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Na + 117 A - 0 K + 3 Cl - 120

Model cell. Intracellular. Extracellula r. +. 30 116 90 4. -. Na + 117 A - 0 K + 3 Cl - 120. +. -. +. +. K + , Cl - à permeab le. Na + , A - à n on permeable. Nernst equation. K + equilibrium potential: no net K + movement.

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Na + 117 A - 0 K + 3 Cl - 120

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  1. Model cell Intracellular Extracellular + 30 116 90 4 - Na+ 117 A- 0 K+ 3 Cl- 120 + - + + K+, Cl-à permeable Na+, A-à non permeable Nernst equation K+ equilibrium potential: no net K+ movement In reality: limited Na+ permeability

  2. Li+ can replace Na+ from the cytoplasmic side but with lower efficiency [Na+]o140 mM 3 : 2 electrogenic Na,K-ATPase [Na+]i 10 mM [K+]i 140 mM [K+]o 5 mM ATP ADP - 90 mV ATP [Ca2+]i ADP K+ 100 nM Ca2+-ATPase [Ca2+]i 2 mM

  3. Nernst equation Goldman – Hodgkin – Katz equation

  4. Extracellular side Cytoplasmic side • E1 conformation • High affinity for Na and ATP • E2 conformation • low affinity for ATP

  5. b-alegység -55k Da - 4 isoform - necessery for activation - S–S links -glycosylated 100 kDa 4 izoforma Ionophor domain: 3,4,5,(8?) transmembrane segment 369 - aspartate

  6. P-type ATP-ases Na, K-ATPase α1 α2 α3 α4 K, H-ATPase (K+-absorption; H+- excretion) stomach parietal cells

  7. P-type ATP-ases SERCA ATPase SERCA 1 striatal muscle SERCA 2 smooth muscle, striatal muscle, heart muscle - phospholambane SERCA 3 platelets, endothelialcells Plazma membrane Ca2+- ATPase PMCA 1 general PMCA 2neuronal - higher affinity for cAMP phosphorylation than PMCA 4 PMCA 3 striatal muscle, brain PMCA 4 general PMCA 5 ATP dependent aminophospholipid translocase phosphatidyl serine, phosphatidyl etanolamine asymmetric membrane distribution

  8. Extracellular. Na+ Citoplasmic ATP K+ ATP

  9. a2b2 tetramer (270 kD) • Optimalphospholipid environment • fluidity

  10. Ouabain Na+ Ca2+ Ca2+ ATP-ase isoforms: at least 5 different genesàa -different sensitivity to ouabain in different tissues

  11. αsubunit isoforms α1 - most cells, in epithelialcells only this one α2 - striatal muscle, brain, heart α3 - neurons, heart α4 - testis Sensitivity to ouabain: Kdα2 >α3 >α1 0.1 pM 30 nM 0.1 mM

  12. Piros gyűszűvirág(Digitalis purpurea)

  13. ~ 30% of the total ATP production In neurons ~ 50 % (Na, K-ATPase: voltage-dependent Na+ channels = 10 :1) At normal [Na+]iand [K+]o àactivity is 10-15% of the maximalàlarge reverse capacity In neurons the activity is increased by 2.5 – 25 folds during action potentials K0.5for ATP is 300 - 800 µM Anoxia!

  14. α subunit isoformes α1 - in most cells, in epithelial cells exclusively α2 - striated muscle, brain, heart α3 - neurons, heart α4 - testis Different sensitivity to cardiac glycosides: Kdα2 >α3 >α1 0.1 pM 30 nM 0.1 mM

  15. Effects of digitalis-like compounds (DLC)

  16. 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 enzimnek Növeli az enzim ATP iránti affinitását Szerepe van a K+ általi aktiválásban Jelentősége:anoxiában Fiziológiásan a vese velőállomány közel anoxiás körülmények között működik Reabszorpciók a Na-pumpa kontrollja alatt állnak Kis mértékű ATP affinitás növekedés → pumpa aktivitás ↑ (Fine tuning! Nagy mértékű affinitas növekedés további ATP ↓ okozna!)

  17. To the proper function of the pump: Na+i and K+o is required [K+]osaturates the binding place [Na+]i< than required to 50 % saturation The pump responds to changes in [Na+]i

  18. 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

  19. Regulation HORMONES Corticosteroids (aldosterone, dexamethazon) aldosterone: long term adaptation to decreased Na+ intake kidney long term effect – increased expression of mRNA of Na,K-ATPase short 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

  20. Na,K-ATPase in specialized cells Kidney:Na reabsorbtion Na/Ca exchange digitalis After stimulation of stretch aktivated channels removal of Na neuron glia

  21. ADRENALIN Tissuespecific effect Activation of Na,K-ATPase in striated muscles decreases hyperkalemic detected after muscle work

  22. Secondary active transports Na cotransporters • *Glucose absorbtion • *Amino acid absorbtion • *Ca2+ (Na+-Ca2+exchanege) • *Cholinuptake into the cholinergic nerve terminal • *Adrenalin, noradrenalin. dopamin, serotonin uptake into the axon terminal • *Na+-H+ exchange • Inhibition by spec inhibitors + ouabain

  23. Na-H exchanger (NHE) -77 mV pHi 7,08 83 nM pHo7,38 44 nM [H+]i = 730 nM pH = 6.13 H+ Na+ 1:1 non electrogenic

  24. 5 izoforma 12 transzmembrán régió NHE 1 általános (basolateralis membrán) regulált, neurotranszmitterek hormonok növekedési faktorok sejt térfogat csökkenés H+ affinitás ↑→ citoplazma alkalinizálás NHE 3 epitel sejtek apikalis membránjában NHE 5 agy, lép, testis

  25. KidneyNa+ reabszorpció • Proximal tubules • (Na+-H+ exchanege) • Collecting tubules • (Na+ channel) Ca = szensav anhidraz

  26. Neurotransmitter ~ pH = 6 ATP H+ ADP H+ Citoplazma

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