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neurotransmitters1.md
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@@ -3,7 +3,7 @@
* More than 100 different molecules
* Two main types–
* small molecule neurotransmitters
- acetylcholine, amino acids, biogenic amines, purines
- acetylcholine, amino acids, monoamines, purines
* peptide neurotransmitters
- polypeptides, 3–36 amino acids in length and often derived from longer polypeptides
@@ -15,24 +15,6 @@ Abnormalities of neurotransmitter function contributes to wide range of neurolog
two types: very small molecule and big molecule neurotransmitters.
--
## Synaptic vesicle types
<div><figcaption class="big">small clear-core vesicles</figcaption><img src="figs/Neuroscience5e-Fig-05.05-2R_copy_30d366b.jpg" width="300px"><figcaption>Neuroscience 5e Fig. 5.5</figcaption></div>
<div><figcaption class="big">large dense-core vesicles</figcaption><img src="figs/Neuroscience5e-Fig-05.05-4R_copy_0b0e2ec.jpg" width="300px"><figcaption>Neuroscience 5e Fig. 5.5</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 fixation aims to stabilize the specimen's macromolecular structure by chemical crosslinking of proteins with aldehydes such as formaldehyde and glutaraldehyde and lipids with osmium tetroxide.
---
## Small-molecule neurotransmitters
@@ -42,7 +24,7 @@ Chemical fixation
<figure style="margin:25px 0;"><figcaption class="big">purines</figcaption><img src="figs/Neuroscience5e-Fig-06.01-3R_copy_2d816ba.jpg" width="300px"><figcaption>Neuroscience 5e Fig. 6.1</figcaption></figure>
</div>
<div><figcaption class="big">amino acids</figcaption><img src="figs/Neuroscience5e-Fig-06.01-2R_copy_55575eb.jpg" width="300px"><figcaption>Neuroscience 5e Fig. 6.1</figcaption></div>
<div><figcaption class="big">biogenic amines</figcaption><img src="figs/Neuroscience5e-Fig-06.01-4R_copy_6c270be.jpg" width="300px"><figcaption>Neuroscience 5e Fig. 6.1</figcaption></div>
<div><figcaption class="big">biogenic amines (monoamines)</figcaption><img src="figs/Neuroscience5e-Fig-06.01-4R_copy_6c270be.jpg" width="300px"><figcaption>Neuroscience 5e Fig. 6.1</figcaption></div>
Note:
@@ -74,8 +56,8 @@ Note:
<div></div>
* Synthesis can occur
* at the soma (neuropeptides)
* at synaptic terminals (small molecule transmitters)
* at the soma (neuropeptides)
* at synaptic terminals (small molecule transmitters)
* Vesicle packaging– requires specific transporters on vesicle membrane. There are small clear-core vesicles (ACh and amino acids) and large dense-core (neuropeptides). Biogenic amines can be in either vesicle type.
</div>
@@ -86,6 +68,9 @@ Small molecules are generated from biosynthetic enzymes
Neuropeptides are generated by translation followed by post-translational processing
*Biogenic amines present in either type of vesicle*
What about unconventional neurotransmitters such as ATP, NO, endocannabinoids? What type of packaging for release if any?
<!-- *synthesis, packaging, secretion, and removal of neurotransmitters*
<figure><img src="figs/Neuroscience5e-Fig-05.03-0R_a8b0a13.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 5.3</figcaption></figure> -->
@@ -98,8 +83,23 @@ large dense-core vesicles
: electron dense centers
: 90–250 nm diameter
--
<!-- Release– small clear-core vesicles release fast, large dense-core vesicles take more effort. Location in synapses is different -->
## Synaptic vesicle types
<div><figcaption class="big">small clear-core vesicles</figcaption><img src="figs/Neuroscience5e-Fig-05.05-2R_copy_30d366b.jpg" width="400px"><figcaption>Neuroscience 5e Fig. 5.5</figcaption></div>
<div><figcaption class="big">large dense-core vesicles</figcaption><img src="figs/Neuroscience5e-Fig-05.05-4R_copy_0b0e2ec.jpg" width="400px"><figcaption>Neuroscience 5e Fig. 5.5</figcaption></div>
Note:
Neurons often make both a conventional small molecule neurotransmitter (such as glutamate, GABA or dopamine) together with one or more neuropeptides. Peptides are generally packaged in large dense-core vesicles, and the small molecule 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 fixation aims to stabilize the specimen's macromolecular structure by chemical crosslinking of proteins with aldehydes such as formaldehyde and glutaraldehyde and lipids with osmium tetroxide.
---
@@ -145,7 +145,7 @@ Note:
---
## Large dense-core vesicles release after high frequency AP stimulation
## Large dense-core vesicles release after high frequency stimulation
<figure><img src="figs/Neuroscience5e-Fig-05.12-0R_5f31ced.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.12</figcaption></figure>
@@ -154,6 +154,13 @@ Note:
* release of small molecule transmitters inside clear core vesicles
* release of both types of neurotransmitter
TODO:
* experimental evidence
* spatial location of release
Release– small clear-core vesicles release fast, large dense-core vesicles take more effort. Location in synapses is different
---
@@ -168,7 +175,7 @@ Note:
* aspartate
* GABA
* glycine
* Biogenic amines
* Monoamines
* dopamine
* norepinephrine
* epinephrine
@@ -195,6 +202,7 @@ ACh: skeletal muscle excitation vs release from vagus nerve that slows down hear
* Ligand gated channel that depolarizes skeletal muscle fibers vs g-protein coupled receptor that results in hyperpolarization of cardiomyocytes.
Typical enzyme rates may be 1000 substrates molecules per second. AChE thought to be one of the fastest enzymes in the body.
choline
: a water soluable essential nutrient
@@ -203,6 +211,9 @@ choline
: choline is part of phophatidylcholine and sphingolipids (sphingomyelin in myelin) phospholipids on cell membranes
: also acetylcholine precursor
ACh discovery and WWI history timeline
---
## Acetylcholine synthesis
@@ -218,6 +229,7 @@ choline acetyltransferase...
VAChT packs ACh into vesicles using the acidic vesicle's proton gradient. The gradient is established through active transport by the standard vacuolar H+-ATPase (V-ATPase), a highly conserved enzyme to convert ATP hydrolysis energy to proton transport across membranes.
--
## AChE Inhibition
@@ -227,7 +239,7 @@ VAChT packs ACh into vesicles using the acidic vesicle's proton gradient. The gr
* 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
* 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>
@@ -236,6 +248,8 @@ VAChT packs ACh into vesicles using the acidic vesicle's proton gradient. The gr
Note:
parasympathetic (Ach) vs sympathetic (norep)
--
## Acetylcholine synthesis video summary
@@ -258,7 +272,7 @@ Note:
* aspartate
* GABA
* glycine
* Biogenic amines
* Monoamines
* dopamine
* norepinephrine
* epinephrine
@@ -294,14 +308,28 @@ Glutamate (glutamic acid) is non-essential a.a. (meaning non-essential per dieta
---
## Glutamate
## Glutamate synthesis
<figure><img src="figs/Neuroscience5e-Fig-06.05-0_9d0ed18.jpg" height="500px"><figcaption>Neuroscience 5e Fig. 6.5</figcaption></figure>
<div style="width:300px;float:left;font-size:0.7em;">
<div></div>
* synthesized from **glutamine** by **glutaminase**
* packaged into vesicles by vesicular glutamate transporters (**VGLUT**) using proton gradient setup by V-ATPase
* removed from cleft by excitatory amino acid transporter **EAAT**
* converted into glutamine by glutamine synthetase in the glial cell
* tranported back to neuron via system N transporter 1 (**SN1**) and system A transporter 2 (**SAT2**)
</div>
<div style="margin:0 20px"><img src="figs/Neuroscience5e-Fig-06.05-0_9d0ed18.jpg" height="500px"><figcaption>Neuroscience 5e Fig. 6.5</figcaption></div>
Note:
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.
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.
@@ -309,23 +337,15 @@ Glutamate in glial cells by EAAT converted into glutamine by enzyme glutamine sy
Glutamine then transported out by different transporter system N transporter 1 (SN1) then back into nerve cells by system A transporter 2 (SAT2).
essential AA: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.
--
<!--
## Glutamate
<figure><img src="figs/Neuroscience5e-Box-05C-1R_copy_8635591.jpg" height="400px"><figcaption></figcaption></figure>
Note:
* synthesized from **glutamine** by **glutaminase**
* packaged into vesicles by vesicular glutamate transporters (**VGLUT**) using proton gradient setup by V-ATPase
* removed from cleft by excitatory amino acid transporter **EAAT**
* converted into glutamine by glutamine synthetase in the glial cell
* tranported back to neuron via system N transporter 1 (**SN1**) and system A transporter 2 (**SAT2**)
TODO: better EM evidence, scale bars etc
-->
--
@@ -354,7 +374,7 @@ As many as a third of synapses in the brain use GABA as an inhibitory transmitte
glycine encephalopathy:
[http://ghr.nlm.nih.gov/condition/glycine-encephalopathy](http://ghr.nlm.nih.gov/condition/glycine-encephalopathy)
from [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.
@@ -379,9 +399,18 @@ Strychnine
---
## Synthesis of the inhibitory neurotransmitter GABA
## GABA synthesis
<figure><img src="figs/Neuroscience5e-Fig-06.08-1R_ec0f42e.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 6.8</figcaption></figure>
<div style="width:300px;float:left;font-size:0.7em;">
<div></div>
* synthesized from glutamate by glutamic acid decarboxylase (**GAD**)
* transported into vesicles by vesicular inhibitory amino acid transporter (**VIAAT**), using proton gradient setup by V-ATPase.
* Removal by neurons and glia by Na⁺ dependent cotransporters for GABA called **GATs**
</div>
<div style="margin:0 20px;"><img src="figs/Neuroscience5e-Fig-06.08-1R_ec0f42e.jpg" height="450px"><figcaption>Neuroscience 5e Fig. 6.8</figcaption></div>
Note:
@@ -391,11 +420,11 @@ transported into vesicles by vesicular inhibitory amino acid transporter (**VIAA
Removal by neurons and glia by Na⁺ dependent cotransporters for GABA called **GATs**
---
--
## Synthesis the inhibitory neurotransmitters glycine
## Glycine synthesis
<figure><img src="figs/Neuroscience5e-Fig-06.08-2R_4f2491c.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 6.8</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-06.08-2R_4f2491c.jpg" height="450px"><figcaption>Neuroscience 5e Fig. 6.8</figcaption></figure>
Note:
@@ -406,7 +435,7 @@ Transported into vesicles by vesicular inhibitory amino acid transporter (**VIAA
Removal by neurons and glia by Na⁺ dependent glycin cotransporters **GATs**
taurine and beta-alanine (other amino acids) can act as agonists for glycine receptors and also gaba receptors to some degree [Mori:2002]
Taurine and beta-alanine (other amino acids) can act as agonists for glycine receptors and also gaba receptors to some degree [Mori:2002]
[Mori:2002]: Mori M., Gahwiler B. H. and Gerber U. (2002) Beta-alanine and taurine as endogenous agonists at glycine receptors in rat hippocampus in vitro. J. Physiol. 539, 191–200
@@ -424,7 +453,7 @@ taurine and beta-alanine (other amino acids) can act as agonists for glycine rec
* aspartate
* GABA
* glycine
* Biogenic amines <!-- .element: class="fragment highlight-red" -->
* Monoamines <!-- .element: class="fragment highlight-red" -->
* dopamine
* norepinephrine
* epinephrine
@@ -438,17 +467,18 @@ Note:
---
## Monoamine neurotransmitters
## Monoamine neurotransmitters (biogenic amines)
* Catecholamines– dopamine, norepinephrine, and epinephrine
* All derived from tyrosine. Tyrosine hydroxylase is the rate limiting step and is a good histological marker for catecholaminergic neurons
* 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:
Monoamines (a subset of biogenic amines. Biogenic amines are monoamines + trace amines like like tryptamine, phenethylamine) regulate many functions in the CNS and PNS. Ranging from homeostatic functions to cognition and attention.
**Monoamines** (a subset of biogenic amines. Biogenic amines are monoamines + trace amines like like tryptamine, phenethylamine, melatonin) 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
@@ -499,11 +529,11 @@ Amphetamine also inhibits DAT as well as a transporter for norepinephrine
* neostriatum
* Part of
* Basal ganglia[1]
* Reward system[2][3]
* Basal ganglia
* Reward system
* Components
* Ventral striatum[2][3][4
* Dorsal striatum[2][3][4]
* Ventral striatum
* Dorsal striatum
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.
@@ -590,16 +620,19 @@ Note:
* Epinephrine/Adrenaline– present at lower levels than the others
* Epinephrine made by neurons in rostral medulla. Project to thalamus and hypothalamus
<!--
---
## Epinephrine
* Adrenaline– present at lower levels than the others
* Made by neurons in rostral medulla. Project to thalamus and hypothalamus
--
## Projections from adrenergic neurons in the human brainstem
<figure><img src="figs/Neuroscience5e-Fig-06.11-3R_9d1377d.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 6.11</figcaption></figure>
-->
---
@@ -609,27 +642,25 @@ Note:
* 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)
* Many antidepressants act by inhibiting serotonin reuptake (selective serotonin reuptake inhibitors-SSRIs; e.g. 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
*See Fig. 6.17 Neuroscience 6e*
Note:
* dorsal raphe and median raphe nuclei. In brain stem. raphe nuclei just ventral to the 4th ventricle stretching from medulla
* vesiclular monoamine transporter **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.
turkey/tryptophan—> sleep? Yes— but not really ([http://www.snopes.com/food/ingredient/turkey.asp](http://www.snopes.com/food/ingredient/turkey.asp)), you’d have to eat a lot more (maybe 3x more) than at a particular meal. And furthermore, lots of protein sources include amounts of tryptophan similar to or greater than that of turkey per gram of food content (including eggs, fish, cheese, also nuts, seeds, legumes).
[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. For depression it can be 3000 mg or more
And besides well timed carbohydrate ingestion with/after tryptophan consumption is important for increasing tryptophan transport from blood vessels and into brain tissue:
[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.
>The small, all-carbohydrate snack is tryptophan's ticket across the blood-brain barrier, where it can boost serotonin levels.
---
@@ -640,12 +671,14 @@ The amount of tryptophan in a single 4-ounce serving of turkey (350 milligrams)
* Mediates arousal and attention
* Histamine receptors are in the immune system and in the CNS. Sedative effects of diphenhydramine (Benadryl) act through the CNS
*See Fig. 6.17 Neuroscience 6e*
Note:
* synthesized from histidine by
* H1 receptors (antagonists used for treating motion sickness because role in vestibular function)
* H2 receptors control secretion of gastrci acid in digestive system
* H2 receptors control secretion of gastric acid in digestive system
*transported into vesicle by VMAT as catecholamines*
@@ -684,7 +717,7 @@ Note:
## Amino acid sequences of peptide neurotransmitters
<figure><img src="figs/Neuroscience5e-Fig-06.17-0_8eb7593.jpg" height="400px"><figcaption> Neuroscience 5e fig. 6.17</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-06.17-0_8eb7593.jpg" height="500px"><figcaption> Neuroscience 5e fig. 6.17</figcaption></figure>
Note:
@@ -754,6 +787,10 @@ Opioids are named because they bind to same postsynaptic receptors as opium.
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.
TODO: opiate drug info
Naloxone is a non-selective and competitive opioid receptor antagonist.
--
## Examples of peptide transmitters– Substance P
@@ -772,25 +809,27 @@ accidental discovery of substance P. Ominous sounding compound from Area 51? No
---
## Unconventional neurotransmitters– Cannabinoids
## Unconventional neurotransmitters– cannabinoids
<div style="width:600px;float:left;font-size:0.7em;">
<div></div>
* Cannabinoids
* Endocannabinoids
* anandamide <img style="display:inline;vertical-align:middle;margin:none;border:none;" src="figs/Anandamide_7fa01d6.svg" height="25px">
* 2-arachidonylglycerol (2-AG) <img style="display:inline;vertical-align:middle;margin:none;border:none;" src="figs/2-Ara-Gl_544fac0.svg" height="25px">
* Δ<sup>9</sup>-tetrahydrocannabinol (THC) <img style="display:inline;vertical-align:middle;margin:none;border:none;" src="figs/Tetrahydrocannabinol_b4f21b0.svg" height="25px">
* main psychoactive compound in *cannabis sativa*/*indica* <img style="display:inline-block;vertical-align:middle;margin:none;border:none;" src="figs/Neuroscience5e-Box-06G-1R_1bc059e.jpg" height="25px">
* anandamide
* 2-arachidonylglycerol (2-AG)
* Δ<sup>9</sup>-tetrahydrocannabinol (THC)
* main psychoactive compound in *cannabis sativa*/*indica*
* Bind to G-protein coupled receptors (GPCRs): CB1 & CB2
* CB1 enriched in substantia nigra, caudate putamen, neocortex, hippocampus, cerebellum
</div>
<div style="float:left;"><figcaption class="big">CB1 expression in rodent</figcaption><img src="figs/Neuroscience5e-Box-06G-4R_ece2b22.jpg" width="300px"><figcaption>Neuroscience 5e Box 6. M. Herkenham, NIMH</figcaption></div>
<!-- <div><img src="figs/Neuroscience5e-Box-06G-3R_64fbca1.jpg" height="100px"><figcaption>Neuroscience 5e Box 6</figcaption></div> -->
<div>
<figcaption class="big">Anandamide</figcaption><img style="margin:none;border:none;" src="figs/Anandamide_7fa01d6.svg" height="100px">
<figcaption class="big">2-AG</figcaption><img style="margin:none;border:none;" src="figs/2-Ara-Gl_544fac0.svg" height="100px">
<figcaption class="big">THC</figcaption><img style="margin:none;border:none;" src="figs/Tetrahydrocannabinol_b4f21b0.svg" height="100px">
</div>
Note:
@@ -875,9 +914,22 @@ Other cannabinoid-like compounds found in other plants (e.g. Echinacea). Some li
: 'Queen Anne's lace'
: domesticated carrots are cultivars of a subspecies
--
## CB1 receptors are expressed widely throughout the forebrain
<div style="float:left;"><figcaption class="big">CB1 expression in rodent</figcaption><img src="figs/Neuroscience5e-Box-06G-4R_ece2b22.jpg" width="600px"><figcaption>Neuroscience 5e Box 6. M. Herkenham, NIMH</figcaption></div>
<!-- <div><img src="figs/Neuroscience5e-Box-06G-3R_64fbca1.jpg" height="100px"><figcaption>Neuroscience 5e Box 6</figcaption></div> -->
Note:
TODO:
* human expression evidence
* human rodent brain comparison
---
## Summary
<figure><img src="figs/Neuroscience5e-Tab-06.01_copy_98ede88.jpg" height="400px"><figcaption>Neuroscience 5e Table 6.1</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Tab-06.01_copy_98ede88.jpg" width="800px"><figcaption>Neuroscience 5e Table 6.1</figcaption></figure>

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neurotransmitters2.md
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@@ -62,7 +62,21 @@ Metabotropic transmitter receptors are G-protein coupled receptors, also known a
* ion channel opens
* ions flow across membrane
Effector enzymes for activated G-proteins include adenylyl cyclase (ATP->cAMP), phopholipase C, guanylyl cyclase (GTP->cGMP) etc. Then downstream second messsaging (cAMP, diacylglycerol, IP3) --> protein kinases, Ca2+. And then more phosphorylation state changes.
Effector enzymes for activated G-proteins include:
* Gs: --> adenylyl cyclase --> ATP--> cAMP --> PKA --> incr prot phosphor
* Gq: phopholipase C --> [DAG --> PKC; IP3 --> Ca^2+^] --> incr prot phosphor, Ca binding proteins
* Gi: --< adenylyl cyclase --< cAMP --< PKA --> decr prot phosphor
* Or guanylyl cyclase (GTP->cGMP) --> Protein kinase G etc.
* All G-protein receptor activations lead to downstream second messsaging (cAMP, diacylglycerol, IP3) --> protein kinases, Ca2+ --> leading to phosphorylation state changes including... ion channels
* Three amplification steps here! (receptor production of G proteins, adenylyl cyclase production of cAMP, protein kinase substrate phosphorylation). Source signal amplification.
* 3% of our genome is codes for protein phosphorlation state genes (500 protein kinases and 200 protein phosphatases)
* cAMP dependent protein kinases (PKA)
* Ca^2+^ - calmodulin depedent protein kinase type II (CaMKII predominant in neurons, most abundant protein component of the post synaptic density)
* Protein kinase C (PKC)- activated by Ca^2+ (moves PKC from cytosol to membrane) and diacylglycerol (DAG) and then phosphorylates substrates
--
@@ -291,7 +305,7 @@ Even though these ionotropic channels opened by ACh are permeable to both Na and
In fact the Na⁺ and K⁺ permeabilities of the nAChR channel are similar, therefore the **magnitudes of the Na⁺ and K⁺ currents depends on the driving forces present for each ion**
---
--
## Na⁺ and K⁺ movements during EPCs and EPPs
@@ -353,7 +367,7 @@ Note:
---
## Excitatory postsynaptic potential (IPSP)
## Excitatory postsynaptic potential (EPSP)
<!-- <figure><figcaption class="big">EPSP mediated by glutamate activating nonselective cation channels</figcaption><img src="figs/Neuroscience5e-Fig-05.21-0_807c820.jpg" width="500px"><figcaption>Neuroscience 5e Fig. 5.21</figcaption></figure> -->
@@ -474,8 +488,7 @@ Note:
<div><video height=400px controls src="figs/Animation05-02SummationofPostsynapticPotentials_OC.mp4"></video><figcaption>Neuroscience 5e Animation 5.2</figcaption></div>
---
<!--
## Midterm 1
```
@@ -487,3 +500,5 @@ median 84
```
<div><img src="figs/Midterm1-hist.png" height="400px"></div>
-->

19
neurotransmitters3.md
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@@ -15,6 +15,13 @@ As we’ve shown in our examples earlier the nAChR receptor is a non-selective c
*nAChR permeable to Na+, K+, and Ca2+*
In physiological solution, calcium flux estimated to be 2% of total current through nAchR. For comparison calcium flux is estimated to be 7% of the current in the voltage gated L-type calcium ion channel. But with high density clustering of many nAchRs at muscle end plate synapses, total calcium flux through these channels could influence the local environment significantly https://doi.org/10.1523/JNEUROSCI.10-10-03413.1990
This Ca^2+^ permeability depends on subunit composition of the nAchR pentamer. mammalian α9α10 receptors receptors show higher calcium ion selectivity (important function in cochlear hair cells) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245820/
from [#Picciotto:2000]:
>some subtypes of nAChR in the brain (those containing the b2 subunit) are located diffusely throughout the membrane of the neuron, with no obvious concentration at the synaptic junction (Hill et al. 1993).
@@ -205,6 +212,8 @@ Note:
* alternative splicing of each of the 4 subunit genes can result in a number of more isoforms
* GluR1 and GluR2 especially important in synaptic plasticity by being upregulated
* Non-selective cation channel like nAChr, but tetramer and less calcium permeability. mRNA editing of a intramembrane domain of the GluR2 subunit switches a glutamine to an arginine. This post translational modification results in AMPA receptors that have resistance to calcium permeability. Though AMPA-R usually contain one or more GluR2 subunits, ones that are missing GluR2 subunits do have more calcium permeability and may be important in developing neurons and early forms of synaptic plasticity in some neurons https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092818/
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@@ -376,11 +385,19 @@ Note:
* 5-HT3 is a ligand-gated non-selective cation channel, thus it is excitatory
* Same basic structure as nACh receptor
* All others are metabotropic– likely that perturbations in these receptors are involved in many neural disorders
* excitatory: 5-HT2,4,6,7
* inhibitory: 5-HT1,5
Note:
most receptors are metabotropic
* 7 members of family
* 5HT1, 5HT5 are Gi: inhibitory (decr cAMP)
* 5HT2,4,6,7 are Gs or Gq: excitatory (incr cAMP or incr IP3/DAG)
* 5HT3 is non selective ionotropic cation channel (excitatory)
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## Catecholamine receptors
@@ -392,6 +409,8 @@ most receptors are metabotropic
Note:
* more examples of catecholamine metabotropic receptors in action later in course (e.g. dopamine D1, D1 types in basal ganglia function)
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