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Ion Channels

Ion Channels

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Ion Channels

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  1. John Koester jdk3 Ion Channels 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 • Ion channels have three basic functional properties • Conduct • Select • Gate • Evolutionary relationships between ion channels • Various factors contribute to ion channel diversity

  3. Ions Cannot Diffuse Across the Hydrophobic Barrier of the Lipid Bilayer

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

  5. 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 • 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

  8. 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 Conduction •Ion Channels Conduct Up to 108 Ions/sec •Speed up fluxes •Do not impart energy •Driving force is provided by electrochemical potential

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

  11. 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 Cation Permeable Na+ K+ Ca++ Na+, Ca++, K+ Anion Permeable Cl -

  13. Structure of K+ Channel HasMultiple Functional Adaptations Selectivity Filter

  14. 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. 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

  17. Gating Can Involve Conformational Changes Along the Channel Walls

  18. Gating Can Involve Plugging the Channel

  19. Gating Can Result from Plugging by Cytoplasmic or Extracellular Gating Particles

  20. There are Five Types ofGating Controls

  21. 1) Ligand Binding Extracellular Cytoplasmic

  22. 2) Phosphorylation

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

  24. 5) Temperature-gated Current Cold-Sensitive Heat-Sensitive 20 25 30 35 40 45 50 Temperature (º C.)

  25. Modifiers of Channel Gating

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

  27. Ion Permeation Can be Prevented by Pore Blockers PCP Glutamate-Activated Channel

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

  29. 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 TinkererThan an Engineer

  31. 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 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 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 • 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

  36. Different Pore-Forming Subunits Combine in Various Combinations

  37. The Same Pore-Forming Subunits CanCombine with Different Accessory Subunits

  38. Alternative Splicing of Pre-mRNA

  39. Post-Transcriptional Editing of pre-mRNA

  40. 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 The Nerve (or Muscle) Cell can be Represented by a Collection of Batteries, Resistors and Capacitors

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

  43. Change in Charge Separation AcrossMembrane Capacitance is Required to Change Membrane Potential + - + + - - + + - - + + - - + - + - + + - - - - + + - - + + - +

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

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

  46. 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 RT [K+]o •ln EK= zF [K+]i PNS, Fig 7-6

  48. An Ionic Battery Contributes to VM in Proportion to theMembrane Conductance for that Ion

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

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