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KiadtaJenő Magyar Megváltozta több, mint 10 éve
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Na + 117 A - 0 K + 3 Cl - 120 Model cell Extracellular Intracellular 30 116 90 4 Nernst equation K + equilibrium potential: no net K + movement In reality: limited Na + permeability - - + + K +, Cl - permeableNa +, A - non permeable + +
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ATP ADP ATP ADP [Ca 2+ ] i K+K+ [Na + ] i 10 mM [Na+] o 140 mM 3 : 2 electrogenic Na,K-ATPase Ca 2+ -ATPase [Ca 2+ ] i 2 mM 100 nM [K + ] i 140 mM [K + ] o 5 mM - 90 mV Li + can replace Na + from the cytoplasmic side but with lower efficiency
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Nernst equation Goldman – Hodgkin – Katz equation
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E 1 conformation •High affinity for Na and ATP E 2 conformation •low affinity for ATP Extracellular side Cytoplasmic side
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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
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P-type ATP-ases Na, K-ATPase α 1 α 2 α 3 α 4 K, H-ATPase (K + -absorption; H + - excretion) stomach parietal cells
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SERCA ATPase SERCA 1 striatal muscle SERCA 2 smooth muscle, striatal muscle, heart muscle - phospholambane SERCA 3 platelets, endothelial cells Plazma membrane Ca 2+ - ATPase PMCA 1 general PMCA 2 neuronal - 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 P-type ATP-ases
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Extracellular. Citoplasmic Na + K+K+ ATP
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2 2 tetramer (270 kD) Optimal phospholipid environment - fluidity
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Ouabain Ca 2+ Na + ATP-ase isoforms: at least 5 different genes -different sensitivity to ouabain in different tissues
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α subunit isoforms α 1 -most cells, in epithelial cells only this one α 2 -striatal muscle, brain, heart α 3 -neurons, heart α 4 - testis Sensitivity to ouabain: K d α 2 > α 3 > α 1 0.1 pM 30 nM 0.1 mM
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Piros gyűszűvirág (Digitalis purpurea)
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~ 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 K 0.5 for ATP is 300 - 800 µM Anoxia!
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α subunit isoformes α 1 -in most cells, in epithelial cells exclusively α 2 -striated muscle, brain, heart α 3 -neurons, heart α 4 - testis Different sensitivity to cardiac glycosides: K d α 2 > α 3 > α 1 0.1 pM 30 nM 0.1 mM
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Effects of digitalis-like compounds (DLC)
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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!)
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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
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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 → [Ca 2+ ] i ↑ Long treatment with cardiac glycosides → → hipertension
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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 K M to Na+?) long term upregulation – described for α 1, α 2, α 3 (smooth muscle, brain, heart) ENDOGENOUS STROFANTIN Regulation
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Na,K-ATPase in specialized cells Kidney:Na reabsorbtion Na/Ca exchange digitalis After stimulation of stretch aktivated channels removal of Na neuron glia
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ADRENALIN Tissuespecific effect Activation of Na,K-ATPase in striated muscles decreases hyperkalemic detected after muscle work
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Na-H EXCHANGETRANSPORTER (NHE) [H + ] i = 730 nM pH = 6.13 Na + H+H+ 1:1 non elektrogenic pH = 7,08 83 nM pH = 7,38 44 nM -77 mV
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Secondary active transports Na cotransporters *Glucose absorbtion *Amino acid absorbtion *Ca 2+ (Na + -Ca 2+ 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
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Na-H exchanger (NHE) [H + ] i = 730 nM pH = 6.13 Na + H+H+ 1:1 non electrogenic pH i 7,08 83 nM pH o 7,38 44 nM -77 mV
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5 izoforma 12 transzmembrán régió NHE 1 általános (basolateralis membrán) regulált, neurotranszmitterek hormonok növekedési faktorok sejt térfogat csökkenés H + affinitás ↑→ citoplazma alkalinizálás NHE 3epitel sejtek apikalis membránjában NHE 5agy, lép, testis
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Kidney Na + reabszorpció Proximal tubules (Na + -H + exchanege) Collecting tubules (Na + channel) Ca = szensav anhidraz
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Neurotransmitter H+H+ Citoplazma ATP ADP H+H+ ~ pH = 6
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