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The neuronal membrane at rest

The neuronal membrane at rest. Introduction. A simple reflex requires the nervous system to collect, distribute, and integrate information! Conducting information over a

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The neuronal membrane at rest

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  1. The neuronal membrane at rest

  2. Introduction • A simple reflex requires the nervous system to collect, distribute, and integrate information! • Conducting information over a distance is possible by using electrical signals • Constraints on nervous system • Ions, instead of electrons • Myelin, instead of rubber insulation • Salty extracellular fluid, instead of air • Problems with Low conductivity, leaky passive conduction are overcome by generating nerve impulse, or action potential (AP) • Do not diminish over distance • Fixed size and duration • Information is encoded by the frequency and pattern of firings • AP generating cells have excitable membrane that has the difference in electrical charges across when at rest (resting membrane potential)

  3. The Cast of Chemicals • Cytosolic and Extracellular Fluid • Water • Key ingredient in intracellular and extracellular fluid • Key feature – water is a polar solvent that has uneven distribution of electrical charge

  4. The Cast of Chemicals • Ions: Atoms or molecules with a net electrical charge • Ionic bond between cations (positive charge) and anions (negative charge) can be broken in water because the charged portions of the water molecules have a stronger attraction for the ions • Spheres of hydration : clouds of water that surround each ion

  5. The Cast of Chemicals • The Phospholipid Membrane • Hydrophilic • Dissolve in water due to uneven electrical charge (e.g., salt) • Hydrophobic • Does not dissolve in water due to even electrical charge (e.g., oil) • Lipids are hydrophobic • Contribute to resting and action potentials • The Phospholipid Bilayer

  6. The Cast of Chemicals • Protein • The type and distribution of protein molecules distinguish neurons from other types of cells • Enzymes • Cytoskeletal elements • Receptors • Special transmembrane proteins

  7. The Cast of Chemicals • Channel Proteins • Having polar groups at each end and nonpolar groups in the middle, these can be suspended in a phopspholipid bilayer • Ion channels are formed from 4-6 similar protein molecules to form a pore • Two important features • Ion selectivity • the diameter of pore • The nature of R groups lining the pore • Gating • Open/closure is regulated by changes in the local microenvironment of the membrane • Ion pumps • Enzymes that use the energy released by the breakdown of ATP to transport certain ions across the membrane • Forms concentration gradient

  8. The Movement of Ions • Diffusion • Dissolved ions are in constant motion in temperature-dependent and random fashion to distribute themselves evenly in the solution • Ions flow down concentration gradient (diffusion) across a phospholipid bilayer when: • Channels are permeable to specific ions • Concentration gradient across the membrane exists

  9. The Movements of Ions • Electricity • Electrically charged particles move in electric field • Electrical current (I), measured in units called amperes (amps) • Defined to be positive in the direction of positive charge movement • Two factors that determine the current • Electrical potential (=voltage, V), measured in units called volts : the force exerted on a charged particle : reflects the difference in charge between the anode and cathode • Electrical conductance (g), measured in units called siemens (S) : the relative ability of an electrical charge to migrate : depends on the number of particles available to carry electrical charge and the ease with which these particles can travel through space

  10. The Movements of Ions • Electricity • Electrical resistance (R) • the relative inability of an electric charge to migrate • measured in units called ohms (W) • simply the inverse of conductance (R = 1/g) • Ohm’s law • I = gV Large V but g=0 I>0 due to channels

  11. The Ionic Basis of The Resting Membrane Potential • Membrane potential: • Voltage across the neuronal membrane (Vm) • Measured by microelectrode • The inside of the neuron is electrically negative with respect to the outside • When the neuron is not generating impulses, the membrane potential (i.e. resting membrane potential) is maintained • Typically for a neuron at rest, Vm = -65 mV

  12. The Ionic Basis of The Resting Membrane Potential • Equilibrium Potential (Eion) • No net movement of ions when separated by a phospholipid membrane : large concentration gradient but no potential • Equilibrium reached when K+ channels are inserted into the phospholipid bilayer • Initially, diffusion rules! • Due to the impermeable A-, net negative charges accumulate inside • Electrical potential difference that exactly balances ionic concentration gradient : ionic equilibrium potential

  13. The Ionic Basis of The Resting Membrane Potential • Equilibrium Potentials • Four important points • Large changes in Vm are caused by minuscule changes in ionic concentrations • For a cell of 50um diameter containing 100mM K+, 0.00001 mM concentration change could take Vm from 0 to -80 mV • Net difference in electrical charge occurs at the inside and outside surfaces of the membrane • Localized charge distribution due to electrostatic interactions • Capacitance : charge storing (on the membrane) measured in units called farad (F) • Rate of movement of ions across membrane is proportional to the difference between the membrane potential and the equilibrium potential (Vm - Eion, ionic driving force) • If concentration difference across the membrane for a given ion is known, • Equilibrium potential can be calculated : Roughly by just the direction of initial movement : Exactly by the Nernst equation

  14. The Ionic Basis of The Resting Membrane Potential • The Nernst Equation • Takes into consideration: • Charge of the ion • Temperature • Ratio of the external and internal ion concentrations • Eion = 2.303 (RT/zF) log([ion]o / [ion]I) • R = gas costant (8.314 J/mol K) • T = absolute temperature (310K at 37oC) • z = charge of the ion • F = Faraday’s constant (96,485 C/mol e-) • [ion]o = ionic concentration outside the cell • [ion]I = ionic concentration inside the cell • 2.303 RT/F = 61.54 mV (at 37oC)

  15. The Ionic Basis of The Resting Membrane Potential • The Distribution of Ions Across The Membrane • Membrane potential depends on the ionic concentrations on either side of membrane • K+ more concentrated on inside, Na+ and Ca2+ more concentrated outside • the ionic concentration gradient is established by the actions of ion pumps

  16. The Ionic Basis of The Resting Membrane Potential • The sodium-potassium pump • breaks down ATP when Na+ is present inside • this chemical energy is used to exchange internal Na+ for external K+ against their concentration gradients • expends as much as 70% of the total amount of ATP utilized by the brain • The calcium pump • Actively transports Ca2+ out of cytosol • Additional mechanisms decrease intracellular [Ca2+] to a very low level (0.0002 mM) • Intracellular calcium-binding proteins • Calcium sequestering organelles such as smooth ER or mitochondria

  17. The Ionic Basis of The Resting Membrane Potential • Relative Ion Permeabilities of the Membrane at Rest • Neurons permeable to more than one type of ion • Relative membrane permeability determines membrane potential • EK = -80 mV and ENa = 62 mV • If their relative permeabilities are equal, the resulting membrane potential will be some averagge between -80 mV and 62 mV • If the membrane is much more permeable to K+, the membrane potential will be closer to EK, which is the actual case (-65 mV is the normal resting potential of neurons) • Goldman equation • Takes into account relative permeability of membrane to different ions • Vm = 61.54 mV log (PK[K+]o +PNa[Na+]o+PCl[Cl-]i) / (PK[K+]i +PNa[Na+]I+ PCl[Cl-]o) • -65 mV is achieved when K+ is about 40 times more permeable than Na+

  18. The Ionic Basis of The Resting Membrane Potential • Potassium channels • Selective permeability of potassium channels is a key determinant in resting membrane potential • Molecular basis for the ion selectivity - lining of pore • Lily & Yuh Nung Jan: cloning of Shaker was a major breakthrough • The amino acid sequence identification of potassium channel led to the finding of other potassium channels : a very large number of different potassium channels exist • Selectivity filter • pore loop region is the key to the K+ selectivity • Common structural feature • Roderick MacKinnon solved the atomic structure to reveal the physical basis of ion selectivity and was awarded with 2003 Nobel Prize in Chemistry

  19. The Ionic Basis of The Resting Membrane Potential • The importance of regulating the external potassium concentration • Resting membrane potential is close to EK because it is mostly permeable to K+ • Membrane potential is particularly sensitive to extracellular [K+] • Increased extracellular K+ depolarizes membrane potential • Evolution of tight regulation mechanisms of extracellular potassium concentration in the brain • Blood-brain barrier limits the movement of potassium • Astrocytes have membrane potassium pumps that concentrate intracellular [K+] • [K+]i is dissipated over a large area • Potassium spatial buffering • Lethal KCl injection depolarization

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