1. Ion Channels John Koester jdk3 References:
4/15/2017
Ion Channels
John Koester
jdk3
References:
•Kandel, Schwartz and Jessell (2000):
Principles of Neural Science, 4th edition, chapter 5
•Hille, B. (2001) Ion Channels of Excitable Membranes,
3rd edition

2. Outline Why ion channels? Channel structure
4/15/2017
Outline
Why ion channels?
Channel structure
Ion channels have three basic functional properties
Conduct
Select
Gate
Evolutionary relationships between ion channels
Various factors contribute to ion channel diversity

3. 4/15/2017
Ions Cannot Diffuse Across the Hydrophobic Barrier of the Lipid Bilayer

4. 4/15/2017
Ion Channels Provide a Polar Environment for Diffusion of Ions Across the Membrane

5. Specialized Functions of Ion Channels
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Specialized Functions of Ion Channels
Mediate the generation, conduction and transmission of electrical signals in the nervous system
Control the release of neurotransmitters and hormones
Initiate muscle contraction
Transfer small molecules between cells (gap junctions)
Mediate fluid transport in secretory cells
Control motility of growing and migrating cells
Provide selective permeability properties important for various intracellular organelles

6. Outline Why ion channels? Channel structure
4/15/2017
Outline
Why ion channels?
Channel structure
Ion channels have three basic functional properties
Conduct
Select
Gate
Evolutionary relationships between ion channels
Various factors contribute to ion channel diversity

7. Channels are Made Up of Subunits
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Channels are Made Up of Subunits

8. Outline Why ion channels? Channel structure
4/15/2017
Outline
Why ion channels?
Channel structure
Ion channels have three basic functional properties
Conduct
Select
Gate
Evolutionary relationships between ion channels
Various factors contribute to ion channel diversity

9. •Ion Channels Act As Catalysts
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Conduction
•Ion Channels Conduct Up to 108 Ions/sec
•Ion Channels Act As Catalysts
•Speed up fluxes
•Do not impart energy
•Driving force is provided by
electrochemical potential
Several orders of mag faster than faster carrier or transporter

10. 4/15/2017
Unlike Channels, Ion Pumps Do Not Provide a Continuous Pathway Through the Membrane
Na+ K+

11. Outline Why ion channels? Channel structure
4/15/2017
Outline
Why ion channels?
Channel structure
Ion channels have three basic functional properties
Conduct
Select
Gate
Evolutionary relationships between ion channels
Various factors contribute to ion channel diversity

12. Ion Channels are Selectively Permeable
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Ion Channels are Selectively Permeable
Cation Permeable
Na+ K+
Ca++
Na+, Ca++, K+
Anion Permeable
Cl -

13. Structure of K+ Channel Has Multiple Functional Adaptations
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Structure of K+ Channel Has Multiple Functional Adaptations
Selectivity
Filter
Alpha helices are polarized, because H-bonds that hold it together act as dipoles

14. Outline Why ion channels? Channel structure
4/15/2017
Outline
Why ion channels?
Channel structure
Ion channels have three basic functional properties
Conduct
Select
Gate
Evolutionary relationships between ion channels
Various factors contribute to ion channel diversity

15. 4/15/2017
Single Channel Openings are All-or-None in Amplitude, With Stochastically Distributed Open and Closed Times
Closed
Open
2 pA
20 msec

16. There are Two Major Types of Gating Actions
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There are Two Major Types of Gating Actions

17. Gating Can Involve Conformational Changes Along the Channel Walls
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Gating Can Involve Conformational Changes Along the Channel Walls

18. Gating Can Involve Plugging the Channel
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Gating Can Involve Plugging the Channel

19. 4/15/2017
Gating Can Result from Plugging by Cytoplasmic or Extracellular Gating Particles

20. There are Five Types of Gating Controls
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There are Five Types of Gating Controls

21. 4/15/2017
1) Ligand Binding
Extracellular
Cytoplasmic

22. 4/15/2017
2) Phosphorylation

23. 4) Mechanical Force-Gated
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3) Voltage-gated
Change Membrane Potential
4) Mechanical Force-Gated
Stretch

24. 5) Temperature-gated Current Temperature (º C.) Cold-Sensitive
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5) Temperature-gated
Current
Cold-Sensitive
Heat-Sensitive
Temperature (º C.)

25. Modifiers of Channel Gating
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Modifiers of Channel Gating

26. Binding of Exogenous Ligands Can Block Gating
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Binding of Exogenous Ligands Can Block Gating
(Curare)
(BTx)
(ACh)

27. Ion Permeation Can be Prevented by Pore Blockers
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Ion Permeation Can be Prevented by Pore Blockers
PCP
Phencyclidine (commonly known as PCP or "angel dust")
Glutamate-Activated Channel

28. Exogenous Modulators Can Modify the Action of Endogenous Regulators
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Exogenous Modulators Can Modify the Action of Endogenous Regulators
Current
Time
Open
Closed
Open
Closed

29. Outline Why ion channels?
4/15/2017
Outline
Why ion channels?
Ion channels have three basic functional properties
Conduct
Select
Gate
Evolutionary relationships between ion channels
Various factors contribute to ion channel diversity

30. Evolution Operates More Like a Tinkerer Than an Engineer
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Evolution Operates More Like a Tinkerer Than an Engineer

31. Ion Channel Gene Superfamilies
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Ion Channel Gene Superfamilies
I) Channels Activated by Neurotransmitter-Binding
(pentameric channel structure):
•Acetylcholine
•GABA
•Glycine
•Serotonin
II) Channels Activated by ATP or Purine Nucleotide- Binding (quatrameric or trimeric channel structure)

32. Ion Channel Gene Superfamilies
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Ion Channel Gene Superfamilies
III) Channels With Quatrameric Structure Related to Voltage-Gated, Cation-Permeant Channels:
A) Voltage-gated:
•K+ permeant
•Na+ permeant
•Ca++ permeant
•Cation non-specific-permeant
B) Cyclic Nucleotide-Gated (Cation non-specific- permeant)
C) TRP Family (Cation Non-specific); Gated by:
• osmolarity
• pH
• mechanical force (hearing, etc.)
• ligand binding
• temperature
D) Channels Activated by Glutamate-Binding •quatrameric channel structure
•cation non-specific permeability

33. Ion Channel Gene Superfamilies
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Ion Channel Gene Superfamilies
IV) “CLC” Family of Cl--Permeant Channels (dimeric structure):
Gated by:
•Voltage
•Cell Swelling
•pH
V) Gap Junction Channels (non-specific permeability; hexameric structure)

34. Outline Why ion channels? Channel structure
4/15/2017
Outline
Why ion channels?
Channel structure
Ion channels have three basic functional properties
Conduct
Select
Gate
Evolutionary relationships between ion channels
Various factors contribute to ion channel diversity

35. Different Genes Encode Different Pore-Forming Subunits
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Different Genes Encode Different Pore-Forming Subunits
Many more channels than genes

36. Different Pore-Forming Subunits Combine in Various Combinations
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Different Pore-Forming Subunits Combine in Various Combinations

37. 4/15/2017
The Same Pore-Forming Subunits Can Combine with Different Accessory Subunits

38. Alternative Splicing of Pre-mRNA
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Alternative Splicing of Pre-mRNA
Hundreds of splice variants in cochlea

39. Post-Transcriptional Editing of pre-mRNA
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Post-Transcriptional Editing of pre-mRNA
Deamination? of adneosine = inosine, changes codon

40. 4/15/2017
Generator Potentials, Synaptic Potentials and Action Potentials All Can Be Described by the Equivalent Circuit Model of the Membrane
PNS, Fig 2-11

41. Equivalent Circuit Model of the Neuron
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Equivalent Circuit Model of the Neuron
The Nerve (or Muscle) Cell can be Represented by a
Collection of Batteries, Resistors and Capacitors

42. The Lipid Bilayer Acts Like a Capacitor
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The Lipid Bilayer Acts Like a Capacitor
Vm = Q/C
∆Vm = ∆Q/C
∆Q must change before
∆Vm can change

43. 4/15/2017
Change in Charge Separation Across Membrane Capacitance is Required to Change Membrane Potential - + + + - - + + - - + + - - + - + - + + - - + - - + - - + + - +

44. The Bulk Solution Remains Electroneutral
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The Bulk Solution Remains Electroneutral
PNS, Fig 7-1

45. Each K+ Channel Acts as a Conductor (Resistance)
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Each K+ Channel Acts as a Conductor (Resistance)
PNS, Fig 7-5

46. 4/15/2017
Ion Channel Selectivity and Ionic Concentration Gradient Result in an Electromotive Force
PNS, Fig 7-3

47. An Ion Channel Acts Both as a Conductor and as a Battery
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An Ion Channel Acts Both as a Conductor and as a Battery
RT [K+]o
EK =
•ln
zF [K+]i
PNS, Fig 7-6

48. 4/15/2017
An Ionic Battery Contributes to VM in Proportion to the Membrane Conductance for that Ion

49. Experimental Set-up for Injecting Current into a Neuron
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Experimental Set-up for Injecting Current into a Neuron
PNS, Fig 7-2

50. Because of Membrane Capacitance, Voltage Always Lags Current Flow
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Because of Membrane Capacitance, Voltage Always Lags Current Flow
t = Rin x Cin t
PNS, Fig 8-3

51. Length Constant l = √rm/ra
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Length Constant l = √rm/ra
PNS, Fig 8-5