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2016-10-03-lecture04.md
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Note:
Might here in other classes, especially human physiology about absolute and relative refractory periods.
Refractory period we've been discussing here is mostly the absolute refractory period-- due to Na+ channel inactivation.
Relative refractory period is the transient hyperpolarization during the undershoot when potassium conductance is still greater than normal-- when K+ conductance returns to resting value the relative refractory period is over. Until this time, a greater secondary depolarizing stimulus will be required to reach AP threshold.
--

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## Structure of the bacterial K⁺ channel
<figure><figcaption class="big">Each subunit has 2 transmembrane domains, 4 subunits make a channel</figcaption><img src="figs/Neuroscience5e-Fig-04.07-2R_5838376.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 4.7</figcaption></figure>
Note:
(Doyle et al, Science 280:69, 1998)
<!-- ## Structure of the bacterial K⁺ channel
3D structure of bacterial K channel. Yellow is the K channel, white are phospholipids, purple Na, green K.
<figure><img src="figs/image4_b687955.png" height="300px"><figcaption></figcaption></figure> -->
---
## Structure of the bacterial K⁺ channel
* Bacteria have K⁺ channels that are very similar in structure to mammalian K⁺ channels. Main difference is that they are not gated by voltage
* Could be crystallized in the bacterial membrane
* 3D structure tells us a lot about function
@@ -459,6 +442,24 @@ Note:
(Doyle et al, Science 280:69, 1998)
---
## Structure of the bacterial K⁺ channel
<figure><figcaption class="big">Each subunit has 2 transmembrane domains, 4 subunits make a channel</figcaption><img src="figs/Neuroscience5e-Fig-04.07-2R_5838376.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 4.7</figcaption></figure>
Note:
(Doyle et al, Science 280:69, 1998)
<!-- ## Structure of the bacterial K⁺ channel
3D structure of bacterial K channel. Yellow is the K channel, white are phospholipids, purple Na, green K.
<figure><img src="figs/image4_b687955.png" height="300px"><figcaption></figcaption></figure> -->
---
## Structure of a bacterial K⁺ channel determined by crystallography
@@ -598,6 +599,8 @@ Note:
Yellow are voltage sensing tm domains
4–8 positively-charged amino acids in the S4 domain. Experiences force in a transmembrane electric field. Is the electric-field sensor for voltage-dependent gating.
K channels are more diverse
- Kv2.1 show little inactivation and are closely related to the delayed rectifier K channels involved in AP repolarization
@@ -722,10 +725,15 @@ charybdotoxin from scorpions K channels
## Diseases caused by altered ion channels
<div style="font-size:0.7em;">
<div></div>
EA1: episodic ataxia type 1 (abnormal limb movements and severe ataxia)
BFNC: benign familial neonatal convulsion. Frequent brief seizures starting in first postnatal week then disappearing in a few months. Mutation mapped to two K⁺ channel genes
</div>
<figure><img src="figs/Neuroscience5e-Box-04D-3R_2e54724.jpg" height="300px"><figcaption>Neuroscience 5e Box 4D</figcaption></figure>

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## Synaptic transmission
* Synapses– functional contacts between neurons
* Two general classes– chemical and electrical synapses
* Chemical– neurons talk to each other by release of neurotransmitters
* Electrical– direct, passive flow of current between neurons
Note:
Thus far we’ve discussed how neurons generate action potentials that propagate down axons with high fidelity over cm’s to to meters of space and the ion channels in the membrane that underly voltage dependent excitability.
But is through synapses that neurons actually talk with one another and it is also through synapses that the nervous system effects behavior function enabling us to interact with the world around us– in other words there are synapses between pairs of neurons that form the basis of inter-neuronal communication as well as synapses on muscle fibers that neurons use to get our muscles to contract.
Now there are two general classes of synapses, chemical...
and electrical...
*todo: motor neuron - muscle fiber model*
<!-- <div><img src="figs/image_bfd15ce.png" height="100px"><figcaption></figcaption></div> -->
---
## Electrical and chemical synapses differ in their transmission mechanisms
<div><figcaption class="big">chemical synapse</figcaption><img src="figs/Neuroscience5e-Box-5A-1_c61ef03.jpg" height="200px"><figcaption>Neuroscience Box 5A</figcaption></div>
<div class="fragment fade-in" data-fragment-index="1"><figcaption class="big">electrical synapse</figcaption><img src="figs/Neuroscience5e-Fig-05.01-1R_4f24cb4.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 5.1</figcaption></div>
<div class="fragment fade-in" data-fragment-index="1"><figcaption class="big">electrical synapse</figcaption><img src="figs/Neuroscience5e-Fig-05-01b_5112455.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 5.1</figcaption></div>
Note:
---
## Electrical synapses
* Less common than chemical synapses
* The cell membranes of two cells are linked together via gap junctions
* Current flows **directly** from one neuron to another via gap junctions– form large pores between cells made up of connexin proteins
* The signal is very fast– the only limit is diffusion
* Signals can go in both directions
* Are used to synchronize electrical activity among populations of neurons
Note:
These electrical synapse or gap junction synapses are thought to be more common among inhibitory interneurons in the brain—
quadrillion synapses, 10^15 in our nervous system
---
## Gap junctions allow current to flow from one cell to the next
<figure><img src="figs/Neuroscience5e-Fig-05.01-3R_f7cb5e4.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.1</figcaption></figure>
Note:
* connexins— extracellular loops and disulfide bridges
* 3.5nm separating the apposed lipid bilayers connected through connexon hemichannels
* 20-40nm separation at a chemical synaptic cleft
* passive ionic current flow, small substance like ATP and second messengers
<!-- <img src="figs/image1_e4cc3f1.png" height="300px"> -->
Current in the presynaptic cell is not felt directly by post-synaptic cell for a chemical synapse.
--
## Electrical synapses
<figure><img src="figs/Neuroscience5e-Fig-05.02-1R_copy_2f541cc.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.2</figcaption></figure>
Note:
In Crayfish an action potential in one neuron spreads quickly to the next
--
## Electrical synapses
<figure><img src="figs/Neuroscience5e-Fig-05.02-2R_copy_3cd5bb0.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.2</figcaption></figure>
Note:
In hippocampal neurons gap junctions can make neurons fire in synchrony
---
## Electrical Synapses: putative functions
* Synchronization of the electrical activity of large populations of neurons
* the large populations of neurosecretory neurons that synthesize and release biologically active peptide neurotransmitters and hormones are extensively connected by electrical synapses
* Synchronization may be required for neuronal development, including the development of chemical synapses
* Synchronization may be important in functions that require instantaneous responses, such as reflexes and pacemakers
Note:
quadrillion synapses, 10^15 in our nervous system
important in diseases of pathological oscillations/synchrony like childhood epilepsy, etc
---
## Chemical synapses
* The majority of connections use chemical synapses
* They form at the synaptic cleft
* Presynaptic cells have synaptic vesicles that have neurotransmitters in them
* Post-synaptic cells have neurotransmitter receptors on the plasma membrane
Note:
---
## Synapse structure as seen by electron microscopy
<div><figcaption class="big">chemical synapse, type 1</figcaption><img src="figs/image2_1bf4990.png" height="200px"><figcaption>[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
<div><figcaption class="big">chemical synapse, type 2</figcaption><img src="figs/image3_5af29bc.png" height="200px"><figcaption>[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
<div><figcaption class="big">synaptic vesicles</figcaption><img src="figs/image4_b39a9f7.png" height="200px"><figcaption>[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
<div><figcaption class="big">synaptic cleft</figcaption><img src="figs/image5_a67adf4.png" height="200px"><figcaption>[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
Note:
* synapse, Gray type 1 is asymmetrical synapse. Usually excitatory synapse. Spherical vesicles.
* synapse, Gray type 2 is symmetrical synapse. Usually inhibitory synapse. Elongated vesicles.
---
## 11 steps of synaptic transmission
<div style="font-size:0.8.em">
<div></div>
1. Neurotransmitter is synthesized and packaged into vesicles
1. An action potential invades the presynaptic terminal
1. Depolarization causes opening of voltage-gated calcium channels
1. There is a rapid influx of Ca²⁺. 1000x concentration difference across the membrane(1x10⁻⁴ mM inside, 1 mM outside)
1. Calcium causes vesicles to fuse with membrane
1. Neurotransmitter is released into cleft
1. Transmitter binds to receptors on postsynaptic cell
1. This opens or closes postsynaptic channels
1. Postsynaptic current flows inside post-synaptic cell
1. Removal of neurotransmitter by glia uptake or enzymatic degradation
1. Retrieval of membrane via endocytosis
</div>
Note:
---
## Synaptic transmission
<figure><img src="figs/Neuroscience5e-Fig-05.03-0_copy_9fad940.jpg" height="500px"><figcaption></figcaption></figure>
Note:
* Action potential in the presynaptic neuron opens voltage-gated Ca²⁺ channels
* Ca²⁺ influx raises [Ca²⁺]i in the nerve terminal
* Elevated [Ca²⁺]i triggers the fusion of synaptic vesicles to the plasma membrane of the presynaptic neuron and exocytosis
* Neurotransmitter is released into the synaptic cleft where it diffuses about
* Neurotransmitter binds to specific receptors in the postsynaptic neuron causing channels in that cell to open or close
* Direct action on ligand gated channels
* Indirect action on G-protein coupled channels
* The neurotransmitter is inactivated and/or removed from the synaptic cleft (active transport into presynaptic neuron or glial cells or both)
* The vesicular membrane is recovered by endocytosis and recycled
---
## The discovery of the neurotransmitter acetylcholine
* Otto Loewi– wanted to figure out how stimulation of vagus nerve caused the heart to slow down
* Vagus nerve (cranial nerve X) has both sensory and motor axons. Regulates heartbeat
* Loewi transfered a solution generated from one heart to slow down another heart even without stimulation
* Demonstrated a diffusible substance was released upon stimulation
Note:
The vagus nerve is responsible for such varied tasks as heart rate, gastrointestinal peristalsis, sweating, and quite a few muscle movements in the mouth, including speech (via the recurrent laryngeal nerve). It also has some afferent fibers that innervate the inner (canal) portion of the outer ear (via the auricular branch, also known as Alderman's nerve) and part of the meninges.
The vagus nerve (/ˈveɪɡəs/ vay-gəs), historically cited as the pneumogastric nerve, is the tenth cranial nerve or CN X, and interfaces with parasympathetic control of the heart and digestive tract. The vagus nerves are paired; however, they are normally referred to in the singular.
The vagus nerve supplies motor parasympathetic fibers to all the organs except the suprarenal (adrenal) glands, from the neck down to the second segment of the transverse colon. The vagus also controls a few skeletal muscles, notable ones being:
* Cricothyroid muscle
* Levator veli palatini muscle
* Salpingopharyngeus muscle
* Palatoglossus muscle
* Palatopharyngeus muscle
* Superior, middle and inferior pharyngeal constrictors
* Muscles of the larynx (speech).
*This means that the vagus nerve is responsible for such varied tasks as heart rate, gastrointestinal peristalsis, sweating, and quite a few muscle movements in the mouth, including speech (via the recurrent laryngeal nerve).*
*It also has some afferent fibers that innervate the inner (canal) portion of the outer ear (via the auricular branch, also known as Alderman's nerve) and part of the meninges. This explains why a person may cough when tickled on the ear, such as when trying to remove ear wax with a cotton swab.[citation needed]*
*Afferent vagus nerve fibers innervating the pharynx and back of the throat are responsible for the gag reflex.*
---
## The discovery of acetylcholine
<div><img src="figs/Neuroscience5e-Fig-05.04-1R_copy_a5a415a.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.4</figcaption></div>
<div class="fragment fade-in" data-fragment-index="1"><img src="figs/Neuroscience5e-Fig-05.04-2R_copy_87d0da2.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.4</figcaption></div>
Note:
Free acetylcholine acts on **muscarinic receptors** which **hyperpolarize** the cells of the SA node and slow the conduction of the action potential through the AV node. This slows heart rate. Acetylcholine also decreases Ca2+ influx which lowers the heart's force of contraction.
--
## The discovery of acetylcholine
<div style="font-size:0.7em;">
<div></div>
Otto Loewi (Austrian)– on the discovery of vagus nerve substance:
>"In the night of Easter Saturday, 1921, I awoke, turned on the light, and jotted down a few notes on a tiny slip of paper. Then I fell asleep again. It occurred to me at six o'clock in the morning that during the night I had written down something most important, but I was unable to decipher the scrawl. That Sunday was the most desperate day in my whole scientific life. During the next night, however, I awoke again, at three o'clock, and I remembered what it was. This time I did not take any risk; I got up immediately, went to the laboratory, made the experiment on the frog's heart, described above, and at five o' clock the chemical transmission of nervous impulse was conclusively proved."
</div>
Note:
---
## Acetylcholine (ACh) shown to be the vagus factor
* Sir Henry Dale purified ACh (1914) and showed that it is vagus nerve substance
* Can apply ACh to muscle and evoke an end plate potential (EPP)
* ACh action has same pharmacology as vagus nerve substance in that it is sensitive to curare (a plant poison that kills by preventing muscle contraction). Competes with curare for receptor binding
* Henry Dale and Otto Loewi shared Nobel prize (1936):
<div style="font-size:0.7em;">
<div></div>
>"for their discoveries relating to chemical transmission of nerve impulses"
</div>
Note:
*Curare was used as a paralyzing poison by South American indigenous people. The prey was shot by arrows or blowgun darts dipped in curare, leading to asphyxiation owing to the inability of the victim's respiratory muscles to contract.*
*Curare /kʊˈrɑːri/[1] or /kjʊˈrɑːri/[2] is a common name for various plant extract alkaloid arrow poisons originating from Central and South America. These poisons function by competitively and reversibly inhibiting the nicotinic acetylcholine receptor (nAChR), which is a subtype of acetylcholine receptor found at the neuromuscular junction. This causes weakness of the skeletal muscles and, when administered in a sufficient dose, eventual death by asphyxiation due to paralysis of the diaphragm.*
---
## Formal criteria that define a neurotransmitter
1. Must be present in the presynaptic neuron
2. Must be released in response to a depolarization and be Ca²⁺ dependent
3. Must have specific receptors localized on the post-synaptic cell
* Note– It does not have to function uniquely as a neurotransmitter (it may have other functions). e.g. glutamate, glycine, ATP
Note:
There are a few criteria that define a neurotransmitter...
---
## Criteria that define a neurotransmitter
<div><figcaption class="big">present in presynaptic cell</figcaption><img src="figs/Neuroscience5e-Box-05A-0R-1_copy_bd28d1f.jpg" height="400px"><figcaption>Neuroscience 5e Box 5A</figcaption></div>
<div class="fragment fade-in" data-fragment-index="1"><figcaption class="big">calcium dependent release</figcaption><img src="figs/Neuroscience5e-Box-05A-0R-2_copy_4c4e5be.jpg" height="400px"><figcaption>Neuroscience 5e Box 5A</figcaption></div>
<div class="fragment fade-in" data-fragment-index="2"><figcaption class="big">specific receptors on post-synaptic cell</figcaption><img src="figs/Neuroscience5e-Box-05A-0R-3_copy_7293cc0.jpg" height="400px"><figcaption>Neuroscience 5e Box 5A</figcaption></div>
Note:
Criteria depicted here
[https://www.quora.com/How-many-types-of-neurotransmitters-are-there-in-a-human-brain](https://www.quora.com/How-many-types-of-neurotransmitters-are-there-in-a-human-brain)
It depends on how you count, but maybe 30 - 100 different molecule types, with 10 of them doing 99% of the work. More than 100 different neurotransmitters have been identified.
There are two main broad categories of neurotransmitters: "Small molecule" neurotransmitters (glutamate, GABA, acetylcholine, biogenic amines (dopamine, serotonin, noradrenaline, and histamine)) and neuropeptides (opioid peptides, substance P). ATP/purines and unsaturated fatty acids like endocannabinoids (anandamide, 2-AG) also can act as neurotransmitters.
<!-- ## Localization of neurotransmitter action
act locally, can alter a few neurons at a time
<div><img src="figs/PN06021_91e5036.jpg" height="100px"><figcaption></figcaption></div>
## Localization of neurotransmitter action
can act at long distances, from the cell body
<div><img src="figs/PN06022_5a86d91.jpg" height="100px"><figcaption></figcaption></div>
-->
---
## Synaptic transmission is quantal
* Synaptic transmission is quantal (composed of discrete units)
* The initial evidence was obtained from studying the release of acetylcholine at neuromuscular junctions
* The synapses between spinal motor neurons and skeletal muscle are simple, large, and peripherally located. Easy to study
* These motor synapses form structures at the neuromuscular junction called **end plates**. This is where the action happens
Note:
How have we come to learn about the properties of chemical synaptic transmission?
---
## Neuromuscular junction
<div><img src="figs/image10_fc0011e.png" height="200px"><figcaption></figcaption></div>
<div><img src="figs/image11_5a29be3.png" height="200px"><figcaption></figcaption></div>
Note:
motor unit is a motor neuron’s axon terminals and all the skeletal muscle fibers it innervates (10 for extraocular muscles, 1000 for thigh muscles). Motor pool is a bunch of motor units of same fiber type.
---
## Muscle action potentials
* Muscles have action potentials too– triggered by stimulus from motor neurons at the neuromuscular junction
* The regenerative action potential travels away from the neuromuscular junction along the muscle fiber
<figure><img src="figs/endplate-muscle-AP_copy_3914f33.jpg" height="200px"><figcaption></figcaption></figure>
Note:
--
## Muscle action potentials
* Recordings in the junction reveal local potential changes at the end plate before a regenerative action potential is produced
<figure><img src="figs/endplate-potential-muscle-AP_copy_3befd61.jpg" height="200px"><figcaption></figcaption></figure>
Note:
--
## Muscle action potentials
* These local potentials are called end plate potentials (EPPs)
* End plate potentials are generated **at the end plate**
<figure><img src="figs/endplate-potential-muscle-AP-curare_copy_6afd350.jpg" height="200px"><figcaption></figcaption></figure>
Note:
---
## End plate potential
A presynaptic action potential releases a lot of ACh, opening channels in the muscle cell. The resulting depolarization is called an end plate potential (EPP).
<div><img src="figs/Neuroscience5e-Fig-05.06-1R_copy_c01be61.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.6</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-05.06-2Rb_copy_4bf3e7d.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.6</figcaption></div>
Note:
End plate potentials evoked by motor neuron stimulation almost are almost always above threshold and result in an action potential along the muscle fiber
---
## Miniature end plate potentials (MEPPs)
* Spontaneous changes in potential even in the absence of an action potential
* Same shape as EPPs but smaller (1 mV vs 50+ mV)
* Sensitive to agents that block ACh receptors
* Removing Ca²⁺ from media reduces EPPs to MEPPs
* Thus EPPs are a bunch of MEPPs added up
Note:
---
## Comparison of MEPPs and subthreshold EPPs
<figure><img src="figs/Neuroscience5e-Fig-05.06-2Rc_copy_864df54.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.6</figcaption></figure>
Note:
* in the absence of stimulation there is spontaneous postsynaptic membrane transients called minature EPPs. Small amplitude.
* Bath in low calcium and stimulate you get small subthreshold EPPs that are about the same size as the MEPPs.
* Examination of the muscle membrane potential at high gain reveals small, spontaneous depolarizations. These are miniature end plate potentials (MEPPs)
---
## Quantal neurotransmission
* By lowering Ca²⁺ one can reduce the amount of transmitter released by an AP
* Here [Ca²⁺] is so low that *many* presynaptic APs fail to release any ACh
* Other APs release 1 to 6 quanta
<figure><img src="figs/Neuroscience5e-Fig-05.07-1R_copy_dd645da.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.7</figcaption></figure>
Note:
If you measure the amplitudes of these small low calcium EPPs and plot their distribution, e.g. this histogram here you can see a certain statistical distribution that indicates these amplitudes fall into discrete steps or quanta showing that the smallest amplitude ones that are about the same size as the spontaneous MEPPs must be result of neurotransmitter release from single synaptic vesicles.
---
## Quantal neurotransmission
* The **MEPP is the quantal event of neurotransmission**. It represents the postsynaptic response to the release of a single vesicle of neurotransmitter
* The EPP is the result of the synchronized release of many vesicles. It is the sum of many MEPPs
* Bernard Katz Nobel prize (1970)
<figure><img src="figs/image12_0957581.png" height="100px"><figcaption>Bernard Katz</figcaption></figure>
Note:
---
## One MEPP = one synaptic vesicle
* Synaptic vesicles are full of neurotransmitter
* In motor neuron one vesicle contains approximately 10,000 molecules of neurotransmitter
* About the same amount needed to invoke an MEPP
Note:
---
## Synaptic vesicles recycle
* All that vesicle fusion– why doesn’t the membrane keep growing and growing?
* Synaptic vesicle membranes get recycled quickly
* Are endocytosed in clathrin coated vesicles which fuse to endosome and bud off again
* Can use a pulse chase experiment to show this
Note:
--
## Local recycling of synaptic vesicles in presynaptic terminals
<figure><img src="figs/Neuroscience5e-Fig-05.09-1R_copy_e1bd0b0.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.9</figcaption></figure>
Note:
(Heuser and Reese, 1973)
---
## Local recycling of synaptic vesicles in presynaptic terminals
<figure><img src="figs/Neuroscience5e-Fig-05.09-2R_copy_4977b31.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.9</figcaption></figure>
Note:
---
## Calcium is required for synaptic vesicle fusion
* Voltage clamping shows that there is an inward Ca²⁺ flux in presynaptic cells that is voltage dependent
* Ca²⁺ can be visualized entering cell after depolarization
* Injection of Ca²⁺ into the presynaptic neuron can drive a post-synaptic potential
* Chelating Ca²⁺ in the presynaptic cell can inhibit post-synaptic potential
Note:
--
## The role of Ca²⁺
<div style="font-size:0.8em; margin:25px 0;">
<div></div>
* If extracellular Ca²⁺ is removed or Ca²⁺ entry is blocked, there will be no release
* Voltage-gated Ca²⁺ channels in the presynaptic membrane provide Ca²⁺ to trigger the release of neurotransmitter
</div>
<div><figcaption class="big">Voltage-clamp presynaptic neuron and block Na⁺/K⁺ currents with TTX/TEA</figcaption><img src="figs/Neuroscience5e-Fig-05.10-0_copy_a76faf6.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.10</figcaption></div>
Note:
(Augustine and Eckert 1984)
--
## The role of Ca²⁺
<div style="font-size:0.8em; margin:25px 0;">
<div></div>
* Intracellular injection of Ca²⁺ into the presynaptic terminal will stimulate release
* Intracellular injection of Ca²⁺ chelator will inhibit release
</div>
<div><figcaption class="big">microinjection of Ca²⁺ into presynaptic terminal</figcaption><img src="figs/Neuroscience5e-Fig-05.11-2R_copy_13a54e8.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.11</figcaption></div>
<div><figcaption class="big">microinjection of Ca²⁺ chelator BAPTA into presynaptic terminal</figcaption><img src="figs/Neuroscience5e-Fig-05.11-3R_copy_6d4bfd9.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.11</figcaption></div>
Note:
* microinjection of Ca²⁺ into squid giant axon presynaptic terminal (Miledi, 1973)
* microinjection of Ca²⁺ chelator BAPTA into squid giant axon presynaptic terminal (Adler et al, 1991)
*Fluorescent dye that binds calcium (Smith et al 1993)*
*squid giant axon from contacts the contractile muscular mantle responsible for water expulsion and squid jet propulsion*
---
## There are lots of proteins involved in synaptic vesicle cycling
* Many specific proteins have been isolated from presynaptic terminals
* Some of these proteins are required for different steps of vesicle cycling: budding, docking, priming, fusion
Note:
<!--
## We know a lot about the proteins involved in vesicle fusion
* Yeast genetics and biochemistry have defined proteins involved in general vesicle fusion (SEC proteins).
* Homologues in synaptic vesicles
* Proteins have been found that are required in specific steps of fusion: budding, docking, priming, fusion.
-->
--
## Presynaptic proteins implicated in synaptic vesicle cycling
<figure><figcaption class="big">Molecular model of a synaptic vesicle</figcaption><img src="figs/Neuroscience5e-Fig-05.13-1R_copy_f29479f.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.13</figcaption></figure>
Note:
Model after Takamori et al 2006
--
## Presynaptic proteins implicated in synaptic vesicle cycling
<figure><figcaption class="big">The vesicle trafficking cycle</figcaption><img src="figs/Neuroscience5e-Fig-05.13-2R_copy_464b425.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.13</figcaption></figure>
Note:
NSF: ATPase NSF important for fusion of vesicle with membranes of the golgi apparatus. NEM senstivie fusion protein.
snaps: soluble NSF-attachment proteins
snares: SNAP receptors
Model after Takamori et al 2006
---
## Molecular mechanisms of synaptic vesicle exocytosis
* SNAP-25 is a plasma membrane SNARE that regulates the assembly of two other SNAREs
* Syntaxin is a plasma membrane SNARE
* Synaptobrevin is a vesicle SNARE
* Together they tether the vesicle to the plasma membrane
* Synaptotagmin is a vesicle Ca²⁺ sensor and helps trigger vesicle fusion
<figure><figcaption class="big">Vesicle bound to plasma membrane</figcaption><img src="figs/Neuroscience5e-Fig-05.14-1R_copy_6de21e5.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 5.14</figcaption></figure>
Note:
NSF
: NEM-sensitive fusion protein (orig found to be important for fusion of vesicles with membranes of Golgi apparatus)
: ATPase
SNAPs
: soluble NSF attachment proteins
SNARES
: 'SNAP receptors'
---
## Molecular mechanisms of synaptic vesicle exocytosis
<figure><img src="figs/Neuroscience5e-Fig-05.14-2R_copy_0df493d.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.14</figcaption></figure>
Note:
---
## Vesicle proteins are the targets of many toxins
* Tetanus toxin– cleaves synaptobrevin
* Botulinum toxins– cleave syntaxin and snap25 (causes botulism)
* alpha-latrotoxin– black widow causes a massive exocytosis of vesicles. Somehow bypasses Ca²⁺ requirement, likely affecting synaptotagmin
Note:
[from https://en.wikipedia.org/wiki/Botulinum_toxin:](https://en.wikipedia.org/wiki/Botulinum_toxin:)
>Cleavage of the SNARE proteins inhibits release of acetylcholine.[45] Hence, botulinum toxins A, B, and E specifically cleave SNAREs, preventing "neurosecretory vesicles" from docking/fusing with the interior surface of the plasma membrane of the nerve synapse, and so block release of neurotransmitter. In inhibiting acetylcholine release, nerve impulses are blocked, causing the flaccid (sagging) paralysis of muscles characteristic of botulism[45]
---
## Synaptic vesicle toxins
Tetanus toxin and various types of botulinum toxin act by preventing exocytosis.
<figure><figcaption class="big">SNARE protein sites cleaved by tetanus and botulinum toxins</figcaption><img src="figs/Neuroscience5e-Box-05B-2-0_copy_0d09c20.jpg" height="400px"><figcaption>Neuroscience 5e Box 5B</figcaption></figure>
Note:
NSF
: NEM-sensitive fusion protein (orig found to be important for fusion of vesicles with membranes of Golgi apparatus)
: ATPase
SNAPs
: soluble NSF attachment proteins
SNARES
: 'SNAP receptors'
---
## Botox
* Dermatologists have been using botulinum toxin (or Botox) for cosmetic purposes
* When injected locally into a particular muscle or surrounding area, Botox causes a paralysis of that muscle due to a blockade of ACh release from the incoming motor nerve fibers. This leads to a reduction of wrinkle lines, although effective for only a few months
<figure><img src="figs/photo_botox_behandlung_a000d47.jpeg" height="200px"><figcaption></figcaption></figure>
Note:
when botox is injected in small amounts, it can effectively weaken a muscle for a period of three to four months
---
## Synaptic transmission summary video
<div><video height=400px controls src="figs/Animation05-01SynapticTransmission.mp4"></video><figcaption>Neuroscience 5e Animation 5.1</figcaption></div>
Note:
---
## Midterm thursday
* Similar format as the practice midterm
* 100 points total, 25% of your grade.
* Covers material in lectures 1–6
* today's material covers Chapter 5, pages 77-95
* Hannah's office hrs this week: Wednesday 3:30 – 5:30pm Biomed 101
Note:
---

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## Neurotransmitters
* Many different kinds, over 100
* There are two main types– small molecule neurotransmitters and neuropeptides
* Abnormalities of neurotransmitter function contributes to wide range of neurological diseases and psychiatric disorders
Note:
So we already defined what a neurotransmitter is. It is a substance that must be present inside a presynaptic neuron, it’s release must be dependent on calcium flux from an AP, and it must have specific receptors on the postsynaptic neuron.
---
## Major categories of neurotransmitters
* Small molecule neurotransmitters– amino acids, purines, biogenic amines
* Peptide neurotransmitters– 3-36 amino acid polypeptides, often derived from longer polypeptides
Note:
---
## Examples of small-molecule neurotransmitters
<div><img src="figs/Neuroscience5e-Fig-06.01-2R_8d4e8d9.jpg" height="100px"><figcaption></figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-06.01-1R_e607c99.jpg" height="100px"><figcaption></figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-06.01-3R_d60bc57.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Examples of small-molecule neurotransmitters
share hydroxylated benzene ring
<div><img src="figs/Neuroscience5e-Fig-06.01-4R_45b484a.jpg" height="100px"><figcaption></figcaption></div>
Note:
most of which share a hydroxylated benzene ring
* -Catechol, also known as pyrocatechol or 1,2-dihydroxybenzene, is an organic compound with the molecular formula C6H4(OH)2
---
## Examples of peptide neurotransmitters
Endogenous opioid peptide.
<div><img src="figs/Neuroscience5e-Fig-06.01-5R_a49bcdd.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Neurotransmitter release can be regulated at many steps
* Synthesis– small molecules are generated from biosynthetic enzymes
* Neuropeptides are generated by translation followed by protein processing
* Packaging into vesicles– requires specific transporters on vesicle membrane, there are different types of vesicles, small clear-core (e.g. ACh and amino acids) and large dense core (neuropeptides), biogenic amines do both. Location in synapses is different
* Release– small vesicles release fast, large-dense take more effort
Note:
---
## The synthesis, packaging, secretion, and removal of neurotransmitters
<div><img src="figs/PN06061_50a5195.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Small molecule neurotransmitters are synthesized at the presynaptic terminal
Raw materials are collected by active transport. Neurotransmitter is synthesized and packaged at terminus.
<div><img src="figs/PN06062_3641612.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Neuropeptides are synthesized in the cell body
Neuropeptides are synthesized in the nerve cell body, loaded into vesicles and transported down the axon via microtublules.
<div><img src="figs/PN06063_3a75543.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Small molecule neurotransmitters
* Acetylcholine
* Amino acids
* Glutamate
* Aspartate
* GABA
* Glycine
* Purines (ATP)
* Biogenic amines
* Dopamine
* Norepinephrine
* Epinephrine
* Serotonin
* histamine
Note:
---
## Acetylcholine
* The neurotransmitter used at the neuromuscular junction. Also used at synapses in visceral motor system and at some CNS synapses– called cholinergic neurons
* Synthesized from acetyl CoA and choline by choline acetyl transferase (ChAT)– its presence is a good indication that the neuron is cholinergic
* Removed from synapse by acetylcholine esterase (AChE) has high activity can cleave 5000 molecules per second
* Sarin “nerve gas” is a AChE inhibitor
Note:
ACh: skeletal muscle excitation vs release from vagus nerve that slows down heart beat (cardiac muscle)—
* -Ligand gated channel that depolarizes skeletal muscle fibers vs g-protein coupled receptor that results in hyperpolarization of cardiomyocytes.
---
## Acetylcholine
acetylcholineesterase (degradation)
choline acetyltransferase (synthesis)
<div><img src="figs/Neuroscience5e-Fig-06.02-0_dd0e243.jpg" height="100px"><figcaption></figcaption></div>
Note:
from krebs cycle you get Acetyl CoA. Na-Choline cotransporter exchanges Na ions for choline.
choline acetyltransferase…
VAChT packs ACh into vesicles.
---
## AChE Inhibition
* Sarin and Soman: toxic irreversible AChE inhibitors. Also known as “nerve gases” for use in chemical warfare.
* Designed to dispersed as a vapor cloud or spray, which allows their entry into the body through skin contact or inhalation. Drug quickly penetrates into bloodstream and is distributed to all organs, including the brain.
* Symptoms: profuse sweating and salivating, uncontrollable vomiting, gasping for breath, convulsing, and gruesome death . These are due to rapid accumulation of ACh and overstimulation of cholinergic synapses throughout the CNS and PNS. Death occurs through asphyxiation due to paralysis of the muscles of the diaphragm.
<div><img src="figs/MQ-ChOpener-6_72250dc.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Acetylcholine synthesis video summary
<div><video height=400px controls src="figs/Animation06-01NeurotransmitterPathwaysAcetylcholine.mp4"></video><figcaption>Neuroscience 5e Animation 6.1</figcaption></div>
Note:
---
## Glutamate
* Most important transmitter for normal brain function.
* Nearly all excitatory neurons in the CNS are glutamatergic.
* Does not cross the blood brain barrier.
* Glutamine is most common precursor glutaminase converts it to glutamate.
* Retrieved from synapse by glutamate transporters in glia and neurons. Glia (astrocytes) turn glutamate to glutamine and spit it back out
* Too much glutamate can kill the post-synaptic neuron (excitotoxicity). A major problem after damage due to stroke.
Note:
Most important neurotransmitter for normal brain function. Almost all excitatory neurons in CNS are glutamatergic. Half of all synapses estimated to use this transmitter. Glutamate is non-essential a.a. (by that I mean non-essential per dietary requirements) that does not cross the blood brain barrier. Synthesized inside neurons by local precursors.
histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.
Monosodium glutamate (MSG, also known as sodium glutamate) is the sodium salt of glutamic acid
---
## Glutamate
<div><img src="figs/Neuroscience5e-Fig-06.05-0_0c18dfb.jpg" height="100px"><figcaption></figcaption></div>
Note:
system A transporter 2 (SAT2) transports glutamine into presynaptic terminal. Metabolized into glutamate by mitochondrial enzyme glutaminase. Also glucose metabolism from Krebs cycle can also produce glutamate. Packaged into vesicles by vesicular glutamate transporters (VGLUT). 3 different VGLUTs identified.
Removed from cleft by excitatory a.a. transporters (EAATs). These are family of 5 Na⁺ dependent glutamate cotransporters. Some in glial cells, some in presynaptic terminals. Glutamate in glial cells by EAAT converted into glutamine by enzyme glutamine synthetase. Then transporter out by different transporter system N transporter 1 (SN1) then back into nerve cells by SAT2.
essential AA: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.
---
## Glutamate
<div><img src="figs/Neuroscience5e-Box-05C-1R_bd8ae08.jpg" height="100px"><figcaption></figcaption></div>
Note:
histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.
---
## Glutamate synthesis video summary
<div><video height=400px controls src="figs/Animation06-02NeurotransmitterPathwaysGlutamate.mp4"></video><figcaption>Neuroscience 5e Animation 6.2</figcaption></div>
Note:
ACh role in Alzheimers: basal forebrain innervation to neocortex vs hippocampus. Cholinergic neuron degradation vs local postsynaptic neuron effects…
---
## GABA and glycine
* Most inhibitory neurons use one or the other.
* Inhibits the ability to fire action potentials.
* GABA (gamma-aminobutyric acid) made from glutamate by glutamic acid decarboxylase (GAD), requires Vitamin B6 as cofactor. B6 deficiency can lead to loss of synaptic transmission.
* Glycine– about 1/2 of neurons in spinal cord use glycine.
* Both GABA and glycine are rapidly taken up by glia and neurons.
* Hyperglycinemia– defect in glycine uptake and removal leading to severe mental retardation.
Note:
As many as a third of synapses in the brain use GABA as an inhibitory transmitter. Most commonly found in local circuit neurons.
glycine encephalopathy:
[http://ghr.nlm.nih.gov/condition/glycine-encephalopathy](http://ghr.nlm.nih.gov/condition/glycine-encephalopathy)
>Glycine encephalopathy, which is also known as nonketotic hyperglycinemia or NKH, is a genetic disorder characterized by abnormally high levels of a molecule called glycine. This molecule is an amino acid, which is a building block of proteins. Glycine also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the brain. Glycine encephalopathy is caused by the shortage of an enzyme that normally breaks down glycine in the body. A lack of this enzyme allows excess glycine to build up in tissues and organs, particularly the brain, leading to serious medical problems.
---
## Glycine
* Inhibitory neurotransmitter
* Makes the post-synaptic membrane more permeable to Cl-. Can result in hyperpolarization of the post-synaptic cell
* Glycine receptor is primarily found in the ventral spinal cord
* Strychnine
* Glycine antagonist which can bind to the receptor without opening the Cl- channel
* (i.e. it inhibits inhibition)
* spinal hyperexcitability
<div><img src="figs/pt58a_e98273a.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Synthesis, release, and reuptake of the inhibitory neurotransmitters GABA and glycine
<div><img src="figs/Neuroscience5e-Fig-06.08-1R_025d494.jpg" height="100px"><figcaption></figcaption></div>
Note:
transported into vesicles by vesicular inhibitory amino acid transporter (VIAAT)
Removal by neurons and glia by Na⁺ dependent cotransporters for GABA called GATs
---
## Synthesis, release, and reuptake of the inhibitory neurotransmitters GABA and glycine
<div><img src="figs/Neuroscience5e-Fig-06.08-2R_cf6cdb2.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Biogenic amines
* Catecholamines– dopamine, norepinephrine, and epinephrine
* Histamine
* Serotonin
* All derived from tyrosine. Tyrosine hydroxylase is the rate limiting step and is a good histological marker for catecholaminergic neurons
* Are implicated in many complex behaviors
Note:
Biogenic amines regulate many functions in the CNS and PNS. Ranging from homeostatic functions to cognition and attention.
* All come from same synthesis pathway
* defects in function implicated in many psychiatric disorders.
* targets of many drugs of abuse
*Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group.*
*reserpine used as antipsychotic, depletes Norep at synaptic terminals by blocking vesicle loading*
* organic structure template: R—NH2*
---
## Catecholamine synthesis
Neuroscience 5e 6.10
<div><img src="figs/Neurscience5e-Fig-6_fc43ebb.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Dopamine
* Produced by the enzyme DOPA decarboxylase
* Made by substantia nigra pars compacta (which connects to corpus striatum for coordination of body movements).
* Does not cross the blood brain barrier, but levadopa (L-DOPA) does.
* Parkinson’s treatments include L-DOPA plus degradation enzyme inhibitors
* Cocaine inhibits uptake of dopamine (inhibits DAT)
<div><img src="figs/image_1d47b5b.png" height="100px"><figcaption></figcaption></div>
Note:
Synthesized in cytoplasm of presynaptic terminals.
Loaded into synaptic vesicles by vesicular monoamine transporter (VMAT). Dopamine in synaptic cleft is terminated by reuptake of dopamine into nerve terminals or glia cells by a Na-dependent dopamine cotransporter called DAT. Cocaine works by inhibiting DAT, increasing dopamine concentrations in synaptic cleft.
Amphetamine also inhibits DAT as well as a transporter for norepinephrine
* Catabolized by monoamine oxidase and catechol O-methyltransferase (COMT). Both neurons and glia contain mitochondrial MAO and cytoplasmic COMT. Inhibitors of these enzymes are targets of some kinds of antidepressants (phenelzine and tranylcypromine)
* Acts throught GPCRs. D3 parallels that of other metabotropic receptors like mAChR. Subtypes act by activating or inhibiting adenylyl cyclase.
* Activation leads to complex behaviors. Antagonists can cause catalepsy (state where difficult to initiate voluntary movement).
* L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines.
* it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase.
*Encephalitis lethargica, sleeping sickness, 40 yrs later Oliver Sacks in NYC treats them with L-DOPA*
* neostriatum
* Part of
* Basal ganglia[1]
* Reward system[2][3]
* Components
* Ventral striatum[2][3][4
* Dorsal striatum[2][3][4]
The corpus striatum, a macrostructure which contains the striatum, is composed of the entire striatum and the globus pallidus. The lenticular nucleus refers to the putamen together with the globus pallidus.
---
## PET scans before and after cocaine
Red means lots of unoccupied dopamine receptors
before
after
<div><img src="figs/image1_d2a2eb1.png" height="100px"><figcaption></figcaption></div>
<div><img src="figs/image2_0ee389f.png" height="100px"><figcaption></figcaption></div>
Note:
striatum.
>Imaging studies in humans show that low striatal D2 receptor binding in cocaine abusers in the striatum correlates with decreases in glucose metabolism in the orbito-frontal cortex and cingulate gyrus, which process drive and affect, and may lead to continued drug-taking behavior (Volkow et al., 1993, 1999)
anterior cingulate cortex
---
## Projections from dopaminergic neurons in the human brainstem
<div><img src="figs/Neuroscience5e-Fig-06.11-1R_adab2f5.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Dopamine synthesis video summary
<div><video height=400px controls src="figs/Animation06-03NeurotransmitterPathwaysDopamine.mp4"></video><figcaption>Neuroscience 5e Animation 6.3</figcaption></div>
Note:
---
## Norepinephrine
* also called noradrenaline
* Comes from dopamine by way of dopamine-β-hydroxylase
* Sympathetic ganglion cells use it– project to visceral motor system (fight or flight response)
* Used as a transmitter from locus coeruleus in brainstem– projects to areas that are involved in sleep, attention, and feeding
* Its reuptake mechanism, the norepinephrine transporter (NET), is a target of amphetamines
Note:
VMAT for loading into vesicles
Norep transporter (NET) is a Na⁺ depedent cotranporter. NET is a target of amphetamines.
alpha and beta adrengergic receptors. GPCRs. Some alphas lead to slow depolarization. Some lead to slow hyperpolarization (acting on different K⁺ channels).
---
## Projections from noradrenergic neurons in the human brainstem
<div><img src="figs/Neuroscience5e-Fig-06.11-2R_fc0c7eb.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Norepinephrine synthesis video summary
<div><video height=400px controls src="figs/Animation06-04NeurotransmitterPathwaysNorepinephrine.mp4"></video><figcaption>Neuroscience 5e Animation 6.4</figcaption></div>
Note:
---
## Epinephrine
* Adrenaline– present at lower levels than the others
* Made by neurons in rostral medulla. Project to thalamus and hypothalamus
Note:
---
## Projections from adrenergic neurons in the human brainstem
<div><img src="figs/Neuroscience5e-Fig-06.11-3R_c9ee16b.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Serotonin
* 5-hydroxytryptamine (5-HT)
* Made from tryptophan
* Reuptake by specific serotonin transporters
* Many antidepressants act by inhibiting serotonin reuptake (selective serotonin reuptake inhibitors-SSRIs). Prozac, Zoloft
* Found primarily in groups of neurons in the raphe region of the pons and upper brainstem
* The raphe nucleus projects widespread in forebrain areas that are implicated in sleep and wakefulness and mood
Note:
VMAT loads this (as well as other monoamines) into synaptic vesicles.
turkey/tryptophan—> sleep? Yes— but not really, you’d have to eat a lot more (3x more according to tryptophan supplements) than typically at thanksgiving meal.
[http://www.snopes.com/food/ingredient/turkey.asp](http://www.snopes.com/food/ingredient/turkey.asp)
Chicken and ground beef contain almost the same amount of tryptophan as turkey — about 350 milligrams per 4-ounce serving.
Swiss cheese and pork actually contain more tryptophan per gram than turkey,
The amount of tryptophan in a single 4-ounce serving of turkey (350 milligrams) is also lower than the amount typically used to induce sleep. The recommendations for tryptophan supplements to help you sleep are 500 to 1,000 milligrams.
[http://www.webmd.com/food-recipes/the-truth-about-tryptophan?page=2](http://www.webmd.com/food-recipes/the-truth-about-tryptophan?page=2)
>The small, all-carbohydrate snack is tryptophan's ticket across the blood-brain barrier, where it can boost serotonin levels. So have your turkey, Somer says, because it will increase your store of tryptophan in the body, but count on the carbohydrates to help give you the mood boost or the restful sleep.
>"Research shows that a light, 30 gram carbohydrate snack just before bed will actually help you sleep better," Somer says.
---
## Histamine
* Made from histidine, metabolized by monoamine oxidase
* Made by neurons in hypothalamus that send projections to all regions of the brain and spinal cord.
* Mediates arousal and attention.
* Histamine receptors are in the immune system and in the CNS. The sedative side effects of Benadryl act through the CNS.
Note:
* H1 receptors (antagonists used for treating motion sickness because role in vestibular function)
* H2 receptors control secretion of gastrci acid in digestive system
*transported into vesicle by VMAT as catecholamines*
---
## Synthesis of histamine and serotonin
<div><img src="figs/Neuroscience5e-Fig-06.14-0_8dfa976.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Widespread projections from histaminergic and serotonergic neurons in the human brain
<div><img src="figs/Neuroscience5e-Fig-06.13-0_4dffa68.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Serotonin synthesis video summary
<div><video height=400px controls src="figs/Animation06-05NeurotransmitterPathwaysSerotonin.mp4"></video><figcaption>Neuroscience 5e Animation 6.5</figcaption></div>
Note:
---
## Peptide neurotransmitters
* 3-36 or so amino acids, cleaved from larger precursor proteins
* Catabolized by peptidases
* 5 general classes, brain/gut peptides, opioid peptides, pituitary peptides, hypothalamic releasing hormones, all others.
* Packaged into large dense core vesicles (amino acids are packaged into small clear core vesicles).
* Generally used as co-transmitters
Note:
* Many peptide known to be hormones also act as neurotransmitters
* melanocyte-stimulating hormone, adrenocorticotropin, Beta-endorphin regulate complex responses to stress
* substance P and opioid peptides involved in the perception of pain
---
## Amino acid sequences of peptide neurotransmitters
<div><img src="figs/Neurscience5e-Fig-7_457014e.jpg" height="100px"><figcaption></figcaption></div>
Note:
---
## Examples of peptide neurotransmitters
Endogenous opioid peptide.
Note:
---
## Synthesis of neuropeptides
Neuropeptides are synthesized as pre-propeptides in the nerve cell bodies.
This includes a signal sequence that targets the peptides to the inside of the endoplasmic reticulum.
The signal sequence is cleaved to form the propeptide.
Note:
---
## Synthesis of neuropeptides
ACTH– adrenocorticotripic hormone
modulation of pain
Note:
Proteolytic processing of the pre-propeptides, pre-proopiomelanocortin and pre-proenkaphalin
Processing the polypeptides that make the final neuropeptdies happens in an neurons cell body. Propeptide packaged into vesicles in golgi network. Final peptide processing occurs after packaging into vesicles. Multiple neuroactive peptides can be released from a single vesicle.
melanocyte-stimulating hormone, adrenocorticotropin, Beta-endorphin regulate complex responses to stress
---
## Synthesis of neuropeptides
<div><img src="figs/Neuroscience5e-Fig-06.16-2R_2af6762.jpg" height="100px"><figcaption></figcaption></div>
Note:
Proteolytic processing of the pre-propeptides, pre-proopiomelanocortin and pre-proenkaphalin
---
## Peptide dense core vesicles
<div><img src="figs/05_003_816f885.jpeg" height="100px"><figcaption></figcaption></div>
Note:
Neurons very often make both a conventional neurotransmitter (such as glutamate, GABA or dopamine) and one or more neuropeptides. Peptides are generally packaged in large dense-core vesicles, and the co-existing neurotransmitters in small synaptic vesicles.
The large dense-core vesicles are often found in all parts of a neuron, including the soma, dendrites, axonal swellings (varicosities) and nerve endings, whereas the small synaptic vesicles are mainly found in clusters at presynaptic locations.
This refers to the larger amount of material inside the dense-core vesicles, which contain not only neurotransmitters, but also proteases and other peptide chains that have been cleaved from the active neurotransmitter.
Greater electron scattering in EM:
Chemical fixation – for biological specimens aims to stabilize the specimen's mobile macromolecular structure by chemical crosslinking of proteins with aldehydes such as formaldehyde and glutaraldehyde, and lipids with osmium tetroxide.
---
## Clear core vesicles release upon a single action potential
Neuroscience 5e 5.12
<div><img src="figs/PN06050_48d4116.jpg" height="100px"><figcaption></figcaption></div>
Note:
release of small molecule transmitters inside clear core vesicles
---
## Large core release after multiple action potentials
Neuroscience 5e 5.12
Note:
release of both types of neurotransmitter
---
## Examples of peptide neurotransmitters
* Substance P– 16 amino acid peptide
* Present in human hippocampus, neocortex, and GI tract (hence a brain-gut peptide)
* Involved in the perception of pain
* Released from C-fibers which carry information about pain and temperature
Note:
accidental discovery of substance P. ominous sounding compound from Area 51? No. It was an unidentified component of power extracts from brain and intestine. High conc. in hippocampus, neocortex, and GI tract. A brain/gut peptide. Release of Subst P in cfibers can be inhibited by spinal interneurons releasing opioid peptides.
---
## Opioids
* Bind to same post-synaptic receptors as opium
* Family with more than 20 members, three basic groups: endorphins, enkephalins, and dynorphins
* Often co-localized with GABA and serotonin
* Tend to act as depressants, used for analgesics
* Repeated use often leads to tolerance and addiction
Note:
Opioids are named because they bind to same postsynaptic receptors as opium.
* -opium poppy cultivated for 5000 yrs
* -opium contains a variety of plant alkaloids, predominantly morphine. Morpheus, greek god of dreams. Very effective analgesic. Fentanyl, synthetic opiate with 80 times analgesic potency of morphine
Opioid peptides distributed throughout the brain. Colocalize with GABA and 5-HT. Tend to be depressants. They act like analgesics when injected intracerebrally. Initiate effects through GPCRs. Activate at low concentrations (nM to uM). mu, delta, kappa opioid receptor subtypes play role in reward and addiction. mu-receptor is primary site for opiate drugs.
---
## Cannabinoids
* Cannabinoids
* Δ9-tetrahydrocannabinol (THC)
* Endocannabinoids
* anandamide
* 2-arachidonylglycerol (2-AG)
* Bind to G-protein coupled receptors (GPCRs): CB1 & CB2
* CB1 enriched in substantia nigra, caudate putamen, neocortex, hippocampus, cerebellum
<div><img src="figs/Neuroscience5e-Box-06G-3R_0a7cb48.jpg" height="100px"><figcaption></figcaption></div>
<div><img src="figs/Neuroscience5e-Box-06G-4R_8fb7d74.jpg" height="100px"><figcaption></figcaption></div>
<div><img src="figs/Neuroscience5e-Box-06G-1R_7963b9b.jpg" height="100px"><figcaption></figcaption></div>
Note:
used for hemp (fiber, oil, seed)
cannabis sativa
cannabis indica
* -A hybrid Cannabis strain (White Widow) (which contains one of the highest amounts of Cannabidiol), flower coated with trichomes, which contain more THC than any other part of the plant
phytocannabinoids (85 active identified in cannabis)
THC:
-agonist of both CB1 and CB2
-mild to moderate analgesic effects (dorsal root ganglion and PAG), antiemetic (anti-nausea)
-tolerance appears to be irregular throughout mouse brain areas
-possesses mild antioxidant activity
* Bioavailability10–35% (inhalation), 6–20% (oral)[3]
* Protein binding97–99%[3][4][5]
* MetabolismMostly hepatic by CYP2C[3]
* Biological half-life1.6–59 h,[3] 25–36 h (orally administered dronabinol)
* Excretion65–80% (feces), 20–35% (urine) as acid metabolites[3]
cannabidiol: a major phytocannabinoid, accounting for up to 40% of the plant's extract. More complex effects than THC, may potentiate effects through CB1 density increases, inhibition of FAAH. Allosteric modulator of mu-opioid receptors. Less understood.
cannabinol: higher affinity for CB2 (but weaker than THC)
Unconventional neurotransmitters. released from neurons, regulated by Ca²⁺, and have specific receptors, but not released from synapses by exocytotic vesicle mechanisms. Often unconventional NTs are associated with retrograde signaling from post to pre.
[from https://en.wikipedia.org/wiki/Anandamide](https://en.wikipedia.org/wiki/Anandamide)
>Anandamide, also known as N-arachidonoylethanolamine or AEA, is an essential fatty acid neurotransmitter derived from the non-oxidative metabolism of eicosatetraenoic acid (arachidonic acid) an essential ω-6 polyunsaturated fatty acid
>Anandamide's effects can occur in either the central or peripheral nervous system. These distinct effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery.[6] The latter are mainly involved in functions of the immune system.
These endocannabinoids are actually unsaturated fatty acids from enzymatic digestion of membrane lipids. Production stimulated by second messengers within postsynaptic neuron, typically a rise in postsynaptic Ca²⁺ concentration.
-anandamide
-2-arachidonylglycerol (2-AG)
Mechanism of release not clear, but likely that these hydrophobic signals diffuse through the postsynaptic membrane to reach cannabinoid receptors on nearby cells. Action terminated by carrier mediated transport into postsynaptic neuron and hydrolyzed by enzyme fatty acid hydrolase (FAAH).
-rimonabant, synthetic drug
GPCRs:
CB1 enriched in substantia nigra, caudate putamen, neocortex, hippocampus, cerebellum
CB2 expressed in cells throughout the immune system. T cells, macrophages, B cells, peripheral nerve terminals (relief of pain), microglial cells
major CB2 targets are: >immune and immune-derived cells (e.g. leukocytes, various populations of T and B lymphocytes, monocytes/macrophages, dendritic cells, mast cells, microglia in the brain, Kupffer cells in the liver, etc.
>multiple intracellular signal transduction pathways are activated. At first, it was thought that cannabinoid receptors mainly inhibited the enzyme adenylate cyclase (and thereby the production of the second messenger molecule cyclic AMP), and positively influenced inwardly rectifying potassium channels (=Kir or IRK).[25] However, a much more complex picture has appeared in different cell types, implicating other potassium ion channels, calcium channels, protein kinase A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun and many more.[#Demuth:2006]
inhibits inhibition on presynaptic GABAergic neurons. Inhibits IPSCs. disinhibitory effect.
[#Demuth:2006]: Demuth DG, Molleman A (2006). "Cannabinoid signalling". Life Sci. 78 (6): 549–63. doi:10.1016/j.lfs.2005.05.055. PMID 16109430.
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## Summary
<div><img src="figs/Neuroscience5e-Tab-06.01_cec3255.jpg" height="100px"><figcaption></figcaption></div>
Note:
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