Signal Transduction Notes

How Does the Signal Work?

Learning Outcomes

  • Describe the ionic changes involved in an action potential.
  • Understand the factors that influence the propagation of an action potential.
  • Understand the two types of refractory periods.
  • Understand what happens at a synapse.
  • Name some examples of neurotransmitters and describe their actions.

Related Module ILOs

  • Understand the structure and function of nerve, bone, and muscular cells and tissues in health and disease.
  • Recognize and apply subject-specific theories, paradigms, concepts, or principles (e.g., concepts of physics and chemistry underlying the function of excitable tissues, mechanical concepts to explain bone function, and different theories about the underlying pathology of neurodegenerative diseases).

Part 1: Membrane Potentials

  • Action Potentials (AP) are created by the movement of cations (Na^+, K^+) across the cell membrane.
  • Ions cross a membrane by:
    • Facilitated Transport (Na^+ and K^+ Leak Channels)
    • Active Transport
  • In a resting cell:
    • K^+ concentration is high inside the cell, with Cl^- contributing to the negative charge.
    • Na^+ concentration is high outside the cell.
  • Na^+/K^+ ATPase Pump:
    • Actively moves 3 Na^+ ions out and 2 K^+ ions into the cell using ATP.
    • Creates concentration gradients.
    • Outside the cell: K^+ (5 mM), Na^+ (140mM)
    • Inside the cell: K^+ (140 mM), Na^+ (15mM)

Resting Membrane Potential

  • The Resting Membrane Potential is the difference in charges between the inside and outside of the cell.
  • In a resting nerve cell, this difference is -70mV, with the outside of the cell being positive.
  • Goldman-Hodgkin-Katz equation:
    • An equation used to calculate the resting membrane potential of a cell.
    • A more complex version of the Nernst Equation.
    • The main difference is that the Nernst equation only considers one ion at a time.

Part 2: Action Potentials

  • Action Potential is the process of depolarization, repolarization, hyperpolarization, and returning to the resting state.
  • Action potential is due to opening and closing of voltage-gated Na^+ and K^+ channels, which respond to the changes in membrane potential.
    1. The Na^+ current depolarizes.
    2. The K^+ current repolarizes and hyperpolarizes.
    3. The Na^+/K^+ pump returns the ion concentration gradients to resting potential.
  • The AP is produced due to the influx (entering) of Na^+ ions and efflux (exiting) of K^+ ions.

Depolarization

  • When the cell is activated, Na^+ gates open.
  • This drives Na^+ ions to move down the gradient (into the cell), making the inside of the cell positive and the outside of the cell negative.
  • The membrane then becomes depolarized.
  • How does local anesthetic lidocaine (lignocaine) work?
    • Lidocaine blocks the Na^+ Channels, preventing the postsynaptic neurons from depolarizing.
    • Without depolarizing, the neuron won’t be able to transmit a signal.
    • This effectively ‘disables ‘the neuron, preventing pain signals from propagating to the brain.

Repolarization

  • The change in action potential signals for the Na^+ channels to close.
  • The K^+ ions rush out of the cell down their concentration gradient.
  • The K^+ ions are released through a delayed rectifier channel.
  • The delay in the channel’s response is what allows for the repolarization.

Hyperpolarization

  • When K^+ ions are leaving out of the cell, some extra leave, reaching a membrane potential of around -85mV.
  • This happens because the K^+ ions are leaving through a delayed rectifier channel which delays closing.
  • The Na^+/K^+ pumps then restore the resting membrane potential of -70mV (repolarization).

Part 3: Refractory Periods

  • Absolute Refractory Period

    • The refractory period is the time taken for the sodium channels to reset.
    • Until then, an action potential is unable to be initiated.
    • To calculate the maximum frequency of AP, we need to find how many cycles (Neuron Refractory Period) can be initiated per second (Hz).
    • Formula: \frac{1 \ cycle}{Refractory \ Period}
    • For example: With a Refractory Period of 1-2ms, what will be the Maximum Frequency of AP?

  • Relative Refractory Period

    • The relative refractory period occurs after the absolute refractory period.
    • During this period, an AP can be initiated as some sodium channels have reset.
    • However, this will require a larger than usual stimulus.

  • On the first graph, the stimulus is just strong enough to trigger an action when the neuron has reached its resting potential.

  • Therefore, a stimulus can only occur after the Neuron refractory period (Absolute Refractory Period + Relative Refractory Period).

  • When a sustained stimulus that can only create an AP when the neuron is completely rested, it will initiate the AP after the RRP.

  • In the second Graph, the stimulus in use is strong enough to initiate an AP during RRP.

  • This means that when this stimulus is sustained (continuous), The AP will activate after each ARP and during RRP.

  • When calculating the Maximum Frequency of AP with a stimulus this strong, the ‘cycle’ in the equation would represent the Absolute Refractory Period only.

AP Propagation

  • Propagation is the spread/transfer of the signal (depolarization) across the cell.
  • In the beginning, a small patch is depolarized (AP initiation).
  • This will create local currents that will spread the depolarization and moving it across the cell.
  • Myelin Sheath:
    • The myelin is a fatty material that surrounds the axons in nerves cells.
    • This material is produced by a glial cell named Schwann cell
    • It wraps around the axon creating an electrical insulation
    • The insulation creates less voltage loss in the propagation and makes it travel faster and further
    • The electrical insulation also reduces energy expenditure as less ions need will pumping back
  • The propagation speed is dependent on the diameter of the axon. The larger the diameter, the faster the conduction velocity.
  • In myelinated axons, the AP is generated in the Nodes of Ranvier (spaces between myelin sheaths) and jump from one node to another at a rapid pace.
  • Diseases
    • Multiple Sclerosis:
      • Immune-mediated disease (Abnormal immune response)
      • Demyelination of axons
      • Slows AP propagation
      • CNS
    • Chronic Guilian Barre Syndrome:
      • Autoimmune disease (Immune system attacks healthy cells)
      • Demyelination of axons
      • Slows AP Propagation
      • Causes Immobility
      • Can recover
      • PNS

Part 4: Synapses

  • Synapses are the areas between one neuron and another (or muscle fibers)
  • Chemical Synapses vs. Electrical Synapse
    • Neurotransmitters (NT) vs. Two neurons linked by gap junctions
    • NT release from vesicles vs. Ions move directly from pre-to post- synaptic neuron
    • NT binds to receptors
  • Chemical Synapses
    • When the AP reaches the axon terminal, Ca^{2+} ions enter the cell through voltage-gate channels that are activated by the AP
    • The Ca^{2+} that entered will cause the synaptic vesicle, that contains the neurotransmitters, to release the NT through exocytosis
    • Neurotransmitters will then bind to ligand-gated ion channels which will allow for the ions to travel through the postsynaptic neuron by allowing the K^+ ions to leave the neuron and Na^+ ions to enter the cell.

Graded Potentials and AP Generation

  • Graded Potentials are generated when ions enter and leave the postsynaptic neuron.
  • These postsynaptic potentials can be Excitatory (EPSP) or Inhibitory (IPSP)
    • EPSP may depolarize a cell by +5mV
    • IPSP may hyperpolarize a cell by -5mV
    • EPSP can cancel out IPSP
    • This allows for summation and decision making
  • Synapses may be excitatory or inhibitory
  • For an AP to occur, the cell must be depolarized by 10mV
  • If the summation of the synapses equaled 10mV or more, an action potential will occur in the axon hillock
  • EPSP & IPSP
    • Neurotransmitters in EPSP open Na^+ and K^+ channels
    • EPSP draw the membrane potential closer to the threshold
    • Neurotransmitters in IPSP open K^+ and Cl^- channels
    • IPSP draw the membrane potential further from the threshold

Part 5: Neurotransmitters

  • Neurotransmitters are molecules that communicate information between neurons and target cells in chemical synapses.

    • Amino Acids
      • Glutamate
      • GABA
      • Glycine
    • Peptides
      • Opioids (Endorphin)
    • Monoamines
      • Serotonin
      • Histamine
      • Catecholamines (NA, A, Dopamine)
    • Other
      • Acetylcholine
    • Function
      • Most Functions
      • Pain
      • Cognitive, Emotion, Attention, ANS
      • Motor Neurons to Skeletal Muscle

  • Acetylcholine

    • Neuromuscular Junction, Parasympathetic NS

  • Glutamate

    • Excitatory, most-used Neurotransmitter in the brain

  • GABA

    • Inhibitory, brain

  • Noradrenaline (Norepinephrine)

    • Stress, Pain Responses, Sympathetic Postganglionic (After Cranial Nerves) Neurons

  • Serotonin

    • Limbic System (Part of the brain responsible for regulating emotions), sleep, mood

  • Dopamine

    • Basal Ganglia (Part of the brain responsible for movement and cognition), Movement patterns

  • Peptides

    • Example: Endorphin: Pain regulation

  • Gases

    • NO (Nitric Oxide) (Memory Formation), CO, H2S

  • Many Others

  • Basal Forebrain and PPN Cholinergic Projections

    • Nucleus Basalis (Group of Neurons in Basal Ganglia) project to the cerebral cortex, limbic system, and motor system
    • Pedunculopontine Nucleus (PPN) (Group of Neurons Located in the upper pons)
    • Disorders
      • Sleep/Wake
      • Alzheimer’s
      • NM Junction Diseases
      • Autonomic Failure

  • Locus Coeruleus NA Projections

    • Locus Coeruleus (Group of neurons in the brainstem That release noradrenaline) projects to the whole CNS, including the SC (Superior Colliculus), responsible for responding to stimulus based on sensory details.
    • Disorders
      • Postural Hypotension
      • Autonomic Failure
      • Depression
      • ADHD

  • Raphe Serotonergic Projections

    • Raphe (Group of Neurons that contain most of the Serotonin-Producing neurons in the Nervous system) projects to the whole CNS, including the SC
    • Disorders
      • Depression
      • Schizophrenia
      • Migraine
      • Anxiety
      • ADHD
      • OCD
      • Nausea

  • Midbrain Dopaminergic Projections

    • Ventral Tegmental Area (VTA) and Substania Nigra pars Compacta (SNc) (Both located at the Top of the Midbrain) project to the frontal cortex and Striatum.
    • Disorders
      • Schizophrenia
      • Control of Pituitary Hormone
      • Vomiting, GI
      • Parkinson’s

Neurotransmitter Removal

  • Diffusion
  • Enzymes that breakdown neurotransmitter (Acetylcholinesterase)
  • Reuptake Pumps
  • Astrocytes (Use transporters, EAAT1 & EAAT2, to remove Glutamate from synapses)
  • Serotonin
    • Serotonin is a neurotransmitter that is important to remove from the synapse after it reacts with receptors because it helps determine the duration and extent of receptor activation.
    • Serotonin is inactivated primarily through reuptake by a plasma membrane serotonin transporter (SERT).
  • Curare
    • Antagonists are molecules which can bind to specific receptors
    • They do not initiate a response
    • Curare binds to the same receptor as Ach
    • This prevents the Ach from binding to its receptors
    • Curare can be used as a muscle relaxant and as paralyzing poison (Blowpipe Darts)