Midterm #3: Membrane Transport Flashcards Preview

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Flashcards in Midterm #3: Membrane Transport Deck (27):
1

3 ways in which molecules can cross membrane barriers:

  1. Diffusion: small, non-polar molecules can spontaneoulsy pass through the bilayer
  2. Passive Transport: larger or more polar molecules can pass through channels down a concentration gradient.  May be tightly regulated
  3. Active transport: solute can also be pumped by transporters against a concentration gradient, in an energy-dependent process  

2

Diffusion Across Membranes

  • Very small nonpolar substance such as O2, N2, CO2 and NO can diffuse through a lipid bilayer
  • The diffusion rate ("flux") depends on:
    • the solubility of the molecule in lipid
    • the concentration gradient across the membrane
  • flow continues until an equilibrium is achieved
    • Larger and polar molecules cannot easily or quickly diffuse across a bilayer and their transport across biological membranes must be mediated by two types of proteins: channels and transporters

3

Channels and Passive Transport

  • Hole in membrane where it can diffuse down concentration gradient 
    • facilitated diffusion 
  • No energy (passive transport)
  • Cannot establish concentration gradients
  • Can be selective
    • provides appropriate size and environment
  • Display substrate specificity with defined Vmax and Km parameters

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4

Two types of channels or pores: Ungated and Gated

  • Ungated:
    • facilitated diffusion of substrates
    • selective/nonselective
    • Ex: Beta-barrel porins, aquaporins
  • Gated or Regulated Channels
    • switch between open and closed states​
    • highly selective (usually small charged ions)
    • Regulated by: membrane potential (voltage), ligand binding, mechanical stress or phosphorylation 
    • Ex: Voltage Gated Na+ Channel, Voltage Dependent Ca+ Channel, GABAA Receptor, Nicotinic-Acetylcholine Receptor 

5

Two types of Gating for Channels

  • Peptide Plug
  • Rotational Gating

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6

Porins

  • AKA: Beta Barrel Channels
  • Outer membrane of gram-negative bacteria and of mitochondria 
  • Form aqeuous channels through membrane
  • Trimers
    • Each subunit forming a 16- or 18-strand membrane spanning beta barrel 
    • Center is lined with charged side chains and is filled with water, forming a passageway for the movement of small molecules 
    • Depending on the nature of the side chains, the porin may be selective for ions, amino acids, or sugar 

7

Aquaporins

  • alpha-type channels
    • several subunits with multiple transmembrane alpha-helices
  • Very sensitive, allowing only the passage of water
  • Narrow channel lined with charged residues and two specifically placed Asn residues at the center of the pore
    • Important role in reabsorption of water in the kidneys, and in water transport in the roots of plants

8

Voltage-Gated Sodium and Potassium Channels

  • Diffusion of ions across membranes depends on concentration gradient and membrane potential
    • called the electrochemical gradient
  • In the resting state, neurons maintain a negative membrane potential with excess extracellular Na+ and intracellular K+
  • Signals are transmitted along nerve cell axons in the form of action potentials mediated by Na/K voltage gated channels. 
    • Inital stimulus causes Na channels to open, Na flows in and depolarizes cell membrane
    • K channels open and K flows out to restore membrane potential 

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9

Name this structure

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  • Tetrodotoxin: found in certain pufferfish, inhibits voltage-gated Na+ channels and causes paralysis 

10

Voltage-Dependent Calcium Channels (VDCC)

  • found in muscle cells and neurons
  • closed at resting membrane potential but activated by depolarization of the membrane 
  • Ca+ entry into the cell, cauing contraction/excitiation
  • Open in milliseconds, but stay open longer giving a more sustained action potential 

11

Calcium Channel Blockers

  • Ex: amlodipine
  • Treat HTN
  • Inhibit VDCC in heart muscle, decreasing cardiac contractility 
    • Decreases cardiac output
  • Inhibit VDCC in arterial smooth muscle causing increase in arterial diameter (vasodialation)
    • Decreases total peripheral resistance 

12

Name This Structure

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Amlodipine

13

Ligand-gated Channels

  • GABAA Receptor is a Cl- channel found in CNS
  • Activation allow Cl into cell, causing hyperpolarization
    • neuronal inhibition
  • Benzodiazepines and barbituates enhance GABAAR activity. 
  • Nicotinic-Acetylcholine Receptor (nAChR) is a gated channel at neuromuscular junction 
    • ACh binding to receptor opens the channel, enabling Na+ to enter and K+ to exit
    • Local depolarization at motor end plate, initiating mucle contraction 
  • Acetylcholinesterase rapidly degrades ACh in the synaptic cleft

14

Name this structure

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GABA: gamma-aminobutyric acid

15

Name this structure

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acetylcholine

16

nAChR inhibitors

  • Non-depolarizing neuromusclar junction agents
    • bind to nAChR and competitvely inihibit ACh binding
    • Curare alkaloids like d-tubocurarine
    • Muscle relaxant like atracurium 
  • Depolarizing neuromuscular junction agents
    • bind to nAChR and open the channel resulting in membrane depolarization
    • Mimic ACh, first causing contraction and then paralysis 
    • Succinylcholine is used via IV. Adjunct to general anesthesia to facilitate tracheal intubation and to provide skeletal muscle relaxation during surgery and mechanical ventilation 

17

Name this structure

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d-tubocurarine

18

Name this structure

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atracurium 

19

Name this structure

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Succinylcholine

20

Uniport, Symport, Antiport

  • Uniport: moves a single substance at a time
  • Symport: transports two different substances in the same direction across membrane
  • Antiport: move two different substances in opposite directions across the membrane

21

Transporters may also operative passively (“facilitated transport”) or actively, through two modes: 

  1. Primary active transport: involves the consumption of ATP
  2. Secondary active transport: is coupled to an exisiting electrochemical gradient 

22

GLUT1

  • passive uniporter
  • transports glucose down a concentration gradient into RBC and many other tissues

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23

Primary Active Transport: The Na/K-ATPase 

  • Maintains the concentration of sodium (extracellular→intracellular) and potassium (intra→extra)
  • Each rxn cycle hydrolyzes 1 ATP, pumps 3 Na out and 2 K in
  • Excitable tissue like nerve and muscle have high Na/K ATPase activity to maintain membrane potential
  • Separate Ca ATPase transporter maintains the Ca gradient for VDCC activity
  • In addition, the concentration gradients can power other co-transport proteins (secondary active transporters)
  • Main consumer of ATP in body at rest

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24

Primary Active Transport: P-Glycoprotein (P-gp) 

  • P-gp (aka: MDR1 or ABCB1) pumps a broad array of xenobiotic compounds out of cytoplasm in an ATP-dependent process.
  • Key player in drug transport in gut, liver, kidney and blood-brain barrier as well as in cancer cell multidrug resistance
  • Many drugs also inhibit P-gp activity, a potential source for drug-drug interaction
  • P-gp inhibitors such as quinidine can substantially increase exposure to the P-gp substrate digoxin

25

Secondary Active Transport​

  • ​Takes advantage of gradient already established by ATPase pump
  • The Na-glucose transporter found in renal epithelial cells of the kidneys is a symport
    • Glucose import is powered by the sodium gradient set up by the Na/K-ATPase
  • The Na/Ca-exchanger (NCX) in cardiac cells is an antiport also powered by sodium gradient.
    • exchanges 3 Na per Ca exported
    • Much faster than Ca-ATPase but has a lower affinity
      • cannot maintain as steep a concentration gradient 

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26

Cardiac Glycosides 

  • natural products that increase the intensity of heart muscle contraction 
  • treat congestive heart failure
  • ​Digoxin
    • Narrow therapeutic index: 0.8-2 ng/mL, toxic is greater than 2.4 ng/mL
  • Steroids that inhibit Na/K-ATPase decreasing the Na gradient
    • Inhibits NCX, attenuates the rapid removal of Ca from the cell 
  • Increase in intracellular Ca increases the contractility of the cardiac muscle and the intensity of cardiac contraction 
  •  

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27

Name this structure

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Digoxin