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molecules to cells > LEC 49 Transporters & Pumps > Flashcards

LEC 49 Transporters & Pumps Flashcards

1
Q

What are transporters?

A

catalysts that work in repeated cycles with the protein alternating between inward-facing and outward facing conformations

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2
Q

Transporters function very similarly with respect to kinetics to what other class of molecules?

A

Enzymes

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3
Q

Direction of net transport through a facilitated diffusion transporter is always in what direction?

A

Down the gradient

High to low concentration

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4
Q

In facilitated diffusion, is ATP required?

A

No

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5
Q

Which glucose transporters are insulin-dependent?

A

GLUT4

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6
Q

What are the insulin-independent glucose transporters?

A

GLUT1, GLUT2 (bidirectional), GLUT3, & GLUT5 (fructose)

BRICKLIPS

Brain, RBCs, Intestine, Cornea, Kidney, Liver, Islet, Placenta, Sperms

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7
Q

How does GLUT1 also function bidirectionally?

think blood-brain barrier

A

GLUT1 is on both sides of the endothelial cell. On the blood side, transport is inward; on the brain side, transport is outward. In both cases transport is from higher concentration to lower concentration

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8
Q

What are some of the main points regarding facilitated diffusion?

A
  • Requires a membrane protein that can be in either inward-facing or outward-facing conformation
  • One substrate at a time; no ATP hydrolysis
  • Substrate saturation
  • Competition between substrates
  • Direction of transport can be either inward or outward, depending on the substrate gradient; transport is always downhill, from high to low concentration.
  • Both empty and substrate-bound forms of the transporter
    can reorient between inward- and outward- facing states

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9
Q

What is primary active transport?

A

Energy of ATP hydrolysis drives uphill transport of one or more substrates, including cations, drugs, lipids (flippase), but not anions

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10
Q

What is the most important example of primary active transport?

A

Na, K - ATPase

Sodium/Potassium Pump

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11
Q

How does the sodium-potassium pump work?

What does it pump and where? What’s required?

A

Pumps 3 Na+ out and 2 K+ in hydrolyzes ATP in the process

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12
Q

Why is the ATP required in the Na/K ATPase?

A

the energy of the ATP is required to overcome the energetically unfavorable conformational changes in order to bind/release the sodium and potassium

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13
Q

Explain the phosphorylation/dephosphorylation of the sodium-potassium pump.

A

2 K+ go into the cell (pump dephosphorylated)

3 Na+ go out of the cell (pump phosphorylated)

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14
Q

Explain the Na/K-ATPase catalytic cycle?

A
  1. 3 cytosolic Na+ bind to E1 conformation (high Na affinity)
  2. E1 phosphorylated by ATP forming E1-P
  3. Conformational change to E2-P which releases the Na+ (low Na affinity) and binds 2 extracellular K+ (high K affinity)
  4. E2-P dephosphorylated and conformational change to E2 which releases to K into the cytosol and returns it to E1

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15
Q

How do ATP-Binding Cassettes work?

A
  • two membrane domains with 6 TM segments each and two nucleotide binding domains
  • Drug, from either cytosol or inner half of lipid bilayer, binds to pocket between the two membrane domains
  • ATP binds to Nucleotide Binding Domains and induces conformational change that expels drug into extracellular medium

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16
Q

Whats another name for a coupled cotransporter?

A

Symporter

Symporter = SAME DIRECTION

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17
Q

What is an example of a coupled cotransporter?

A

2 Na-Glucose (SGLT)

Slide 19

18
Q

How does SGLT (sodium-glucose cotransporter) work?

A
  • In glucose-absorbing epithelial cells, the inward Na+ gradient across the luminal (apical) membrane drives downhill Na+ influx via SGLT.
  • SGLT couples Na+ influx to glucose influx, and the Na+ gradient drives glucose influx against a concentration gradient, with no ATP hydrolysis.

Slide 19

19
Q

Which cotransporter is a target of Furosemide (Lasix)?

A

Na-K-2Cl Cotransporter

Slide 21

20
Q

How does the Na-K-2Cl cotransporter work?

A
  • Couples the transport of 1 Na+, 1 K+, and 2 Cl- ions in the same direction
  • No ATP hydrolysis, but regulation by phosphorylation
  • Driving force is normally inward because the inward Na+ and Cl- gradients overcome the outward K+ gradient

Slide 21

21
Q

How does Na-K-2Cl- Cotransporter couple the ion fluxes?

A

By constraining the translocation event to all sites filled or all sites empty (same idea as 2 Na-Glucose cotransporter, but now there are 4 substrates)

Slide 21

22
Q

What is another name for coupled exchangers?

A

Antiporters

Slide 22

23
Q

What are coupled exchangers?

A

Substrates are required to move in opposite directions

Slide 22

24
Q

What makes antiporters different from symporters in terms of their conformational changes (translocation event)?

A

translocation event requires bound substrate; empty transporter cannot re-orient between inward-facing and outward-facing

Slide 22

25
Q

How does the Na-H exchanger work?

A

Inward Na+ gradient drives efflux of H+; this is a mechanism for extruding acid from cells

Slide 23

26
Q

How does the 3Na-Ca exchanger work?

A

Inward Na+ gradient drives Ca2+ efflux. Inward Na+ gradient is only ~ 10x, but the 3:1 exchange (with one net positive charge going inward) makes the energetics favorable for Ca2+ efflux, even against a large gradient

Slide 23

27
Q

How does Cl-HCO3 exchange work as a part of CO2 transport in tissue capillaries?

A

Cl- influx, HCO3- efflux across basolateral membrane of acid-secreting epithelia and in red blood cells

Slide 23

28
Q

What are the functions of ion gradient?

A
  • Resting membrane potential, action potential.
  • Ca2+ signaling in muscle, nerve, secretion.
  • Coupled transport of nutrients (glucose, amino acids).
  • Reuptake of neurotransmitters (targets of many drugs).
  • Transepithelial absorption, secretion.
  • Cell volume regulation.
  • Cytosolic pH regulation (Na+-H+ exchange).

Slide 25

29
Q

What is the only transporter in humans that mediates Na efflux?

A

Na/K ATPase

Slide 27

30
Q

What drug inhibits the Na/K ATPase and is related to the stimulation of cardiac contractility?

A

Digoxin

Slide 28

31
Q

Where in the cell is Ca2+ stored?

A

ER or SR

Slide 29

32
Q

Why is cytosolic concentration of Ca2+ kept at low levels?

A

This allows small increases in free [Ca2+]to act as a signal for muscle contraction, secretion, and other functions

Slide 29

33
Q

What transporter pumps Ca2+ into the SR/ER?

A

SR/ER Ca2+ - ATPase

Slide 29

34
Q

How is Ca2+ pumped out of the cell?

A
  • a related P-type ATPase pumps Ca2+ across plasma membrane
  • In heart and some neurons, 3Na-Ca exchanger pumps Ca out of the cell

Slide 29

35
Q

How does calcium enter the cell?

A

Calcium ion channels

Slide 29

36
Q

How does digoxin elevate cardiac cytosolic Ca2+?

A
  • Digoxin level sufficient to block about 10% of Na pumps
  • Intracellular Na increases slightly
  • Increased [Na] causes decreased driving force for Na-Ca exchange
  • less Ca2+ extrusion by exchanger
  • Increased cytosolic Ca2+ and increased force of contraction

Slide 30

37
Q

What are the clinical uses of Digoxin?

A
  • Heart failure (+contractility)
  • Atrial fibrilation (-conduction @ AV node & depression of SA node

Slide 31

38
Q

What are the adverse effects of Digoxin?

A
  • Cholinergic effects (N/V/D)
  • Blurry yellow vision
  • arrhythmias
  • AV block
  • Hyperkalemia (digoxin upsets pump-leak balance for K+ and increased extracellular [K]

Slide 31

39
Q

How does malignant hyperthermia occur?

What is the mechanism?

A
  • inhaled anesthetics or succinylcholine induce severe muscle contractions & hyperthermia
  • mutations in ryanodine receptor (RYR1 gene) cause Ca2+ release from SR
  • increased PM & SERCA Ca-ATPase activities d/t increased intracellular Ca2+ results in lower ATP which in turn causes an increase in Oxidative Phosphorylation
  • Causes an increase in body tempurature

Slide 32

40
Q

How does the MDR1 pump work?

A
  • MDR1 pumps drugs out of cells, but hydrophobic drugs diffuse back in.
  • This creates a pump-leak steady state, in which cellular drug concentration depends on MDR1 expression.

Low MDR1 expression = higher cytosolic drug concentration

Slide 33

molecules to cells (20 decks)

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