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BIOCHEMISTRY 3 > Membrane transport Na+/K+ ATPase > Flashcards

Membrane transport Na+/K+ ATPase Flashcards

1
Q

Na+/K+ ATPase

A
  • antiporter on PM
  • helps maintain resting potential, facilitate transport and regulate cellular volume, functions as signal transducer to regulate MAPK, ROS, intracellular calcium
  • responsible for 1/5 of energy expenditure, in neurons 50%
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2
Q

Structure of Na/K ATPase

A
  • hydrophilic AA residue mainly in extra and intracellular loops
  • sugar residues at extracellular hydrophilic loop
  • hydrophobic AA residues mainly in transmembrane domain
  • amino NH3 terminal at end of extracellular loop
  • carboxyl terminal in intracellular loop
  • alpha2, beta2 tetramer
  • alpha subunit: 100kDa, 4 isoforms
  • beta subunit: 55kDa, many isoforms, necessary for activity, S-S links glycosylated
  • Steroid binding site, sugar units, ATP binding site
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3
Q

Types of transport

A
  • simple diffusion
  • facilitated diffusion
  • primary active transport
  • secondary active transport
  • ion channel
  • ionophore mediated ion transport
    uniport/ symport / antiport
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4
Q

P-type ATPases

A
  • alpha-helical bundle primary transporters
  • catalyse autophosphorylation of Asp residue
  • appear in at least 2 conformations: E1 and E2
  • mostly pump cations, also Flippases
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5
Q

Examples of P-type ATPases

A
  • Na+/K+ ATPase
  • H+ ATPase (PM)
  • H+/K+ ATPase (stomach parietal cell)
  • sarco/ER Ca2+ ATPase
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6
Q

Types of SERCA

A
  • SERCA 1: striatal muscle
  • SERCA 2: smooth and cardiac muscle, striatal m
  • SERCA 3: platelets and endothelial cells, non muscle cells
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7
Q

Types of Plasma membrane ATPases(PCMA)

A
  • PCMA 1: general
  • PCMA 2: neuronal
  • PCMA 3: striatal muscle and brain
  • PCMA 4: general
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8
Q

Mechanism of Na/K ATPase pump

A
  1. E1- ATP
  2. E1- ATP- 3Na+
  3. E1- P- 3Na+
  4. E2- P- 2Na+
  5. E2- P
  6. E2- P- 2K+
  7. E2- 2K+
  8. E2- 2K+- ATP
  9. E1- 2K+- ATP
  10. E1- ATP again
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9
Q

Mechanism of SERCA

A
  1. Ca2+ binds to transmembrane (M) domain and ATP bind to nucleotide (N) domain
  2. Phosphoric group transferred to Asp351 residue in P domain (requires Mg2+)
  3. Ca2+ released from lumen
  4. Activator (A) domain moves, ADP released
  5. P domain dephosphorylated
  6. A domain returns to original, releases Mg2+
  7. P and M domain resets
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10
Q

Ouabain (Strophantine)

A
  • poisonous cardiac glycoside
  • potent inhibitor of Na/K ATPase
  • works especially in high conc. in vitro / intravenously
  • Digoxin: same structure, more lipophilic cardiac glycoside, replaces Ouabain
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11
Q

Alpha subunit isoforms

A
  • alpha1: in most cells + epithelial cells + kidney outer medulla
  • alpha2: striatal muscle + brain + heart + smooth m. + adipocytes
  • alpha3: neurons + heart + ovary + leukocytes
  • alpha4: testis
    sensitivity to ouabain:
    alpha2(0,1pM) - alpha3(>30nM) - alpha1(0,1mM)
    Km:
  • K+e.c.: 0,5mM
  • ATP: 0,15mM
  • Na+i.c.: 10-20mM
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12
Q

Gamma subunit

A
  • regulator of Na/K ATPase in certain tissues.
  • regulates transport kinetic of alpha subunit
  • Tissue specific in kidney, pancreas and fetal liver
  • 7,2kDa, 1transmembrane domain
  • function: increase pump affinity to ATP
  • important in anoxia
  • 7 isoforms
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13
Q

Regulation of Na+/K+ ATPase

A
  1. Corticosteroids (aldosterone, dexamethazone)
  2. Long term effect (increased expression of Na+ pump)
  3. Mineralocorticoid type 1 receptor
  4. Glucocorticoid type 2 receptor
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14
Q

Mineralocorticoid type 1 receptor

A
  • expressed in many tissues
  • cytosolic receptor
  • activated upon ligand binding
  • receptor-ligand complex translocated into nucleus and binds to HREs in promoter region
  • trans-repression: no ligand binding, receptor interacts with heat shock proteins and prevents transcription
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15
Q

Hyperaldosterism

A
  • generally from adrenal cancer
  • hypertension and edema- excessive Na+ and H2O retention
  • excretion of K+ - muscle weakness, paralysis
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16
Q

Glucocorticoid type 2 receptor

A
  • expressed in most cells
  • regulates genes controlling development, metabolism, immune response
  • pleiotropic
  • receptor-GR complex:
  • upregulates expression of anti-inflammatory proteins in nucleus
  • represses expression of pro-inflammatory proteins in cytosol
17
Q

Aldosterone

A
  • adaptation in kindney to decreased Na+ or increased K+ intake
  • long term up regulation: isoform specific
  • alpha1: vacular smooth m
  • alpha2: heart
  • alpha3: brain
  • short term effect: increased activity of enzyme
  • translocation of pump to PM and increase in affinity of enzyme to Na+
18
Q

Dopamine

A
  • natriuretic effect
  • synthesized in kindey proxiaml tubule
  • paracrine + autocrine effects
  • inhibits Na/K ATPase - decreased Na+ reabs.
  • D1 and D2 receptors phosphorylated by PKA and PKC
19
Q

Epinephrine

A
  • in skeletal muscle stimulates K+ uptake by Na/K ATPase
  • important during extreme exercise - hyperkalemia - E counteracts this effect
  • bind to beta2 adrenergic receptor- decrease K+ conc e.c.
20
Q

Norepinephrine

A
  • in kidney antagonistic effect of dopamine

- in brain restores ion conc. of Na+ and K+ after nerve impulses fired

21
Q

Insulin

A
  • short term effect: direct stimulation of Na/K ATPase
  • in skeletal m.- only in oxidative slow twitch muscle - translocation of enzyme to PM
  • long term effect: increased/ decreased expression
22
Q

Secondary active transports: Na+ co-transport

A
  • glucose and AAs
  • choline uptake into cholinergic nerve terminals
  • epinephrine, norepinephrine, dopamine and serotonin repute by nerve terminal
23
Q

Na+/H+ exchanger

A
  • not electrogenic- 1H+ for 1Na+
  • highly dependent of pH
  • 5 isoforms with 12 transmembrane domains:
  • NHE1: general
  • NHE3: epithelial cells, apical enterocytes
  • NHE5: brain, testis
24
Q

Proton antiporter, VMATs

A
  • 12 transmembrane segments
  • broad selectivity
  • isoforms:
  • VMAT1: brain, neuroendocrine cells
  • VMAT2: neurons, adrenal chromaffin cells
  • VAChT: cholinergic synapses
  • inhibited by H+ ionophores
25
Q

ABC transporters

A
  • vitamin B12 importer
  • homodimer, 10 transmembrane helical domains in each monomer + 2 nucleotide-binding domains
  • ATP dependent
  • transporter for AAs, peptides, metal ions, lipids, bile salts, drugs
  • located in PM, mitochondrial membrane, ER
  • transport agains conc. gradient
  • mutations cause eg. cystic fibrosis, retinal degradation, anemia, Tangier disease
26
Q

Multi-drug transporter (MDR1)

A
  • ABC transporter
  • pumps hydrophobic compounds out of cell
  • tumor resistance agains anti tumor drugs
27
Q

Tangier disease

A
  • defect in gene for ABC transporter ABCA1
  • reduced ability to transport cholesterol out of cell
  • leads to accumulation of cholesterol
  • reduced level of HDL - hypoalphalipoproteinemia
28
Q

Gamma subunit in heart (FXYD1, phospholemman)

A
  • when dephosphorylated it decreases the Na+ affinity of the α-subunit
  • adrenergic β1 receptor stimulation → PKA stimulation →
    phosphorylation of phospholemman → [Na+]i [Ca2+]i ↓ -prevention of arrythmia
29
Q

Gamma subunit in kidney (FXYD2)

A
  • increases the affinity of the enzyme for ATP
  • Kidney medulla is nearly anoxic under physiological conditions
  • Some reabsorptions are under the control of the Na+-pump
  • Moderate increase in the affinity for ATP → increased pump activity
    (Fine tuning! Large affinity increase would cause further ATP ↓ !)
30
Q

Endogenous cardiac glycosides

A
  • sterioid structure
  • synthesized in zona fasciculate from progesterone
  • plasma conc.: 10-9 M
  • role: regulation of vascular tone
31
Q

Glucose transporter in proximal tubule in kidney

A
  • Glucose 160-180 g/day in the filtrate completely reabsorbed
  • SGLT2 – low affinity (Kt 6 mM) large capacity transporter
  • inhibitor in diabetes – glucosuria
  • SGLT1 – high affinity low capacity transporter
32
Q

ABC transporters

A

ABCA1 – cholesterol, phopholipid transport - reverse cholesterol transport
ABCA3 – translocation of pulmonary surfactant lipids
mutation: respiratory distress syndrome
ABCB1 (MDR1 or P-glycoprotein, multidrug resistence transporter) - transport of lipophylic compounds – protection against toxins - increased expression in tumor cells: drug resistence
ABCB4 – canalicular membrane of hepatocytes
bile acid, phospholipid transport into the bile
ABCC1 (MRP-1, multidrug resistence protein)
- phospholipids, glutathione conjugates, anti-tumor drugs (also other than lipophylic!)
CFTR (ABCC7, cystic fibrosis transmembrane conductance regulator) - Cl- flux in apical membrane of epithelial cells
mutation: cystic fibrosis (thick mucus in the bronchi and pancreas
- blockage, infection, foetal ileus

BIOCHEMISTRY 3 (17 decks)

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