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Channels, Carriers and Pumps

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Anion channels. Different types: Extracellular ligand-gated Cl- channels ... groups at the 'mouth' of the channel can attract cations and push away anions. ... – PowerPoint PPT presentation

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Title: Channels, Carriers and Pumps


1
Channels, Carriers and Pumps
2
Characteristics of Membrane Channels
  • Nonenergetic - protein-lined membrane openings
    that mediate downhill flow of ions or molecules
    (almost) as if they were diffusing in free
    solution.
  • Selective most channels prefer one ion species
    or one family of molecules, but selectivity
    varies. This means that some part of the channel
    interior must serve as a selectivity filter.
  • Usually can open and close (channels that are
    always open are called pores) channels
    typically open and close spontaneously, but may
    also be voltage-gated or chemically gated. This
    means that some part or parts of the channel
    structure must serve as a gate or gates.
  • Some channels serve as receptors for extrinsic
    chemical messages hormones or neurochemical
    transmitters these are termed ionotropic
    receptors.

3
Ion channels are electrical conductors
  • The current that flows through a single channel
    is the product of the electrochemical driving
    force (V) and the single-channel conductance (G).
  • Classically, an individual channel was regarded
    as having a characteristic conductance, but a
    number of channels are now known that have
    multiple open states with different conductances.

4
Ion channels ionophores
  • Gramicidin is an antibiotic obtained from the
    bacterial species Bacillus brevis
  • Gramicidin is a peptide of 15 amino acids
  • Its sequence contains alternatively D- and
    L-amino acids and the molecule builds a helix
    with an inner pore of 0.4 nm in diameter.
  • Two molecules build a transmembrane, unspecific
    cation channel through which K and Na can
    permeate. The channel is open whenever the two
    molecules are in position with each other

5
Ion channels Gramicidin A
  • Let us determine permeation of Na through a
    Gramicidin A channel
  • We take Ficks law to calculate the number of Na
    ions crossing the channel.
  • Suppose DNa is 1.33 cm2 s-1, c1-c2 is 100 mmol/l
    and that x1-x2 is the thickness of a membrane (5
    nm). After converting all terms to cm, we obtain

6
What is measured?
  • Below models and channel current traces of
    voltage-dependent K and Na channels in an axon.
  • Na channel has two gates and four states, K
    channel has one gate and two states

7
Gap junction channels
  • Very unspecific!
  • Connecting different cells.
  • Each channel consists of 2 connexons. Each
    connexon consists of 6 connexins. Each connexin
    is a polypeptide that crosses 4 times the
    membrane.
  • The pore has a diameter of 1.5-2.0 nm
  • Inorganic ions, water, and many small organic
    molecules (like amino acids) up to about 1200 D
    can pass the gap junction channel.

8
A weakly specific cation channel
  • The nicotinic acetylcholine receptor an example
    of an ionotropic receptor
  • Hardly discriminates between Na and K.
  • Heteropentamer a2ß?d
  • Each subunit has 4 transmembrane helices (M1-M4)

9
There are lots of potassium channels
  • Many different families of K channels with very
    different structure and function
  • Delayed rectifier K-channels
  • Inward rectifier K-channels
  • Ca-sensitive K-channels
  • ATP-sensitive K-channels
  • Na-activated K-channels
  • Cell volume sensitive K-channels
  • Type A K-channels
  • Receptor-coupled K-channels

10
Sodium channels I
  • Voltage-dependent Na channels
  • Similar structure to voltage-dependent K
    channels, but here the channel is formed by one
    huge protein sequence with 4x6 membrane spanning
    helices
  • Action potential!

11
Sodium channels II
  • Epithelial Na channels (not voltage-dependent)
  • a2ß?, with each subunit having 2 transmembrane
    helices
  • Important for transepithelial Na absorption in
    tight epithelia (distal nephron, distal colon,
    amphibian skin and bladder, freshwater fish gill,
    other freshwater animals
  • Important for sensing salt!

12
Calcium channels
  • Voltage-dependent Ca-entry channels
  • L-type (long lasting) Ca channel a1C, a1D,
    a1F, or a1S, a2d, b3a
  • N-type Ca channel a1A, a2d, b4a
  • P-type Ca channel a1B, a2d, b1b
  • Q-type Ca channel a1A, a2d, b4a
  • R-type Ca channel a1G, a1H, a1I
  • T-type Ca channel a1G, a1H, a1I
  • Ligand-gated Ca channels
  • Homotetramer complex, 6 transmembrane helices
  • Ca release channels Ryanodine receptors
  • Calcium channel and Inositol-1,4,5-triphosphate
    (IP3) receptor in ER
  • Calcium channel and receptor of nicotinic
    acid-ADP (NAADP)
  • Calcium channel and receptor of sphingolipíds
  • Functions
  • In general cause an increase in cellular Ca
    which is a messenger for many processes

13
Anion channels
  • Different types
  • Extracellular ligand-gated Cl- channels
  • Cystic fibrosis transmembrane conductance
    regulator (CFTR)
  • Voltage-gated Cl- channels
  • Nucleotide sensitive Cl- channel
  • Intracellular Cl- channel
  • Calcium-activated Cl- channel
  • Functions
  • involved in NaCl absorption and secretion across
    epithelia
  • HCl secretion in mammalian stomach
  • Cell volume regulation
  • Postsynaptic, inhibitory GABA and Glycin receptors

14
All these channels? How can they be distinguished?
  • Ion selectivity
  • Conductance
  • Pharmacology (Activators/Inhibitors)
  • Localization
  • Molecular structure

15
Ion channels How do they distinguish between
ions?
  • Selectivity for charge
  • Negatively charged groups at the mouth of the
    channel can attract cations and push away anions.
    Positively charged groups at the mouth of the
    channel can attract anions and push away cations.
  • Selectivity for size
  • The diameter of the pore could determine the size
    of the particles that can pass.
  • Interestingly, channels with 6, 5 and 4
    transmembrane domains were found

Gap junction
Unspecific cation channel
Voltage-dependent cation channels
Ø 1.5-2.0 nm Ø 0.65 nm Ø 0.3-0.5 nm
  • But there is still a problem!

16
Ion channels How do selectivity filters work?
  • Why do Na ions (rNa 0.095 nm) not permeate
    through K channels (rK 0.133 nm)?

Na K
  • K ions permeate through K channels without
    their hydrated shell (naked). Amino acid side
    groups of the channel protein mimic the presence
    of the water molecules in a way that K ions can
    easily give up their hydrated shell and pass
    through the channel.
  • Na ions are smaller and their naked form is
    not stabilized by K channels. Together with
    their hydrated shell Na ions are too big to pass
    K channels.

17
Ion channels How do they distinguish between
ions?
  • K ions travel naked through their channels. Na
    ions travel together with a water molecule.
  • Naked Na ions are not stabilized in K channels.
    They cannot strip off their hydrate shell. K
    ions with a water molecule are too big to pass
    Na channels. Their naked form is not stabilized
    either.

18
Distinguishing carriers and channels
19
Carrier molecules must interact specifically with
each molecule transported
20
Carrier saturation
  • Passive transport by simple diffusion is
    described by Ficks law
  • Here, the rate is determined by the gradient
  • Facilitated diffusion through carriers does not
    only depend on the concentration gradient of the
    substrate, but also on the number of carriers, on
    their turnover (which determines Vmax) and on
    their affinity to the substrate.
  • Carriers show saturation!
  • Channels show saturation only at very high
    concentrations.
  • Free diffusion across the membrane saturates only
    when the membrane area becomes rate limiting.

21
Active Transport
  • Metabolic energy is spent to drive solutes
    against their chemical or electrochemical
    gradients
  • The driving force may be
  • reducing power (H transport by ETC)
  • ATP (Na/K pump, V-type H pump) we call these
    primary active transport
  • Transmembrane gradient of some other substance
    (frequently Na), which is the result of primary
    active transport we call these secondary active
    processes

22
P-type ATPases
  • P-ATPases form an intermediate during their
    reaction cycle in which phosphate is covalently
    bound to the ATPase.
  • P-ATPases are much smaller proteins (less
    subunits) than V- and F-ATPases and they have a
    different mechanism.
  • P-ATPases make a flip-flop conformational change
    that exposes ion binding sites to different sides
    of the membrane.
  • They generate transmembrane ion gradients and
    transmembrane voltages.
  • In this way they can energize other transporters
    and, thus, many transport processes.
  • There are several families of P-ATPases
  • Na/K-ATPase (in almost all animal cells)
  • K/H-ATPase (stomach acidification in mammals)
  • Ca2-ATPase (in plasma membranes and in
    endomembranes, e.g. ER)
  • K-ATPase (in plant plasma membranes)

23
Na/K- ATPase
  • Two subunits
  • Operates in membranes as dimer (a2ß2)
  • Translocates 3 Na ions out of the cell in
    exchange for 2 K ions.
  • Na and K distributions across the plasma
    membrane are kept away from diffusional
    equilibrium by the Na/K pump. The energy is
    provided by hydrolysis of ATP.
  • Is electrogenic and contributes to membrane
    voltage (only slightly though 6-15 mV).
  • It is a major part of the energy budget of
    excitable cells, especially small ones.
  • It is inhibited by specific drugs ouabain,
    digitalis and other cardiac glycosides derived
    from plants.

24
The cycle of the Na/K ATPase or Na/K pump
25
Cotransport and exchange gradient-mediated
active transport
  • Examples of cotransporters
  • NK2C cotransporter (renal tubule) Na, K, 2 Cl-,
    inhibited by furosemide-type diuretics
  • NCC Na-amino acid cotransporter (most cells,
    inc. intestinal cells)
  • SGLT Na -coupled glucose transporter 2
    Na/glucose (intestine, renal tubule, blood-brain
    barrier)

26
The Na/glucose cotransporter
27
Examples of countertransporters
  • Na/Ca exchanger (keeps intracellular Ca four
    orders of magnitude lower than extracellular
    Ca)
  • Cl-/HCO3- exchanger transports Cl- into
    cytoplasm in exchange for metabolic HCO3-
  • Na/H exchanger keeps intracellular pH and
    HCO3- above their equilibrium values
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