Overview
This lecture covers two linked topics: how action potentials propagate along an axon, including the effect of diameter and myelin on conduction speed and the specific mechanism of saltatory conduction, and how information is passed on at the chemical synapse, including the two families of postsynaptic receptor, the drug and toxin targets found along that pathway, and the main neurotransmitter classes.
Action Potential Recap and Refractory Periods
- Action potentials are initiated at the axon hillock/initial segment.
- A depolarizing local potential can open voltage-gated Na+ channels; Na+ channel opening drives further depolarization, and once enough channels open at the initial segment, a large population opens together, producing a sudden large Na+ influx.
- The events that produce the AP waveform, in order: Na+ channel opening, Na+ current (depolarization to a peak near +30 mV), Na+ channel closing, K+ channel opening, K+ current (repolarization), K+ channel closing.
- Absolute refractory period: no stimulus, however large, can generate another AP, because voltage-gated Na+ channels are inactivated.
- Relative refractory period: an AP can be generated, but only by a very large stimulus, because the depolarizing effect of the stimulus is dampened by the relatively high K+ permeability at this time.
- The refractory period behind an active region is what prevents the AP from propagating backwards.
Propagation Along Unmyelinated Axons
- As an AP develops at one segment (depolarizing it to +30 mV), Na+ ions spreading from the open channels produce a graded, local depolarization that quickly brings the next segment to threshold.
- An AP then develops at that next segment while the previous segment begins repolarizing and becomes refractory.
- This repeats segment by segment along the axon. Propagation is unidirectional because the region just behind the active zone is in the absolute refractory period and cannot be re-excited.
- This is continuous conduction: every patch of membrane along the axon must be depolarized in turn.
- Increasing axon diameter reduces resistance to current flow along the axon, so conduction velocity increases with diameter, but even large-diameter unmyelinated axons stay under about 30 m/sec.
- Two problems with relying on diameter alone: the membrane still leaks current, and continuous conduction is still required at every point along the axon.
Myelination and Saltatory Conduction
- Myelination increases axon insulation, which increases membrane resistance (), reduces membrane capacitance, and further reduces current leak. Myelination is a bigger contributor to conduction speed than diameter, though both are relevant.
- Myelinated axons reach far higher conduction velocities at much smaller diameters than unmyelinated axons (up to roughly 100 m/sec at about 12 μm diameter, versus unmyelinated axons remaining below about 30 m/sec even at diameters over 800 μm).
- In a myelinated axon, current cannot flow across the insulated internodal membrane, so the local current produced at one node spreads electrotonically (very fast) under the myelin to the next node of Ranvier, bringing it to threshold; an AP then develops at that node while the previous node repolarizes and becomes refractory.
- This node-to-node pattern is called saltatory (“jumping”) conduction: the AP appears to jump from node to node, because the fast electrotonic spread under each internode is followed by only a brief active step at each node.
- Saltatory conduction is much faster than continuous conduction, and allows high conduction velocity in axons of relatively small diameter, so many more axons can be packed into a given axon tract.
Consequences of Demyelination
- Demyelinating conditions include Guillain-Barré syndrome, multiple sclerosis, and trauma.
- Normal conduction produces an evenly spaced train of action potentials as the impulse passes each node of Ranvier through intact myelin.
- Demyelinated conduction produces five possible consequences:
- Decreased conduction velocity
- Frequency-related block
- Total conduction block
- Ectopic impulse generation
- Increase in mechanosensitivity
Synapse Structure and the Sequence of Chemical Transmission
- The presynaptic bouton contains synaptic vesicles clustered near actin filaments, with a Ca2+ channel and docking/fusion proteins concentrated at the active zone (dense projection) facing the synaptic cleft; vesicle membrane is recycled via an endosome and clathrin-coated pits.
- Postsynaptic receptors for the neurotransmitter sit on the postsynaptic membrane across the cleft.
- Sequence of events at a chemical synapse:
- Neurotransmitter molecules are synthesized and packaged into vesicles.
- An action potential arrives at the presynaptic terminal.
- Voltage-gated Ca2+ channels open and Ca2+ enters.
- The rise in Ca2+ triggers fusion of synaptic vesicles with the presynaptic membrane.
- Transmitter molecules diffuse across the synaptic cleft and bind specific receptors on the postsynaptic cell.
- Bound receptors activate the postsynaptic cell.
- The neurotransmitter is broken down, taken up by the presynaptic terminal or other cells, or diffuses away from the cleft.
Postsynaptic Receptors: Ionotropic and Metabotropic
- Ionotropic receptors: the receptor is also the ion channel. When no ligand is bound the channel is closed; neurotransmitter binding opens the channel directly and ions flow across the membrane.
- Metabotropic (G-protein-coupled) receptors: not just ion channels, they also engage biochemical pathways, and can either excite or inhibit the postsynaptic cell. Used by acetylcholine, biogenic amines, neuropeptides and purines. Sequence: neurotransmitter binds the receptor, a G protein is activated, G protein subunits or intracellular messengers modulate a separate ion channel protein, the channel opens, and ions flow across the membrane.
- Acetylcholine acting through the two receptor types produces opposite effects in different tissues:
- Skeletal muscle: ACh acts on the nicotinic ACh receptor channel (ionotropic), directly activating the channel, depolarizing the membrane, and triggering an action potential and muscle contraction.
- Atrial muscle: ACh acts on the muscarinic ACh receptor (metabotropic) via a heterotrimeric G protein; release of the beta-gamma subunit activates an inward rectifier K+ channel, hyperpolarizing the membrane and decreasing heart rate.
Synaptic Targets of Drugs and Toxins
Chemical neurotransmission allows more sophisticated signal processing than direct electrical transmission, and its individual steps are targets for toxins and for therapeutic drugs, illustrated on a cholinergic synapse:
- Neuronal Na+ channel: blocked by tetrodotoxin, saxitoxin
- K+ channel: blocked by dendrotoxin
- Ca2+ channel: blocked by omega-conotoxin
- ACh release: blocked by tetanus toxin, botulinum toxin
- Muscle Na+ channel: blocked by tetrodotoxin, saxitoxin, mu-conotoxin
- AChR channel: agonists acetylcholine and nicotine; antagonists d-tubocurarine and alpha-bungarotoxin
- Acetylcholinesterase: inhibited by physostigmine, DFP
Therapeutic examples given: serotonin uptake blockers in depression, and acetylcholinesterase inhibitors in myasthenia gravis (MG).
Neurotransmitters and Neuropeptides
Neurotransmitter classes and example sites of action:
- Small molecule
- Acetylcholine: brain, NMJ, autonomic endings, basal ganglia, GI tract
- Amino acids (glutamate, GABA, glycine): brain, spinal cord, retina
- Biogenic amines (adrenaline, noradrenaline, dopamine, serotonin, histamine): brain, spinal cord, sympathetic endings
- Purines (ATP, adenosine): brain, autonomic ganglia
- Peptide: brain, spinal cord, pituitary gland
- Gas (nitric oxide, carbon monoxide): brain, spinal cord, GI tract
The neurotransmitter table's own cross-reference for peptide examples points to "Slide 15", which does not match this note's slide numbering (slide 15 here covers saltatory conduction). The peptide examples the table is pointing to are the neuropeptide table below.
Neuropeptide examples by class:
- Hypothalamic hormones: CRH, GHRH, GnRH (LHRH), oxytocin, somatostatin, TRH, vasopressin
- Neuropeptide Y
- Opioid peptides: beta-endorphin, dynorphin, leu-enkephalin, met-enkephalin
- Tachykinins: neurokinin alpha, neurokinin beta, neuropeptide K, substance P
- VIP-glucagon family: GLP-1, peptide histidine-leucine, PACAP, VIP
- Others: alpha-MSH, ACTH, BNP, CCK, galanin, hypocretin/orexin, insulin, motilin, neurotensin, PrP, secretoneurin, urocortin
Self-test
- Describe the sequence of channel events that produces the depolarizing and repolarizing phases of an action potential.
- Distinguish the absolute refractory period from the relative refractory period, and explain how the refractory period enforces unidirectional propagation.
- Describe, step by step, how an action potential propagates along an unmyelinated axon.
- Explain why conduction velocity increases with axon diameter in unmyelinated axons, and state the two problems with relying on diameter alone.
- Describe the three membrane changes produced by myelination that increase conduction velocity.
- Explain what is meant by saltatory conduction and why it is faster than continuous conduction.
- List the five consequences of axon demyelination described in the lecture.
- List, in order, the seven steps of chemical synaptic transmission from neurotransmitter synthesis to its removal from the synaptic cleft.
- Distinguish ionotropic from metabotropic postsynaptic receptors in terms of structure and mechanism.
- Using the acetylcholine example, explain how the same neurotransmitter produces contraction at the skeletal neuromuscular junction but a decrease in heart rate at the atrium.
- Name a toxin or drug that blocks each of: the neuronal Na+ channel, the presynaptic Ca2+ channel, and the muscle AChR channel.
- Give one therapeutic example of a drug class targeting the synapse in depression and one targeting the synapse in myasthenia gravis.
- List the classes of neurotransmitter presented in the lecture (including the small-molecule subtypes), with one example from each.
- A patient has progressive limb weakness with reduced conduction velocity on nerve conduction studies and no evidence of axon damage. Which process discussed in this lecture is most likely disrupted, and what would you predict happens to a train of closely spaced action potentials at the affected site?
Answers
Reveal answers
- A depolarizing local potential opens voltage-gated Na+ channels; enough Na+ channel opening drives further depolarization until a large population opens together, producing a rapid Na+ influx (Na+ current) that gives the rising phase to about +30 mV. This is followed by Na+ channel closing and K+ channel opening (K+ current), producing repolarization, then K+ channel closing.
- Absolute refractory period: no stimulus, however large, can generate another AP, because voltage-gated Na+ channels are inactivated. Relative refractory period: an AP can be generated, but only by a very large stimulus, because the stimulus’s depolarizing effect is dampened by the relatively high K+ permeability at that time. Because the membrane just behind an active region is refractory, it cannot be re-excited, so the AP can only move forward.
- As an AP develops at one segment (depolarizing it to +30 mV), Na+ ions spreading from the open channels produce a graded local depolarization that brings the next segment to threshold; an AP develops there while the previous segment begins repolarizing and becomes refractory. This repeats segment by segment, always moving forward because the preceding segment is refractory.
- Increasing diameter reduces resistance to current flow along the axon, so conduction velocity increases. Problems: the membrane still leaks current, and continuous conduction is still required, i.e. every patch of membrane must be depolarized in turn.
- Myelination increases axon insulation, which increases membrane resistance (), reduces membrane capacitance, and reduces current leak.
- Saltatory conduction is where the action potential appears to “jump” from node of Ranvier to node of Ranvier: electrotonic spread of current along the internodal region under the myelin is very fast, so conduction is much faster than continuous (unmyelinated) conduction, and it allows high conduction speed in axons of relatively small diameter.
- Decreased conduction velocity; frequency-related block; total conduction block; ectopic impulse generation; increase in mechanosensitivity.
- (1) Neurotransmitter is synthesized and packaged into vesicles. (2) An action potential arrives at the presynaptic terminal. (3) Voltage-gated Ca2+ channels open and Ca2+ enters. (4) The rise in Ca2+ triggers fusion of vesicles with the presynaptic membrane. (5) Transmitter diffuses across the synaptic cleft and binds specific receptors on the postsynaptic cell. (6) Bound receptors activate the postsynaptic cell. (7) The neurotransmitter is broken down, taken up by the presynaptic terminal or other cells, or diffuses away from the cleft.
- Ionotropic receptors: the receptor protein is itself the ion channel, so neurotransmitter binding directly opens the channel. Metabotropic (G-protein-coupled) receptors: the receptor and the ion channel are separate proteins linked by a heterotrimeric G protein; neurotransmitter binding activates the G protein, whose subunits or intracellular messengers modulate the separate channel, opening it indirectly. Metabotropic receptors can be excitatory or inhibitory.
- At the neuromuscular junction, ACh acts on the nicotinic ACh receptor channel (ionotropic), directly opening the channel, depolarizing the membrane and triggering an action potential and contraction. At the atrium, ACh acts on the muscarinic ACh receptor (metabotropic); its G protein’s beta-gamma subunit activates an inward rectifier K+ channel, hyperpolarizing the membrane and decreasing heart rate. The opposite effects arise because the same transmitter acts on different receptor types coupled to different downstream channels.
- Neuronal Na+ channel: tetrodotoxin or saxitoxin. Presynaptic Ca2+ channel: omega-conotoxin. Muscle AChR channel: d-tubocurarine or alpha-bungarotoxin (antagonists).
- Serotonin uptake blockers are used in depression; acetylcholinesterase inhibitors are used in myasthenia gravis.
- Small molecule: acetylcholine (example: acetylcholine itself); amino acids (e.g. glutamate, GABA or glycine); biogenic amines (e.g. dopamine, noradrenaline, adrenaline, serotonin or histamine); purines (e.g. ATP or adenosine). Peptide (e.g. substance P or vasopressin). Gas (e.g. nitric oxide or carbon monoxide).
- This presentation suggests demyelination (as seen in conditions such as Guillain-Barré syndrome or multiple sclerosis) rather than axonal damage. For a train of closely spaced action potentials, demyelination would be expected to produce frequency-related block, in addition to the general decrease in conduction velocity.