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How Do Neurons Transmit Informa3on?
Important parts of the process:
Biological Membranes
• The membrane of a neuron is a lipid bilayer.
• The membrane is semi-‐permeable -‐ this is cri3cal for producing a difference in poten3al (electrical charge) across the membrane
• This poten3al difference is produced by ions
– Ca3ons: posi3vely charged ions (ex. Sodium = Na+, Potassium = K+)
– Anions: nega3vely charged ions (ex. Chloride = Cl-‐)
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Biological Membranes
• The neuronal membrane has proteins embedded in it:
• Ion Channels (channel proteins = doorways): allow selected ions to pass in and out of a cell (ex. Na+, K+, Ca++, Cl-‐)
• Receptors: site where neurotransmiPer binds, causing an immediate (ion channels open) or delayed (intracellular signaling is ac3vated as with a signal protein) effect
• Ac3ve transporters: pull certain substances into the cell (ex. glucose, reuptake of neuro-‐transmiPers)
The Res3ng Membrane Poten3al
• Membrane Poten3al – the difference in electrical charge
between the inside and outside of a membrane
• Res3ng Membrane Poten3al – In the res3ng state:
• more Na+ and Cl-‐ ions are outside
• more K+ ions and nega3vely charged proteins are on the inside
Copyright 2001
Allyn & Bacon
Neuron at Rest
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The Res3ng Membrane Poten3al
• It’s between -‐60 and -‐70mV for most neurons
• The inside of the neuron is nega3ve rela3ve to the outside
Forces That Maintain the Res3ng Membrane Poten3al:
• Concentra3on Gradient: Na+ more concentrated outside the cell, tends to drive it into the cell. What about K+?
• Electrical gradient: more posi3ve charge outside the cell tends to drive Na+ into the cell. What about K+?
Copyright 2001 Allyn & Bacon Copyright 2001 Worth Publishers
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Forces That Maintain the Res3ng Membrane Poten3al:
• Differen3al (selec3ve permeability): In res3ng neurons, K+ and Cl-‐ ions pass through the membrane easily, Na+ with difficulty, and proteins-‐ not at all.
• Sodium-‐potassium pumps (use cellular energy): 3 Na+ ions are pumped out for every 2 K+ ions pumped in.
Copyright 2001 Allyn & Bacon Copyright 2001 Worth Publishers
Passive and Ac3ve Forces Maintain the Res3ng Poten3al
• Passive -There is a small, passive leak of K+ out of the cell (K+ 20X more concentrated inside the cell); there are large numbers of negatively charged amino acids/proteins that can’t move out of the cell (about 100X more concentrated inside the cell – this is a large reserve of negative charge)
• Active (uses cellular energy) - Sodium-potassium pump actively maintains the unequal distribution of positive ions across the membrane: 3 Na+ ions out /2 K+ ions in
Copyright 2001 Allyn & Bacon Copyright 2001 Worth Publishers
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The Res3ng Membrane Poten3al
• A very nice web-‐based anima3on showing how this comes about can be found at:
• hPp://bcs.whfreeman.com/thelifewire/content/chp44/4402001.html (for PC)
• hPp://bcs.whfreeman.com/thelifewire/content/chp44/4401s.swf (for MAC)
Graded Poten3als
• Neurons release chemicals called neurotransmi+ers when they fire
• NeurotransmiPers diffuse across the synap3c clebs and bind to receptors on the post-‐synap3c side
Copyright 2001
Worth Publishers
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Graded Poten3als
• Excitatory Postsynap3c Poten3als (EPSPs) – depolariza3ons (ex. -‐71 to -‐68 mV) -‐
increase the likelihood that the neuron will fire
• Inhibitory Postsynap3c Poten3als (IPSPs) – hyperpolariza3ons (ex. -‐68 to -‐ 71 mV)-‐
decrease the likelihood that the neuron will fire
Copyright 2001
Worth Publishers
Postsynap3c Poten3als Are Graded Poten3als
• Their amplitude is propor3onal to the intensity of the input – Stronger s3muli produce bigger EPSPs or IPSPs
• Neurons combine together (integrate) individual poten3als -‐ the total determines whether the neuron will fire an ac3on poten3al
• Neurons integrate incoming signals in two ways: – Over space
– Over 3me
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Copyright 2001
Allyn & Bacon
Copyright 2001
Allyn & Bacon
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Postsynap3c Poten3als and Ac3on Poten3als
• The sum of the postsynap3c poten3als reaching the axon hillock (the axon poten3al trigger-‐zone) determines whether an ac3on poten3al will occur.
Elements of The Ac3on Poten3al
• Voltage-‐dependent Ion Channels
– opened by a change in membrane poten3al
• Absolute Refractory Period
– brief period aber ini3a3on of an ac3on poten3al when another one cannot be fired (Na+ channels temporarily inac3vated)
• Rela3ve Refractory Period – ac3on poten3al can be
fired, but it requires a greater than normal degree of s3mula3on
Copyright 2001
Allyn & Bacon
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The Firing Of An Ac3on
Poten3al Is An All-‐or-‐none Process
The Rate Law:
Copyright 2001
Worth Publishers
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The Ac3on Poten3al
The Ac3on Poten3al • Another nice web-‐based anima3on showing how this comes about can be found at:
hPp://bcs.whfreeman.com/thelifewire/content/chp44/4402002.html
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Propaga3on of an Ac3on Poten3al Is a Regenera3ve Process
Postsynap3c Poten3als and Ac3on Poten3als
• Postsynap3c poten3als (PSP) are graded poten3als
– Their amplitude is propor3onal to the intensity of the input s3mulus and decreases with distance from the source (they are generally decremental)
• The sum of the postsynap3c poten3als reaching the axon hillock (the axon poten3al trigger-‐zone) determines whether an ac3on poten3al will occur.
• Ac3on poten3als are not graded poten3als – The size of an ac3on poten3al does not vary with s3mulus intensity,
only the rate of firing
• Ac3on poten3als are non-‐decremental
– They arrive at the terminals of the axon the same size that they leb the axon hillock
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Local Anesthe3cs
• Produce loss of sensa3on in limited area of body
• Many act by blocking Na+ channels, and thus blocking ac3on poten3als in the affected area – Examples: Lidocaine (Xylocaine) and Novocain
General Anesthe3cs
• Produce unconsciousness • Some decrease brain ac3vity by opening some types of potassium channels wider than usual
• Thus, when a s3mulus starts to excite a neuron by opening sodium channels, K+ ions exit about as fast as the Na+ ions enter, preven3ng most ac3on poten3als
– Examples: ether and chloroform
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Fun with Fugu?
• Puffer fish (fugu) is considered a delicacy in Japan
• Some species contain tetrodotoxin (blocks voltage-‐sensi3ve sodium channels)
• Very small amounts can shut down signaling to a fatal degree
• A recipe for fishy revenge!
Copyright 2006, Houghton Mifflin
Mechanisms for Increasing the Speed an Ac3on Poten3al
• Increasing Size of Axon – Giant axon of the squid can reach a diameter of 1 mm
• Insula3ng the Axon – Myelina3on
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Saltatory Conduc3on in Myelinated Axons
Myelin decreases resistance along the axon, thus conduction in myelinated axons is typically faster than in non-myelinated axons of the same diameter
Copyright 2001
Allyn & Bacon
Saltatory Conduc3on in Myelinated Axons
• Ions can pass through the axonal membrane only at the nodes of Ranvier
• Current diminishes as it travels rapidly, but passively along the axon between the nodes of Ranvier, but it is s3ll strong enough to open voltage-‐gated channels clustered at the next node
• Ac3on poten3als are ac3vely regenerated at the nodes
Copyright 2001
Worth Publishers
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Saltatory Conduc3on in Myelinated Axons
• Conduc3on along the mylinated sec3on of the axon is extremely rapid
• The ac3ve regenera3on of the ac3on poten3al at the nodes introduces a slight delay (La3n: saltare “to skip or jump”)
• Saltatory conduc3on is more energy efficient
Copyright 2001
Worth Publishers
Synapses: How Neurons Communicate
• Synthesis, packaging and transport of neurotransmi7er molecules
• Release of neurotransmi7ers • Deac;va;on of neurotransmi7ers
• Ac;on of neurotransmi7ers at receptor sites
• Classes of neurotransmi7ers
Colored electron micrograph of axon terminals from many neurons forming synapses on a cell body
Copyright 2006, Houghton Mifflin
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Synapses: How Neurons Communicate
Synthesis, Packaging And Transport Of Neurotransmi7er (NT) Molecules
• Small-‐molecules NTs –(ex. amino acids, monoamines, acetylcholine) – Typically synthesized in
synap;c bu7on – Packed into small vesicles
by bu7on’s Golgi – Stored in clusters next to
the presynap;c memebrane
Copyright 2001
Allyn & Bacon
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Synthesis, Packaging And Transport Of Neurotransmi7er (NT) Molecules
• Large-‐molecules NTs -‐ (neuropep;des) synthesized in soma (ex. endorphins)
– Assembled on ribosomes in the cell body
– Packaged in larger vesicles by the soma’s Golgi
– Transported by microtubules to terminal bu7ons
– Stored farther from presynap;c membrane that small-‐molecule neurotransmi7ers
Copyright 2001
Allyn & Bacon
Electron Micrograph: Cross Sec3on Of A Synapse
Copyright 2001
Allyn & Bacon
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Electron Micrograph: Cross Sec3on Of A Synapse
Copyright 2006, Houghton Mifflin
Electron Micrograph: Cross Sec3on Of A Synapse
Copyright 2001
Allyn & Bacon
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Release of Neurotransmi7ers
Release of Neurotransmi7ers
• Ac3on poten3al arrives
• Voltage-‐sensi3ve calcium channels open
• Ca++ enters the presynap3c buPon
• Induces the “docking” and fusion of synap3c vesicles to membrane
• Exocytosis: neurotransmiPer is released into the synap3c cleb
Action potential arrives Synaptic
vesicle
Vesicle docks to membrane
Ca++ enters cell
Vesicle fuses NT released
Copyright 2001
Worth Publishers
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EXOCYTOSIS
Copyright 2001
Worth Publishers
Hal3ng Synap3c Transmission -‐ Deac3va3on of NeurotransmiPers
Mechanisms to terminate neurotransmitter action: - Reuptake - Enzymatic Degradation
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RECEPTORS AND RECEPTOR SUBTYPES
• Any molecule that binds to a receptor is a ligand of that receptor.
• Thus, neurotransmitors are ligands of their receptors.
X X
RECEPTORS AND RECEPTOR SUBTYPES
• Receptors are proteins embedded in the membrane that bind neurotransmiPers
• They are specific for par3cular neurotransmiPers: a “lock and key” arrangement (ex. acetylcholine won’t bind to a glutamate receptor)
X X
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RECEPTORS AND RECEPTOR SUBTYPES
• Receptor subtypes: Several different receptor proteins can bind the “same” neurotransmiPer (ex., acetylcholine binds both “nico3nic” and “muscarinic” acetylcholine receptors)
neurotransmitter
Receptor 1 Receptor 2
NeurotransmiPers Can Influence A Postsynap3c Neuron In Fundamentally Different Ways By Binding To Either Ionotropic
Or Metabotropic Receptors
• Ionotropic Receptors – Binding of neurotransmiPer opens,
or closes, an ion channel
• Metabotropic Receptors – Binding of neuro-‐transmiPer
ac3vates signal proteins and G proteins
• G protein subunit breaks off and binds to an ion channel, or s3mulates produc3on of an second messenger
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Major Classes of NeurotransmiPers
• Small-‐molecule Neurotransmi7ers
• Large-‐molecule (pep;de) Neurotransmi7ers
• Soluble gases
Small-‐molecule Neurotransmi7ers
• Monoamines 1. Dopamine -‐ movement, a7en;on, learning, reward -‐ degenera;on of Substan;a Nigra in midbrain = Parkinson’s disease (loss of DA) -‐ schizophrenia (too much DA release) 2. Norepinephrine and Epinephrine (Adrenaline) -‐ released by sympathe;c n.s. and adrenals -‐ control alertness/wakefulness; alarm 3. Serotonin
-‐ control of ea3ng, sleep, and arousal -‐ inhibits dreaming (LSD blocks serotonin)
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Small-‐molecule Neurotransmi7ers
• Acetylcholine – contracts skeletal muscles (neuromuscular junc;on)
– parasympathe;c nervous system
Small-‐molecule Neurotransmi7ers
• Amino Acids – Excitatory amino acids
• (ex., glutamate, aspartate) • excitatory neurotransmi7ers producing EPSPs
– Inhibitory amino acids • 1. Gamma-‐aminobutyric acid (GABA)
» inhibitory neurotransmi7er producing IPSP » degenera;on in basal ganglia
• 2. Glycine » inhibitory neurotransmi7er » normally inhibits motor neuron ac;vity in spinal cord
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Large-‐molecule (pep;de) Neurotransmi7ers
• Very diverse types and func;ons – Examples:
• endorphins (endogenous opiates; pain) • cholecystokinin (gut pep3de; food intake) • vasopressin (fluid regula3on)
Soluble gases • Small molecules with very different neurotransmiPer
characteris3cs
• Produced in cytoplasm by enzymes and diffuses freely across lipid bilayers to neighboring neurons
– Examples:
• Nitric oxide – regulates vascular relaxa3on – involved in learning and memory
• Carbon monoxide – also regulates vascular relaxa3on – regulates peristal3c relaxa3on
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Many Drugs and Toxins Act By Mimicking Or Blocking The Ac3on Of A NeurotransmiPer
Copyright Thomson & Wadsworth, 2003
Many Drugs and Toxins Act By Mimicking Or Blocking The Ac3on Of A NeurotransmiPer
• The tetanus toxin blocks the receptors for the inhibitory neurotransmiPer GABA.
• As a result, the disease causes extreme muscle spasms that may lead to the ripping of muscles and the breaking of bones.
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Many Drugs and Toxins Act By Mimicking Or Blocking The Ac3on Of A NeurotransmiPer
• The tetanus toxin blocks the receptors for the inhibitory neurotransmiPer GABA.
• As a result, the disease causes extreme muscle spasms that may lead to the ripping of muscles and the breaking of bones.
• Because spasms occur first in the jaw and neck, tetanus is also sometimes called “Lockjaw”
Many Drugs and Toxins Act By Mimicking Or Blocking The Ac3on Of A NeurotransmiPer
• There are about 100 cases of tetanus per year in the US • There are about a million deaths per year worldwide due
to tetanus
• Even in a well equipped hospital 30-‐40% die
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Many Drugs and Toxins Act By Mimicking Or Blocking The Ac3on Of A NeurotransmiPer
• There are about 100 cases of tetanus per year in the US • There are about a million deaths per year worldwide due
to tetanus
• Even in a well equipped hospital 30-‐40% die
Interestingly, curare derivates are some times used to treat tetanus
