst equation
K+ equilibrium potential: no net K+ movement
In reality: limited Na+ permeability
i
o
K
Kln *
zF
RT KE
-
-
+
+
K+, Cl- permeable Na+, A- non permeable
+
+
ATP
ADP
ATPADP
[Ca2+]i
K+
[Na+]i 10 mM
[Na+]o140 mM3 : 2 electrogenic
Na,K-ATPase
Ca2+-ATPase [Ca2+]i 2 mM
100 nM
[K+]i 140 mM
[K+]o
5 mM
- 90 mV
Li+ can replace Na+
from the cytoplasmic sidebut
with lower efficiency
Nernst equation
V
iK
oK
lnzF
RTk
E
mV
oK
iK
log*58kE
i-
oo
o-
ii
ClPNaPKP
ClPNaPKP58xlogEm
-ClNaK
-ClNaK
Goldman – Hodgkin – Katz equation
E1 conformation•High affinity for Na and ATP
E2 conformation •low affinity for ATP
Extracellular side
Cytoplasmic side
Ionophor domain: 3,4,5,(8?) transmembrane segment
369 - aspartate
-alegység -55 k Da - 4 isoform - necessery for activation - S–S links -glycosylated
100 kDa 4 izoforma
P-type ATP-ases
Na, K-ATPaseα1
α2
α3
α4
K, H-ATPase (K+-absorption; H+- excretion) stomach parietal cells
SERCA ATPaseSERCA 1 striatal muscleSERCA 2 smooth muscle, striatal muscle, heart muscle -
phospholambaneSERCA 3 platelets, endothelial cells
Plazma membrane Ca2+- ATPasePMCA 1 generalPMCA 2 neuronal - higher affinity for cAMP phosphorylation
than PMCA 4 PMCA 3 striatal muscle, brainPMCA 4 generalPMCA 5
ATP dependent aminophospholipid translocase phosphatidyl serine, phosphatidyl etanolamine asymmetric membrane distribution
P-type ATP-ases
Extracellular.
Citoplasmic
Na+
K+
ATP
ATP
22 tetramer (270 kD)
Optimal phospholipid environment- fluidity
Ouabain
Ca2+
Ca2+
Na+
ATP-ase isoforms:
at least 5 different genes -different sensitivity to ouabain in different tissues
α subunit isoforms
α1 - most cells, in epithelial cells only this oneα2 - striatal muscle, brain, heartα3 - neurons, heartα4 - testis
Sensitivity to ouabain:
Kd α2 > α3 > α1
0.1 pM 30 nM 0.1 mM
Piros gyűszűvirág(Digitalis purpurea)
~ 30% of the total ATP production
In neurons ~ 50 % (Na, K-ATPase: voltage-dependent Na+ channels
= 10 :1)
At normal [Na+]i and [K+]o activity is 10-15% of the maximal large reverse capacity
In neurons the activity is increased by 2.5 – 25 folds during action potentials
K0.5 for ATP is 300 - 800 µMAnoxia!
α subunit isoformes
α1 - in most cells, in epithelial cells exclusivelyα2 - striated muscle, brain, heartα3 - neurons, heartα4 - testis
Different sensitivity to cardiac glycosides:
Kd α2 > α3 > α1
0.1 pM 30 nM 0.1 mM
Effects of digitalis-like compounds (DLC)
Regulation
γ – subunit (1978)
szövet-specifikus Na, K-ATPáz regulátor (vese, pancreas, fötális máj)7.2 KDa (58 aminosav) - egy transzmembrán domain Nem integráns része az enzimnekNöveli az enzim ATP iránti affinitásátSzerepe van a K+ általi aktiválásban
Jelentősége:anoxiábanFiziológiásan a vese velőállomány közel anoxiás körülmények között működikReabszorpciók a Na-pumpa kontrollja alatt állnakKis mértékű ATP affinitás növekedés → pumpa aktivitás ↑(Fine tuning! Nagy mértékű affinitas növekedés további ATP ↓ okozna!)
To the proper function of the pump: Na+
i and K+o is required
[K+]o saturates the binding place
[Na+]i < than required to 50 % saturation
The pump responds to changes in [Na+]i
ESSENTIAL HYPERTENSION(SODIUM - VOLUME dependent – low renin level)
Kidney Na+ excretion ↓ ↓[Na+] plasma ↑ ↓Circulating blood volume ↑
? ↓ ? Ouabain release – adrenal cortex ↓ Vascular tone ↑ [Na+]i ↑ → Na - Ca exchange → [Ca2+]i ↑ Long treatment with cardiac glycosides → → hipertension
HORMONES
Corticosteroids (aldosterone, dexamethazon)aldosterone: long term adaptation to decreased Na+ intake
kidneylong term effect – increased expression of mRNA of Na,K-ATPaseshort term effect – increased activity of enzymee (decrease of KM to Na+?)
long term upregulation – described for α1, α2, α3 (smooth
muscle, brain, heart)
ENDOGENOUS STROFANTIN
Regulation
Na,K-ATPase in specialized cells
Kidney:Na reabsorbtion
Na/Ca exchangedigitalis
After stimulation ofstretch aktivatedchannelsremoval of Na
neuronglia
ADRENALIN
Tissuespecific effectActivation of Na,K-ATPase in striated musclesdecreases hyperkalemic detected after muscle work
Secondary active transports
Na cotransporters
*Glucose absorbtion*Amino acid absorbtion*Ca2+ (Na+-Ca2+exchanege)*Cholin uptake into the cholinergic nerve terminal*Adrenalin, noradrenalin. dopamin, serotonin uptake into the axon terminal*Na+-H+ exchange
Inhibition by spec inhibitors + ouabain
Na-H exchanger (NHE)
i
o
H
Hln
zF
RT77
[H+]i = 730 nM pH = 6.13
Na+
H+
1:1 non electrogenic
pHi 7,0883 nM
pHo 7,3844 nM
-77 mV
5 izoforma12 transzmembrán régióNHE 1 általános (basolateralis membrán)
regulált, neurotranszmitterekhormonoknövekedési faktoroksejt térfogat csökkenés
H+ affinitás ↑→ citoplazma alkalinizálás
NHE 3 epitel sejtek apikalis membránjában
NHE 5 agy, lép, testis
KidneyNa+ reabszorpció
Proximal tubules(Na+-H+ exchanege)
Collecting tubules(Na+ channel)
Ca = szensav anhidraz
Neurotransmitter
H+
Citoplazma
ATP
ADP
H+
~ pH = 6