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  • Cells are enclosed in a lipid membrane that excludes the internal environment from the external environment; allowing cellular homeostasis
    • Not only do we have different substances inside, but also a different voltage due to ion concentrations
  • Excitable cells are those that use electrical signals to function
    • Neurons in the brain
      • Respond to sensory stimulus with an electrical signal and communicate with each other using electrical signals. Cell bodies grouped into discrete nuclei, with millions of axons projecting to other areas and communicating with them
      • Clinical implications:
        • Diseases – epilepsy (excessive uncontrolled excitations), anxiety, depression, damage due to stroke, schizophrenia etc
        • Drugs – alcohol, sedatives etc
    • Cardiac, skeletal and smooth muscle cells
      • Action potentials cause influx of calcium causing contraction
      • Clinical implications:
        • Diseases – arrhythmia, tachycardia, paralysis, gut spasms
        • Drugs – anti-arrhythmia, anti-hypertensives, muscle relaxants
    • Secretory and absorbing epithlial cells
      • Glands, kidney, lungs, gastro-intestinal tract
        • Electrical signals can cause the release of different secretions, peristalsis
      • Clinical implications:
  • Diseases – diarrhoea, cystic fibrosis (disorder of ion transport), renal disease, saliva, metabolic disorders
  • Drugs – anti-diabetes, diuretics, etc
  • Ventricular muscle AP takes 200-300ms, whereas nerve cell action potentials take about 1ms
    • This is because the ion channels have different gating kinetics
  • Today we focus on about how action potentials are generated and propagate

Ion movement

  • Cell function (electrical signals) are caused by movement of charged ions across cell membranes
    • Controlled by ion concentrations and selective membrane permeability
      • Ion channels are embedded in the lipid bi-layer membrane and selectively allow ions through
  • Balance between moving in and out of a cell
  • What determines whether an ion moves in or out of a cell?
    • The ion must be first allowed to get across (permeate) the membrane via a channel
      • Most ions are soluble and cannot cross the non-polar membrane
    • concentration gradient (chemical force)
    • as ions are charged they are influenced by the electrical potential across a cell membrane (electrical force)
    • electrochemical driving force = chemical + electrical forces on ions

Ion channels

Ions need a water-filled pathway to travel in and out of the cell because of their hydration layer

  • Facilitated diffusion proteins that are embedded and traverse cell membranes
    • Made up of an opening and closing (gating) mechanism that allows/disallows permeation of ions through its aqueous pore
    • Can be selective (selective ion pores) based on various amino acid patterns
  • Allow cells to produce and transducer electrical signals
  • Selectivity filter:
    • GYG amino acid sequence (the K+ channel selectivity sequence)
      • K+ is allowed through this gate, so when it opens, K+ can permeate
  • Gate:
    • Stimulus (eg, acid) causes a conformational change that allows opening of the gate
  • Yeast K+ channel (in mammals as well) is a 4-subunit channel, which is 3 Angstroms, just big enough for a K+ ion to pass through, but without its hydration layer
    • Thus the K+ has to shed water and directly interact with amino acids forming the selectivity filter (GYG). Na+ ions can't interact as well as K+, Cl- can't interact at all and Ca++ is repelled. Thus ion channels achieve selectivity
    • The gate is cone-shaped, and stimulus will open the conical end allowing substances to pass though (changing conformation allows the ion to pass through.) This could be caused by voltage, neurotransmitter, or intracellular messenger (e.g. ADP), or stretch of membrane

Gating of ion channels

  • An open gate is a conducting conformation of the ion channel
    • A closed gate is a non-conducting conformation of the ion channel
  • Methods of gating:
    • Extracellular ligand (A)
    • Intracellular ligand (B)
    • Voltage (C)
    • Stretch
    • Background/leaky channels

What determines whether an ion moves in or out of a cell

  • 1) The ion must be first allowed to get across (permeate) the membrane via a channel. Note that the channel is not directional
  • 2) electrochemical driving force

The electrochemical driving force

  • Chemical
    • Based on concentration gradients
      • Pumps use energy to establish these gradients
    • Eg: Sodium pumps (Na+/K+/ATPase, Na+/K+)
      • Normally in cells there is high K+ in the cell and high Na+ outside
        • Thus, this pump is used to maintain this gradient (pumps Na out and K in)
      • P-type pump
      • Exists in every animal cell, is the most important protein, 50% of ATP in the brain is used to fuel this pump
      • Can be blocked by ouabain and cardiac glycosides like digoxin
      • Uses about 1/2 the ATP in your body
      • Key player in pathophysiology of ischaemia
      • Process:
        • Converts ATP to ADP and causes 2 K+ ions to enter the cell and 3 Na+ ions to leave

Normal concentration gradients for common ions

  • Na high outside, low inside
  • K high inside, low outside
  • Ca high outside, low inside
  • Cl high outside, low inside
  • H+ high inside, low outside

Resting membrane potential

  • Resting membrane potential is generated by the relative concentrations of ions moving in and out of the cell at any time
    • Porous K+ channels:
  • An excess of negative charge forms inside the membrane
  • An excess of positive charge forms outside the membrane
  • The negative potential opposes the efflux of K+ ions
    • Thus the K+ continues to efflux until this negative electrical gradient balances the chemical gradient causing there to be zero net flux
    • Ie: the electrochemical equilibrium is reached where the membrane potential is enough to completely oppose the chemical driving force
  • Even a small change in the [K+] inside and outside will make a strong electrical force. Movement of K+ out will cause inhibition of K+ efflux. This produces an electrochemical equilibrium
    • The size of the electrical force is proportional to the size of the chemical concentration

Equilibrium potential (Nernst potential)

  • z, F, R, T are all constants depending on the surrounding conditions and on the particular ion
  • See equation + remember it
  • For various ions at 37C, we get:
    • Na+ : +67 mV
    • K+ : -98 mV
    • Ca++ : +129 mV
    • Cl- : -90 mV
  • If we only had K-selective channels in the membrane, the potential would be about -98 mV
  • If we only had Na-selective channels, we would get Na rushing in, getting +67 mV

Resting Vm is close to EK+, but not exactly equal

  • Thus nerve cells at rest have a membrane potential that is negative, because we mostly have K+ channels open. Thus the membrane potential is very susceptible to changes in potassium concentration (e.g. epilepsy, kidney disease)

The resting potential

  • The resting potential is determined by the relative balance between the different ions and their electrochemical forces (so Nernst Potential is only good in theory - we have many different types of channels)
    • If cell is only permeable to K+, membrane potential is the equilibrium potential for K+ = -98mV o If cell is only permeable to Na+, membrane potential is the eq. potential for Na+ = +67 mV
      • Thus, if cell is permeable to both, Vm (membrane potential) is somewhere between these
  • Generally, membrane is 100x more permeable to K+ than Na+, thus Vm of rest is low
  • By controlling membrane permeability, membrane potentials can be controlled
    • Ie: duration, level, range etc and thus cell function controlled
  • Resting membrane potential is largely dependent on K+ permeability
    • Ie: as external [K+] is changed, Vm often follows the EK except at low K+ concentration
  • Vm can be formulated by the Goldman-Hodgkin Katz (GHK) equation (weighted average of all their Nernst potentials):

Gating of Ion Channels

Changing between non-conducting to conducting conformations (to propagate an action potential)

  • Main modes of gating:
    • extracellular ligand (A)
      • (eg LGICs at synapses)
    • intracellular ligand (B)
      • (eg, cyclic nucleotide channels, ATP- sensitive K+ channels)
    • voltage (C)
      • (Vdep Na+, K+, Ca2+ and Cl channels)
    • stretch
      • (cation, Ca2+, Cl-)
    • background or leak channels
      • (typically K+ or Cl-)

Voltage gated channels and the action potential

  • Fastest gate to open is the voltage-gated Na channel, so we'll get depolarisation (because of the resting potential of Na)
    • Sodium ions would rush in until it reaches about +67 mV, but a second gate stops the Na rushing in (want very brief action potentials)
  • Voltage-dependent K channel is a bit slower, but once it's open, it aims for -98mV, so K+ flows out. This causes repolarisation of membrane potential, overshooting resting value (hyperpolarisation).
  • Then the two populations of channels close and we get our resting state

Brian’s ward

  • Stroke causes:
    • a lack of blood O2
      • decreased ATP
        • thus, reduced ion channel activity
    • thus, increased extracellular K+ and decreased intracellular K+
    • also: pH changes including adenosine and decreased ATPase activity
  • This affects membrane potentials:
    • At rest, K+ efflux is normally due to electrochemical forces, so with increased extracellular K+, there is reduced chemical driving forces resulting in more intracellular K+
      • Thus the membrane is more positive (depolarised), because we'll have less electrochemical driving force for K+ efflux
  • Depolarisation causes:
    • Voltage dependent channels to be activated
    • And thus, increased transmitter release

Mechanisms for excitotoxicity

  • Glutamate transporter is fuelled by Na+ influx and K+ efflux, to suck in glutamate. So our glutamate transporter is reversed, so you get Glu buidup in synapses, activating NMDA receptors.
  • Na-Ca exchanger uses the electrochemical driving force to push out Ca. If the Na/K ATPase is not working, then we get Ca buildup inside cells, which can be a bad thing in too high levels

Important concepts

  • Steady state vs equilibrium
    • At rest, there is a steady state by it is not equilibrium. There is a still a driving force but no net current flow because there is still some K+ and Cl- efflux and Na+ influx
  • Concentrations of Na+ or K+ ions during action potentials
    • Do not change significantly and are often recovered quickly via pumps o Ca2+ is the exception because it has a low intracellular concentration
      • Thus, larger concentration changes can result from smaller volumes and pumps are required to quickly reset concentrations