1/3/2005. Ion Channels. Outline. Specialized Functions of Ion Channels. Outline

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1 References: Ion Channels John Koester jdk3 Kandel, Schwartz and Jessell (2000): Principles of Neural Science, 4th edition, chapter 5 Hille, B. (2001) Ion Channels of Excitable Membranes, 3rd edition Ions Cannot Diffuse Across the Hydrophobic Barrier of the Lipid Bilayer Ion Channels Provide a Polar Environment for Diffusion of Ions Across the Membrane 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 1

2 Channels are Made Up of Subunits Conduction Unlike Channels, Ion Pumps Do Not Provide a Continuous Pathway Through the Membrane Ion Channels Conduct Up to 10 8 Ions/sec Ion Channels Act As Catalysts Speed up fluxes Do not impart energy Na K Driving force is provided by electrochemical potential Ion Channels are Selectively Permeable Cation Permeable Na K Ca Na, Ca, K Anion Permeable Cl 2

3 Structure of K Channel Has Multiple Functional Adaptations Selectivity Filter Single Channel Openings are AllorNone in Amplitude, With Stochastically Distributed Open and Closed Times Closed There are Two Major Types of Gating Actions Open 2 pa 20 msec Gating Can Involve Conformational Changes Along the Channel Walls Gating Can Involve Plugging the Channel 3

4 Gating Can Result from Plugging by Cytoplasmic or Extracellular Gating Particles There are Five Types of Gating Controls 1) Ligand Binding 2) Phosphorylation Extracellular Cytoplasmic 3) Voltagegated Change Membrane Potential 5) Temperaturegated 4) Mechanical ForceGated Stretch Current ColdSensitive HeatSensitive Temperature (º C.) 4

5 Binding of Exogenous Ligands Can Block Gating (Curare) Modifiers of Channel Gating (ACh) (BTx) Ion Permeation Can be Prevented by Pore Blockers Exogenous Modulators Can Modify the Action of Endogenous Regulators Current PCP Time Open Closed Open GlutamateActivated Channel Closed Evolution Operates More Like a Tinkerer Than an Engineer 5

6 Ion Channel Gene Superfamilies I) Channels Activated by NeurotransmitterBinding (pentameric channel structure): Acetylcholine GABA Glycine Serotonin II) Channels Activated by ATP or Purine Nucleotide Binding (quatrameric or trimeric channel structure) Ion Channel Gene Superfamilies III) Channels With Quatrameric Structure Related to VoltageGated, CationPermeant Channels: A) Voltagegated: K permeant Na permeant Ca permeant Cation nonspecificpermeant B) Cyclic NucleotideGated (Cation nonspecificpermeant) C) TRP Family (Cation Nonspecific); Gated by: osmolarity ph mechanical force (hearing, etc.) ligand binding temperature D) Channels Activated by GlutamateBinding quatrameric channel structure cation nonspecific permeability Ion Channel Gene Superfamilies IV) CLC Family of Cl Permeant Channels (dimeric structure): Gated by: Voltage Cell Swelling ph V) Gap Junction Channels (nonspecific permeability; hexameric structure) Different Genes Encode Different PoreForming Subunits Different PoreForming Subunits Combine in Various Combinations 6

7 The Same PoreForming Subunits Can Combine with Different Accessory Subunits Alternative Splicing of PremRNA PostTranscriptional Editing of premrna Generator Potentials, Synaptic Potentials and Action Potentials All Can Be Described by the Equivalent Circuit Model of the Membrane PNS, Fig 211 Equivalent Circuit Model of the Neuron The Lipid Bilayer Acts Like a Capacitor V m = Q/C V m = Q/C The Nerve (or Muscle) Cell can be Represented by a Collection of Batteries, Resistors and Capacitors Q must change before V m can change 7

8 Change in Charge Separation Across Membrane Capacitance is Required to Change Membrane Potential The Bulk Solution Remains Electroneutral PNS, Fig 71 Each K Channel Acts as a Conductor (Resistance) Ion Channel Selectivity and Ionic Concentration Gradient Result in an Electromotive Force PNS, Fig 75 PNS, Fig 73 An Ion Channel Acts Both as a Conductor and as a Battery An Ionic Battery Contributes to V M in Proportion to the Membrane Conductance for that Ion PNS, Fig 76 E K = RT [K ] ln o zf [K ] i 8

9 Experimental Setup for Injecting Current into a Neuron Because of Membrane Capacitance, Voltage Always Lags Current Flow τ = R in x C in τ PNS, Fig 72 PNS, Fig 83 Length Constant λ = r m /r a PNS, Fig 85 9