Excitable cells 1

• Excitable cells


  Cells that can generate action potentials, e.g. neurons and muscle cells
• Overview


  1. Part 1 (today): Why we have excitable cells, The resting membrane potential

  2. Part 2 (today): The action potential (nerve impulse)

  3. Part 3 (next week): Neurotransmission across central synapses and the neuromuscular junction
• Faulty cellular communication


  At the heart of many neurological disorders (e.g. motor neuron disease, multiple sclerosis, depression)
• Better knowledge of cellular communication


  Improves understanding of neurological diseases, why certain drugs are prescribed, patient communication
• Why do cells need to communicate?

  To synchronise events, to integrate function, to adapt to their environment, to turn pathways on and off
• Types of communication


  • Between cells (hormones, neurotransmission, electrical)
  • Within cells (slow, fast)
• Hormonal signalling

  General, slow, sustained, 'ball park' control (e.g. chemical hormones in local or systemic circulation)
• Autocrine signalling


  Occurs in neurons, in the CNS, in the PNS, muscles, smooth, striated
• Electrical signalling


  A form of intracellular communication via rapid changes in membrane potential, local, fast, transient, accurate
• Membrane potential


  The potential difference across the cell membrane, with the inside negative to the outside
• Resting membrane potential


  The voltage across the membrane of an inactive (non-signalling) neuron
• How the resting membrane potential arises

  Cells have a lipid bilayer membrane, the membrane is impermeable to small charged atoms/molecules, but there are pores (ion channels) and pumps embedded in the membrane that are differentially permeable to different ions, ions move across the membrane through passive and active processes
• Crucial ions contributing to the resting potential

  • Sodium (Na+), potassium (K+), negatively charged intracellular proteins and organic phosphates
• Na+ permeability


  There are far fewer channels for Na+, making it relatively impermeable to Na+
• K+ permeability


  There are lots of large anions (A-) fixed inside the cell, allowing K+ to flow out via 'leak channels'
• Na+/K+ ATPase pump


  Pumps Na+ out of the cell and K+ in, requires a lot of energy
• Electrochemical gradient


  Consists of a chemical gradient (concentration difference inside and out) and an electrical gradient (ionic charge difference across the membrane)
• Equilibrium state

  When the electrical and chemical gradients are equal and opposite, resulting in no net movement of ions
• Nernst equation


  Determines the equilibrium potential for an ion present on both sides of a membrane
• Equilibrium potentials


  • EK = -80 mV, ENa = +60 mV, ECl = -65 mV
• Resting membrane potential (RMP)


  The potential across the membrane when the cell is at rest, approximately -70 mV
• Goldmann equation

  Accounts for the differential permeability of the membrane to multiple ions, gives the true resting membrane potential
• The unequal distribution of ions leads to a negative charge inside the cell
• The RMP is maintained by: fixed anions (A-) inside the cell, the active transport of Na+ out of the cell (Na+/K+ ATPase), the high permeability of the membrane to K+ (leak current)
• The action potential


  A rapid, transient change in membrane potential, an all-or-nothing phenomenon
• Voltage-gated ion channels


  Ions cross the membrane through the voltage-gated Na+ channel and the voltage-gated K+ channel, which open at particular voltages
• The voltage-gated Na+ channel (VGSC) opens rapidly when the membrane potential reaches -55 mV, allowing Na+ to rush into the cell down its concentration gradient, causing further depolarization
• Voltage-gated ion channels


  Ions cross the membrane through:
• Voltage-gated ion channels


  • Open at particular voltages (membrane potentials)
  • When open, allow the passage of ions into or out of the cell
  • Are selective for particular ions on the basis of size (e.g. Na+ vs K+) and charge (cation vs anion)
  • Active
  • Inactive
• Not to be confused with the non-gated K+ leak channel or Na+/K+ ATPase pump!
• Voltage-gated Na+ channel (VGSC)

  • When the membrane potential reaches -55 mV, the VGSCs open very rapidly
  • Na+ rushes into the cell down its concentration gradient
  • Causing further depolarization
  • The Na+ channel stays open for less than 1 ms
  • The channel undergoes time-dependent inactivation
  • Na+ is pumped out of the cell causing repolarization
  • The Na+ channel returns to its closed state
• Voltage-gated sodium channels


  • Can exist in three states: open, inactivated, closed
  • voltage-gated, fast
  • time dependent, fast
  • time dependent, slow
• Voltage-gated K+ channel (VGKCs)

  • When the membrane potential reaches -55 mV, VGKCs open (slowly)
  • K+ moves out of the cell down its concentration gradient
  • Causing repolarization
  • When the membrane potential repolarizes to -15 mV, the voltage-gated K+ channels close (slowly)
• Current flow


  • Na+ moves inward increasing membrane potential towards the +ve
  • K+ moves outward decreasing membrane potential
  • The ions are charged so carry current
  • The two currents summate to make the action potential
• Voltage-gated K+ channels


  • Opens slowly
  • K+ moves down its concentration gradient out of the cell
  • The voltage-gated K+ channels close slowly, allowing too much +ve charge to leave the cell
  • This results in the 'after hyperpolarization' (AHP)
• Absolute refractory period


  For a short time after an action potential has been generated, the membrane is incapable of generating another action potential
• • After opening, Na+ channels become inactivated
  • Inactivated channels must return to the closed state before they can open again
• Action potential generation


  1. Stimulation of neurotransmitter receptors (e.g. ligand gated ion channels) around the cell body

  2. Causes small changes in membrane potential called excitatory postsynaptic potentials (EPSPs) or inhibitory postsynaptic potentials (IPSPs)

  3. EPSPs and IPSPs occurring close in time will summate

  4. At threshold (-55mV), VGSCs open
• Action potential initiation


  • An action potential will start when the membrane reaches the threshold for opening of VGSCs
  • Action potentials start at the axon hillock, where there are many VGSCs
• Action potential propagation


  1. Immediately adjacent to a region of depolarized membrane the charge is opposite

  2. Ions move to try to equalise this potential difference along the axon

  3. The adjacent section reaches threshold (-55mV) and Na+ channels open

  4. The region behind the AP is refractory forcing the direction of travel