diff --git a/neurophysiology4.md b/neurophysiology4.md
index ebc620b..c2dc523 100644
--- a/neurophysiology4.md
+++ b/neurophysiology4.md
@@ -96,9 +96,11 @@ In hippocampal neurons gap junctions can make neurons fire in synchrony
* 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
+ * brainstem neurons involved in breathing
* 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
@@ -107,6 +109,10 @@ important in diseases of pathological oscillations/synchrony like childhood epil
Electrical synapses and synchronization characterisitc of cells that stimulate pulses of pituitary hormones (e.g oxytocin/vasopressin secretion).
+medulla and pons, medulla: nucleus ambiguous, pre-botzinger complex, solitay nucleus
+
+connexins (chordates), innexins, pannexins, (invertebrates)
+
---
## Chemical synapses
diff --git a/neurotransmitters1.md b/neurotransmitters1.md
index 221eb2c..6452604 100644
--- a/neurotransmitters1.md
+++ b/neurotransmitters1.md
@@ -1,73 +1,92 @@
## 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
+* More than 100 different molecules
+* Two main types–
+ * small molecule neurotransmitters
+ - acetylcholine, amino acids, biogenic amines, purines
+ * peptide neurotransmitters
+ - polypeptides, 3–36 amino acids in length and often derived from longer polypeptides
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.
+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.
----
+Abnormalities of neurotransmitter function contributes to wide range of neurological diseases and psychiatric disorders
-## Major categories of neurotransmitters
+two types: very small molecule and big molecule neurotransmitters.
-* Small molecule neurotransmitters– acetylcholine, amino acids, biogenic amines, purines
-* Peptide neurotransmitters– 3-36 amino acid polypeptides, often derived from longer polypeptides
+--
+
+## Synaptic vesicle types
+
+
small clear-core vesiclesNeuroscience 5e Fig. 5.5
+
large dense-core vesiclesNeuroscience 5e Fig. 5.5
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.
+
---
-## Examples of small-molecule neurotransmitters
+## Small-molecule neurotransmitters
acetylcholineNeuroscience 5e Fig. 6.1purinesNeuroscience 5e Fig. 6.1
-
amino acidsNeuroscience 5e Fig. 6.1
+
amino acidsNeuroscience 5e Fig. 6.1
+
biogenic aminesNeuroscience 5e Fig. 6.1
Note:
Not expected to know chemical formulas for any neurotransmitters
----
-
-## Examples of small-molecule neurotransmitters
-
-biogenic aminesNeuroscience 5e Fig. 6.1
-
-
-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
+## Peptide neurotransmitters
peptidesmethionine enkephalin: an endogenous opioid peptide; Neuroscience 5e Fig. 6.1
Note:
+- also called neuropeptides
+
- usually 3-30 amino acids long
- more than 100 peptides
---
-## Neurotransmitter release can be regulated at many steps
+## Neurotransmitter synthesis
-* Synthesis–
- * Small molecules are generated from biosynthetic enzymes
- * Neuropeptides are generated by translation followed by post-translational 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 can be in either vesicle type. Location in synapses is different
-* Release– small clear-core vesicles release fast, large dense-core vesicles take more effort
+
+
+
+* Synthesis can occur
+ * 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.
+
+
Note:
+Small molecules are generated from biosynthetic enzymes
+
+Neuropeptides are generated by translation followed by post-translational processing
+
+
@@ -79,13 +98,21 @@ large dense-core vesicles
: electron dense centers
: 90–250 nm diameter
+
+
+
---
## Small molecule transmitters are synthesized at the presynaptic terminal
+
+
+
Enzymes produced in nerve cell body are transported down axon. Neurotransmitter is synthesized and packaged at synaptic terminal.
-Neuroscience 5e Fig. 5.5
+
+
+
Neuroscience 5e Fig. 5.5
Note:
@@ -99,9 +126,14 @@ Note:
## Peptide transmitters are synthesized in the cell body
+
+
+
Neuropeptides are synthesized in the nerve cell body, loaded into vesicles, and transported down the axon via microtubules.
-Neuroscience 5e Fig. 5.5
+
+
+
Neuroscience 5e Fig. 5.5
Note:
@@ -111,26 +143,6 @@ Note:
* proteolytic processing of propeptides by enzymes to produce peptide neurotransmitter
* peptide neurotransmitter diffuses away, degraded by proteolytic enzymes (typically on extracellular surface)
----
-
-## Synaptic vesicle types
-
-
small clear-core vesiclesNeuroscience 5e Fig. 5.5
-
large dense-core vesiclesNeuroscience 5e Fig. 5.5
-
-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.
-
-
---
## Large dense-core vesicles release after high frequency AP stimulation
@@ -183,14 +195,20 @@ 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.
---
-## Acetylcholine
+choline
+: a water soluable essential nutrient
+: quaternary ammonium salt
+: present in plant and animal tissues
+: choline is part of phophatidylcholine and sphingolipids (sphingomyelin in myelin) phospholipids on cell membranes
+: also acetylcholine precursor
-
-**choline acetyltransferase** (synthesis)
-**acetylcholinesterase** (degradation)
-Neuroscience 5e Fig. 6.2
+---
+
+## Acetylcholine synthesis
+
+
+Neuroscience 5e Fig. 6.2
Note:
@@ -198,7 +216,7 @@ from krebs cycle you get Acetyl CoA. Na-Choline cotransporter exchanges Na ions
choline acetyltransferase...
-VAChT packs ACh into vesicles
+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.
--
@@ -274,7 +292,7 @@ Glutamate (glutamic acid) is non-essential a.a. (meaning non-essential per dieta
*Monosodium glutamate (MSG, also known as sodium glutamate) is the sodium salt of glutamic acid*
---
+---
## Glutamate
@@ -283,9 +301,13 @@ Glutamate (glutamic acid) is non-essential a.a. (meaning non-essential per dieta
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.
+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.
+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.
+
+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.
@@ -298,6 +320,13 @@ essential AA: histidine, isoleucine, leucine, lysine, methionine, phenylalanine,
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**)
+
--
## Glutamate synthesis video summary
@@ -312,11 +341,11 @@ ACh role in Alzheimers: basal forebrain innervation to neocortex vs hippocampus.
## 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
+* Inhibitory neurons primarily use GABA or glycine
+* Activation of GABA or glycine receptors typically reduces probability of firing action potentials
+* GABA (gamma-aminobutyric acid)– made from glutamate by glutamic acid decarboxylase (GAD)
+ * GAD requires Vitamin B6 as cofactor
* 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:
@@ -348,27 +377,40 @@ Strychnine
: highly toxic, colorless, bitter crystalline alkaloid
: from *Strychnos nux-vomica* native to India, Sri Lanka, and Indonesia
+---
---
-
-## Synthesis, release, and reuptake of the inhibitory neurotransmitters GABA and glycine
+## Synthesis of the inhibitory neurotransmitter GABA
Neuroscience 5e Fig. 6.8
Note:
-transported into vesicles by vesicular inhibitory amino acid transporter (VIAAT)
+synthesized from glutamate by glutamic acid decarboxylase (**GAD**)
-Removal by neurons and glia by Na⁺ dependent cotransporters for GABA called GATs
+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**
-## Synthesis, release, and reuptake of the inhibitory neurotransmitters GABA and glycine
+---
+
+## Synthesis the inhibitory neurotransmitters glycine
Neuroscience 5e Fig. 6.8
Note:
+Synthesized from glucose by serine hydroxy-methlytransferase (**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 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]
+
+
+[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
+
---
## Small molecule neurotransmitters
@@ -396,7 +438,7 @@ Note:
---
-## Biogenic amines
+## Monoamine neurotransmitters
* Catecholamines– dopamine, norepinephrine, and epinephrine
* Histamine
@@ -406,7 +448,7 @@ Note:
Note:
-Biogenic amines 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) 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
@@ -434,7 +476,7 @@ Note:
* 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)
+* Cocaine works by inhibiting the dopamine cotransporter DAT
Note:
@@ -480,7 +522,7 @@ striatum.
anterior cingulate cortex
-->
---
+---
## Projections from dopaminergic neurons in the human brainstem
@@ -506,7 +548,7 @@ Note:
* 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
+* Used as a transmitter from locus coeruleus in brainstem (rostral pons)– projects to areas that are involved in sleep, attention, and feeding
* Its reuptake mechanism, the norepinephrine transporter (NET), is a target of amphetamines
Note:
@@ -517,7 +559,15 @@ Norep transporter (NET) is a Na⁺ depedent cotranporter. NET is a target of amp
alpha and beta adrengergic receptors. GPCRs. Some alphas lead to slow depolarization. Some lead to slow hyperpolarization (acting on different K⁺ channels).
---
+norepinephrine also released into blood by adrenal medulla of adrenal gland
+
+locus coeruleus
+: input– hypothalamus, cingulate cortex, amygdala, cerebellum, raphe nuclei
+: output– everywhere, spinal cord, brainstem, cerebellum, hypothalamus, thalamus, amygdala, cerebral cortex
+: activation mediates an excitatory effect, giving rise to arousal/wakefulness
+
+
+---
## Projections from noradrenergic neurons in the human brainstem
@@ -536,22 +586,21 @@ Note:
Note:
----
+* Epinephrine/Adrenaline– present at lower levels than the others
+* Epinephrine made by neurons in rostral medulla. Project to thalamus and hypothalamus
+
+
-Note:
---
@@ -560,47 +609,54 @@ 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; 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.
+* 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.
[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.
+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,
-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
-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)
+[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
+* Made from histidine, a metabolite of monoamine oxidase
+* Released by neurons in hypothalamus (tuberomammilary nucleus) that send projections to all parts 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
+* Histamine receptors are in the immune system and in the CNS. Sedative effects of diphenhydramine (Benadryl) act through the CNS
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
*transported into vesicle by VMAT as catecholamines*
----
+
+diphenhydramine
+: benadryl
+: inhibits H1 receptors
+: also has some serotonin reuptake inhibitor capability
+: also has some anticholinergic (muscarinic) capability
+
+--
## Synthesis of histamine and serotonin
@@ -608,24 +664,6 @@ Note:
Note:
---
-
-## Widespread projections from histaminergic and serotonergic neurons in the human brain
-
-Neuroscience 5e Fig. 6.13
-
-
-Note:
-
-
---
-
-## Serotonin synthesis video summary
-
-
Neuroscience 5e Animation 6.5
-
-Note:
-
---
## Peptide neurotransmitters
@@ -651,7 +689,7 @@ Note:
Note:
---
+---
## Synthesis of neuropeptides
@@ -687,29 +725,15 @@ ACTH
: increases production of cortisol in adrenal glands
---
+
---
-
-## Examples of peptide transmitters– Substance P
-
-* 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 powder 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.
---
@@ -730,11 +754,27 @@ 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.
+--
+
+## Examples of peptide transmitters– Substance P
+
+* 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 powder 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.
+
+
+
+
---
## Unconventional neurotransmitters– Cannabinoids
-
+
* Cannabinoids
@@ -748,7 +788,7 @@ Opioid peptides distributed throughout the brain. Colocalize with GABA and 5-HT.
-
CB1 expression in rodentNeuroscience 5e Box 6
+
CB1 expression in rodentNeuroscience 5e Box 6. M. Herkenham, NIMH
@@ -759,6 +799,8 @@ Unconventional neurotransmitters. Released from neurons, regulated by Ca²⁺, a
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.
+Ohno-Shosaku *Neuron* 2001: endocannabinoids act on cannabinoid receptors (CB1) to reduce GABA release from presynaptic inhibitory neurons. Inhibiting inhibition (disinhibition).
+
-anandamide
-2-arachidonylglycerol (2-AG)
@@ -786,12 +828,9 @@ Psychotropic
: psychoactive
: chemical substance that changes brain function resulting in altered perception, mood, or conciousness
-* cannabis sativa
-* cannabis indica
-* phytocannabinoids (85 active identified in cannabis)
-
-* used for hemp (fiber, oil, seed)
-* 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
+* cannabis sativa | cannabis indica
+ * used for hemp (fiber, oil, seed)
+ * phytocannabinoids (85 active identified in cannabis)
THC:
* agonist of both CB1 and CB2
@@ -842,7 +881,3 @@ Other cannabinoid-like compounds found in other plants (e.g. Echinacea). Some li
## Summary
Neuroscience 5e Table 6.1
-
-Note:
-
----
diff --git a/neurotransmitters2.md b/neurotransmitters2.md
index 6137d34..94c6f9e 100644
--- a/neurotransmitters2.md
+++ b/neurotransmitters2.md
@@ -1,34 +1,27 @@
## Neurotransmitter receptors
-* Embedded in the plasma membrane of post-synaptic cell
-* Two classes of neurotransmitter receptors–
- * receptors that are ion channels themselves (**ionotropic** or 'ligand-gated' ion channel)
- * receptors that interface with separate ion channels (**metabotropic**, or G-protein coupled receptors)
-* Ultimately, the binding of neurotransmitter results in the opening of ion channels and ion flux. This leads to either depolarization or hyperpolarization of the membrane potential depending on the **types of ions** flowing through the channel pores and the ions' respective **electrochemical driving forces**
+
+
+
+* Neurotransmitter receptors are embedded in the plasma membrane of the post-synaptic cell and are always one of the following:
+ 1. ion channels (**ionotropic** or 'ligand-gated' ion channel)
+ 2. receptors that interface with separate ion channels (**metabotropic**, or G-protein coupled receptors)
+* Neurotransmitter receptor activation following ligand (neurotransmitter) binding results in the opening of ion channels and ionic flux. This ion flux is the postsynaptic current (or 'end plate' current for a muscle cell)
+* These postsynaptic currents result in depolarization or hyperpolarization of the membrane potential (postsynaptic potential or 'end plate' potential) depending on the **types of ions** flowing through the channel pores and the ions' respective **electro-chemical driving forces**
+
+
Note:
-Today we will dive a bit deeper into the structure and function of neurotransmitter receptors... last time was a warm up
+Diving a bit deeper into the structure and function of neurotransmitter (NT) receptors now...
-For synaptic transmission, neurotrans receps are generally located in the post-synaptic membrane (*though there are exceptions, e.g. some transmitter receptors may be located on pre-synaptic membrane or at non synaptic site in the cell*).
+For synaptic transmission, NT receps are generally located in the post-synaptic membrane (*though there are exceptions, e.g. some transmitter receptors may be located on pre-synaptic membrane or at non synaptic site in the cell*).
-Two classes...
+Two classes of NT receptors.
-In either case, neurotransmitter binding will result in ion channels opening and ion flux across the post-synaptic membrane. Whether this results in hyperpolarization or depolarization of the membrane will be due to the types of ions flowwing through the channels and their respective electrical/chemical driving forces (Nernst)
+In either case, NT binding will result in ion channels opening and ion flux across the post-synaptic membrane. Whether this results in hyperpolarization or depolarization of the membrane will be due to the types of ions flowing through the channels and their respective electrical/chemical driving forces (Nernst)
-
+Changing the postsynaptic membrane potential inturn affects the **electrochemical** driving forces regulating ion flux. So currents may change amplitude and direction during the course of a postsynaptic potential. Read on...
---
@@ -54,6 +47,8 @@ The ionotropic receptors are the ones you’ve probably seen in our synaptic dia
## Metabotropic neurotransmitter receptors
+* G-protein coupled receptor signalling results in modulation of nearby ion channels for metabotropic receptors.
+
Neuroscience 5e fig. 5.16
@@ -68,7 +63,7 @@ Metabotropic transmitter receptors are G-protein coupled receptors, also known a
* ions flow across membrane
----
+--
## Neurotransmitter receptors video summary
@@ -76,14 +71,13 @@ Metabotropic transmitter receptors are G-protein coupled receptors, also known a
Note:
-
---
## Nicotinic acetylcholine receptors (nAChR)
* Ionotropic receptor
-* ACh binds the nAChR– opens the channel
-* ACh causes nAChR to open transiently and stochastically (patch clamp studies)
+* Acetylcholine (ACh) binds the nAChR– this opens the channel
+* ACh causes nAChR to open *transiently* and *stochastically* (patch clamp studies)
* An action potential causes lots of ACh molecules to be released simultaneously, transiently opening many nACh receptors
* The summed current flow into the muscle cell is called the end plate current (EPC). Current flow changes the transmembrane potential of the muscle, the end plate potential (EPP), which triggers an action potential
@@ -93,14 +87,20 @@ So to understand the properties of ionotropic neurotransmitter receptors lets st
nACh Receptors are ionotropic or ligand-gated receptors where the ligand is ACh and are the receptor you’ve heard the most thus far, being the one that underlies end plate currents at the neuromuscular junction that cause end plate potentials in muscle cells.
-ACh causes...
+stochastic
+: having a random probability distribution or pattern that may be analyzed statistically but may not be predicted precisely
---
## Patch clamping shows ACh gated currents through nicotinic ACh receptors
-
Patch clamp recording of current through single nAChR. Channels open for varying amounts of time while ACh is bound.Neuroscience 5e Fig. 5.17
+
+Patch clamp recording of current through single nAChR.
+Channels open for varying amounts of time while ACh is bound.
+
+Neuroscience 5e Fig. 5.17
+
Note:
@@ -118,38 +118,41 @@ If this piece of membrane and channel is from a muscle cell than a bunch of thes
## Activation of nAChR at neuromuscular synapses
-
end plate currents in a voltage-clamped muscle cellNeuroscience 5e Fig. 5.17
+
end plate currents in a voltage-clamped muscle cellNeuroscience 5e Fig. 5.17
-depolarizing end plate potential recorded in muscle cell due
-to the inward end plate currents
+depolarizing end plate potential recorded
+in muscle cell due to the inward end plate currents
Neuroscience 5e Fig. 5.17
Note:
-Indeed imagine we are doing an experiment where we stimulate a motor neuron and we record end plate currents in a muscle cell...
+Imagine we are doing an experiment where we stimulate a motor neuron and we record end plate currents in a muscle cell...
-...then these traces on the left show inward currents through these ionotropic ACh channels in the muscle cell, showing the currents stemming from a single channel, 10 channels, and hundreds of thousands of channels. Notice the amplitudes of the currents scale.
+...then the traces on the left show inward currents through these ionotropic ACh channels in the muscle cell, showing the currents stemming from a single channel, 10 channels, and hundreds of thousands of channels. Notice the amplitudes of the currents scale.
-...and this panel on the right shows postsynaptic potential change or end plate potential produced by the EPC as we discussed previously
+...and the panel on the right shows postsynaptic potential change or end plate potential produced by the EPC as we discussed previously
-As we will learn in a few minutes, the channel opened by ACh lets mostly Na⁺ through resulting in these inward currents that depolarize the muscle cell, resulting in EPPs and typically resulting in APs as we’ve discussed before.
+As we will learn shortly, the channel opened by ACh lets mostly Na⁺ through resulting in these inward currents that depolarize the muscle cell, resulting in EPPs and typically resulting in APs as we’ve discussed before.
+
+[from http://www.ncbi.nlm.nih.gov/books/NBK21586/](http://www.ncbi.nlm.nih.gov/books/NBK21586/):
+
+>Two factors greatly assisted in the characterization of the nicotinic acetylcholine receptor. First, this receptor can be rather easily purified from the electric organs of electric eels and electric rays; these organs are derived from stacks of muscle cells (minus the contractile proteins) and thus are richly endowed with this receptor. (In contrast, this receptor constitutes a minute fraction of the total membrane protein in most nerve and muscle tissues.) Second, α-bungarotoxin, a neurotoxin present in snake venom, binds specifically and irreversibly to nicotinic acetylcholine receptors.
+
+* acetylcholine causes opening of a cation channel in the receptor capable of transmitting 15,000 – 30,000 Na⁺ or K⁺ ions a millisecond
-[from http://www.ncbi.nlm.nih.gov/books/NBK21586/: ](http://www.ncbi.nlm.nih.gov/books/NBK21586/)
-* *acetylcholine causes opening of a cation channel in the receptor capable of transmitting 15,000 – 30,000 Na⁺ or K⁺ ions a millisecond*
-* - >Two factors greatly assisted in the characterization of the nicotinic acetylcholine receptor. First, this receptor can be rather easily purified from the electric organs of electric eels and electric rays; these organs are derived from stacks of muscle cells (minus the contractile proteins) and thus are richly endowed with this receptor. (In contrast, this receptor constitutes a minute fraction of the total membrane protein in most nerve and muscle tissues.) Second, α-bungarotoxin, a neurotoxin present in snake venom, binds specifically and irreversibly to nicotinic acetylcholine receptors.
---
-## How do we figure out what ions flow through the nicotinic ACh receptor?
+## What ions flow through the nicotinic ACh receptor?
-
+
-* Recall from Nernst equation– the equilibrium potential of a cell for ion *x* is the potential at which the electrochemical driving forces is balanced for ion *x* (i.e there is no net flow of ion *x* at the equilibrium potential *Ex*)
-* Thus if one measured the ACh dependent current flow at different potentials, one could determine the membrane potential (*Vm*) where current is 0. This is called the **reversal potential** or *Erev*
+* Nernst equation– the equilibrium potential of a cell for ion *x* is the potential at which the electrochemical driving forces is balanced for ion *x* (i.e there is no net flow of ion *x* at the equilibrium potential *Ex*)
+ * Thus if one measured the ACh dependent current flow at different potentials, one could determine the membrane potential (*Vm*) where there is no net ion flux (*Ix* = 0). This is called the **reversal potential** or *Erev*
* The end plate current (EPC) at the muscle cell must therefore be *IACh* and is equal to the driving force on an ion multiplied by its permeability (remember Ohm's law: *I = gV*)
* *IACh = gACh(Vm – Erev)*
* Predicts that current will be inward at potentials more negative than *Erev*, becomes small at potentials approaching *Erev*, and then becomes outward at potentials more positive then *Erev*
@@ -172,7 +175,7 @@ This would then predict that current will be inward at potentials more negative
---
-## Influence of the postsynaptic Vm on end plate currents
+## Measure postsynaptic (end plate) currents while stimulating motor neuron
voltage-clamping a postsynaptic muscle fiberNeuroscience 5e Fig. 5.18
@@ -193,26 +196,32 @@ Note:
So let’s imaging what the current-voltage relationships would look like for different channel selectivities. Remember the reversal potential is when there there is no net ion flux, so it 0 nA on all these graphs and if a channel is selective to only K, it would be equal to the Ek.
-If the channel was selective only to Na, than the Erev would be equal to ENa. Same for chloride.
+If the channel was selective only to Na, than the Erev would be equal to ENa. Same for chloride.
If the channel was a non-selective cation channel (passing both K and Na) then the current-voltage relationship would look like...
11Na, 12Mg, 17Cl, 19K, 20Ca
-*Ca2+ ions flow through CaV channels at a rate of ~106 ions s−1, but Na+ conductance is 500fold less through CaV channels*
-*extracellular [Na+] is nearly 70fold higher than Na+, thus Ca2+ selectivity is crucial*
-*Ca2+ and Na+ have nearly identical diameters (~2 Å)*
-*Ca2+ selectivity from high affinity binding, preventing Na+ permeability. Multi site pore, with knock on mechanism to push Ca2+ ions through* [#Tang:2014]
+*Ca2+ ions flow through CaV channels at a rate of ~106 ions s−1, but Na+ conductance is 500fold less through CaV channels* [#Tang:2014]
+*extracellular [Na+] is nearly 70fold higher than Ca2+, thus Ca2+ selectivity is crucial* [#Tang:2014]
+*Ca2+ and Na+ have nearly identical diameters (~2 Å)* 1 Å = 100 pm (Ca2+ larger atomic size, but Na+ has larger ionic size|hydration shell).
+*Ca2+ selectivity is from high affinity binding, preventing Na+ permeability. Multi site pore, with knock on mechanism to push Ca2+ ions through* [#Tang:2014]
[#Tang:2014]: Tang, L., Gamal El-Din, T. M., Payandeh, J., Martinez, G. Q., Heard, T. M., Scheuer, T., Zheng, N., and Catterall, W. A. (2014). Structural basis for Ca2+ selectivity of a voltage-gated calcium channel, Nature, 505(7481), 56-61. PMID 24270805
---
-## Influence of the postsynaptic Vm on end plate currents
+## Postsynaptic Vm affects the magnitude and direction of end plate currents
-Effect of Vm on postsynaptic muscle fiber end plate currentsNeuroscience 5e Fig. 5.18, Takeuchi J Physiol 1960
+
+
+Effect of Vm on postsynaptic muscle fiber end plate currents.
+Inward current is down, outward current is up.
+*Notice the current reverses at 0 mV*
+
+Neuroscience 5e Fig. 5.18, Takeuchi J Physiol 1960
Note:
@@ -224,7 +233,7 @@ We already know that ACh is essential for the end plate currents-- therefore we
---
-## Influence of the postsynaptic Vm on end plate currents
+## Postsynaptic Vm affects the magnitude and direction of end plate currents
Expected Erev if nAChR permeable only to K⁺, Cl⁻, or Na⁺Neuroscience 5e Fig. 5.18
Observed Erev is in between Ek and ENaNeuroscience 5e Fig. 5.18, Takeuchi J Physiol 1960
@@ -424,7 +433,7 @@ IPSP
* Most neurons are somewhere between 10–20 mV below threshold. If everything was linear that it would take the sum of 50 or so inputs to trigger AP
* Not so simple. Some inputs are bigger than others, the inputs can be summed differently– spatially or temporally
* A single neuron can have as many as 10,000 different synapses. Some excitatory some inhibitory, some strong some weak. Some at the tips of dendrites, some near the cell body
-* A neuron integrates all this information and either fires a spike or not
+* Integration of all the postsynaptic potentials determines whether the neuron fires an action potential
Note:
@@ -814,14 +823,18 @@ Chavas and Marty performed Gramacidin perforated patch recordings from young rat
## GABA receptors bind many interesting things
+
+
+
Basic Neurochemistry 6e Fig. 16.2
Note:
-Start at around 1:23
[from: https://en.wikipedia.org/wiki/Barbiturate#Mechanism_of_action](https://en.wikipedia.org/wiki/Barbiturate#Mechanism_of_action)
@@ -885,18 +898,19 @@ Opioid peptides distributed throughout the brain. Colocalize with GABA and 5-HT.
* ATP is contained in all synaptic vesicles
* Has specific receptors on post-synaptic cells
- * P2X
- * A2A adenosine receptor (blocked by caffeine)
-* Generally excitatory in nature
+ * P2X– ionotropic non-selective cation channel
+ * A2A– adenosine receptor (blocked by caffeine)
* Used in spinal cord, motor neurons, and other ganglia
Note:
-Another neurotransmitter that we didn’t talk much about last time is
+Another neurotransmitter that we didn’t talk much about last time is ATP.
Receptors for ATP and adenosine are widely distributed through the nervous system as well as other tissues.
-One class of purinergic receptors for ATP and adenoscie are P2X-receptors which are ionotropic non-selective cation receptors. Others are GPCRs like A2A adenosine receptor throughout brain and heart, adipose tissue, and kidney. Xanthines like caffeine and theophylline block adenosine receptors and this is thought to be the cause of its stimulant effects.
+One class of purinergic receptors for ATP and adenosine are P2X-receptors which are ionotropic non-selective cation receptors.
+
+Other purinergic receptors are metabotrobic GPCRs like A2A adenosine receptor throughout brain and heart, adipose tissue, and kidney. Xanthines (e.g. caffeine and theophylline) block adenosine receptors. This is thought to be the cause of its stimulant effects.
---
@@ -908,6 +922,3 @@ One class of purinergic receptors for ATP and adenoscie are P2X-receptors which
* Because postsynaptic neurons are usually innervated by many different inputs, it is the combination of EPSP and IPSPs that determines whether a cell fires and if an action potential occurs
Note:
-
-
----
diff --git a/neurotransmitters3.md b/neurotransmitters3.md
new file mode 100644
index 0000000..de91c17
--- /dev/null
+++ b/neurotransmitters3.md
@@ -0,0 +1,435 @@
+## Cholinergic receptors
+
+* Best studied– the nicotinic ACh receptor (nAChR)
+* Pentamer- 5 subunits to make a pore. Selective for cations
+* Nicotine can mimic ACh to stimulate receptor, this is called an agonist. Most effects of nicotine go through this receptor
+* nACh receptors produce EPSPs
+* Many toxins specifically bind to and block nicotinic receptors called antagonists
+* alpha-bungarotoxin (snake venom)– binds to alpha subunit of nAChR very tightly and prevents ACh from activating it
+
+Note:
+
+As we’ve shown in our examples earlier the nAChR receptor is a non-selective cation channel. Or another way to think of it is that it is selective for cations.
+
+5 subunits
+
+*nAChR permeable to Na+, K+, and Ca2+*
+
+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).
+
+a number of alpha and beta subunits have expression throughout brain (medulla, superior colliculus, cortex, beta2 subunit expression 'very high' in thalamus). Only alpha3 KO mice have high mortality [#Picciotto:2000].
+
+[#Picciotto:2000]: Picciotto, M. R., Caldarone, B. J., King, S. L., and Zachariou, V. (2000). Nicotinic receptors in the brain. Links between molecular biology and behavior, Neuropsychopharmacology, 22(5), 451-65. PMID 10731620
+
+Low (nM) concentrations of nicotine are found in the blood of moderate smokers (Henningfield et al. 1983). These are sufficient to enhance excitatory transmission in cultures of neurons from the medial habenula or the hippocampus (Gray et al. 1996; McGehee et al. 1995) [#Picciotto:2000]
+
+Many effects of nicotine probably through presynaptic or preterminal nAChRs instead of through postsynaptic AChRs (Léna et al. 1993; Marshall et al. 1997; McGe- hee et al. 1995; Summers and Giacobini 1995; Vidal and Changeux 1993; Wonnacott et al. 1990; Yang et al. 1996) [#Picciotto:2000]
+
+
+
+
+---
+
+## Structure of the nACh receptor
+
+* 5 subunits come together to make a pore
+* Each subunit has 3-4 membrane spanning domains
+* In muscles the receptor has 2α, β, δ, γ, ε subunits. The α subunits bind ACh, both need to be bound for channel to open. α subunits also binds bungarotoxin and nicotine
+* Multiple isoforms for each subunit, depending on which isoform is in channel get different properties
+* In neurons its slightly different. 5 subunits 3α:2β. Bungarotoxin only inhibits muscle nACh receptors
+
+Neuroscience 5e Fig. 6.3
+
+Note:
+
+The alpha subunits bind ACh.
+
+---
+
+## Muscle nAChR
+
+* Pentamers of 2α1, β1, γ, δ in fetal mammals vs. 2α1, β1, δ, ε in adult mammal
+* ACh, nicotine, curare, and bungarotoxin binding sites are on the α1 subunits
+* Pore diameter 10x bigger than Na⁺ channels (3 nm vs 0.3 nm)
+
+Neuroscience 2e 2001
+
+
+Note:
+
+Changes in subunit composition during development.
+
+curare is a competitive antagonist.
+
+
+---
+
+## Ligand gated ion channels
+
+* Built up of 4 or 5 monomers
+* Each monomer spans the membrane 3 or 4 times
+* Each monomer contributes properties
+* Mixing and matching from a large pool of monomer isoforms creates receptors with different properties
+
+Neuroscience 2e 2001
+
+
+Note:
+
+Ligand gated channels in general are made up of 4 or 5 subunit monomers.
+
+
+---
+
+## Muscarinic ACh receptors
+
+* Muscarine, a poisonous mushroom alkaloid, is an agonist
+* Metabotropic (G-protein coupled receptors), mediates most ACh effects in the brain
+ * typically linked to K⁺ channel opening that results in inhibitory postsynaptic potentials (IPSPs)
+* 5 or so isoforms
+* mAChR blockers are used for pupil dilation (atropine), motion sickness (scopolamine) and asthma treatment (ipratropium)
+
+
[*Amanita muscaria*, Onderwijsgek, CC BY-SA 3.0 nl](https://commons.wikimedia.org/w/index.php?curid=21983879)
+
+
Neuroscience 5e Fig. 6.4
+
+
+Note:
+
+- seven transmembrane spanning domains
+- coupled to G proteins
+- causes variety of slow postsynatpic responses
+- highly expr in striatum and varous forebrain regions
+- activate inward rectifier K⁺ channels (allow more K current at hyperpolarized potentials)
+- or Ca²⁺ activated K⁺ channels
+- exert inhibitory influence on dopamine mediated motor effects
+- though in hippocampus mAChRs are excitatory, acting by closing KCNQ type K⁺ channels
+
+*Also found in ganglia of PNS. Mediate peripheral cholinergic responses of autonomic effector organs like heart, smooth muscle, exocrine glands. Inhibition of heart rate by vagus nerve.*
+
+* KCNQ...
+* mutations in four out of five KCNQ genes underlie diseases including cardiac arrhythmias, deafness and epilepsy.
+* [http://www.ncbi.nlm.nih.gov/pubmed/11252765](http://www.ncbi.nlm.nih.gov/pubmed/11252765)
+* KCNQ/M (Kv7) very slow voltage-gated K channels, suppress repetitive firing
+* Inhibited by ACh and many neurotransmitters, but enhanced by others
+* [http://physiolgenomics.physiology.org/content/22/3/269](http://physiolgenomics.physiology.org/content/22/3/269)
+
+atropine
+: from deadly nightshade family
+: dilate pupils, treat slow heart rate
+: anticholinergic, muscarinic antagonist
+: inhibits parasympathetic nervous system
+: WHO essential medicine
+
+scopolamine
+: colorless, odorless alkaloid drug
+: competitive antagonist, antimuscarinic
+: motion sickness, postoperative nausea and vomiting
+: WHO essential medicine
+: from flowering plant genus *Scopolia*
+
+ipratropium
+: opens up medium and large airways of lungs by causing smooth muscles to relax
+: anticholinergic and muscarinic antagonist
+: treats obstructive pulmonary disease and asthma
+: WHO essential medicine
+
+*Clitocybe dealbata*
+: muscarine can occur in this species sufficient concentrations to be deadly
+: commonly found growing in lawns in North America an Europe
+: white flat topped
+
+ [*Amanita muscaria*, Onderwijsgek, CC BY-SA 3.0 nl](https://commons.wikimedia.org/w/index.php?curid=21983879)
+ : red mushroom with white speckles
+ : muscarine first isolated from this species in 1869
+ : muscarine actually only in trace amounts in this species
+ : muscimol is a predominent compound from this mushroom though
+
+---
+
+## Glutamate receptors
+
+* Both ionotropic and metabotropic
+* Ionotropic– AMPA/Kainate receptors and NMDA receptors (named after the agonists that stimulate them)
+ * All are non-selective ion channels with Erev close to 0 (above threshold therefore excitatory)
+ * Formed from an association of 4 subunits. There are a variety of possible subunits which can combine to create many receptor isoforms
+
+Note:
+
+* form tetramers
+* Kainate receptors, or KARs, are ionotropic receptors that respond to the neurotransmitter glutamate.
+* Kainic acid (kainate) is a natural marine acid present in some seaweed. Kainic acid is a potent neuroexcitatory amino acid that acts by activating receptors for glutamate
+
+* Domoic acid is a structural analog of kainic acid and proline.
+* Domoic acid (DA) is a kainic acid analog neurotoxin that causes amnesic shellfish poisoning
+
+---
+
+## Glutamate receptor subunit types
+
+
+
+Note:
+
+---
+
+## AMPA/Kainate receptors
+
+* ionotropic glutamate receptors that allow Na⁺ or K⁺ ion flow
+* multi-subunit channels (typically as heterotetramers from a pair of GluR2 plus a pair of GluR1, GluR3, or GluR4)
+* evoke EPSPs that are large and fast
+* AMPA receptors are more common than Kainate receptors
+
+Neuroscience 5e Fig. 6.6
+
+Note:
+
+* Each AMPAR is composed of 4 subunits and has four sites to an agonist like glutamate can bind (one per subunit)
+* 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
+
+
+---
+
+## NMDA receptor
+
+
+
+
+* Glutamate receptors that allow flow of Ca²⁺ as well as Na⁺ and K⁺. As a result EPSPs produced by NMDA receptors can increase the Ca²⁺ concentration in the neuron. Acts as a second messenger to activate cellular processes
+* Formed as a heterotetramer of 4 subunits (typically 2 NR1 and 2 NR2 subunits)
+* Needs a co-agonist, glycine to open channel
+* Blocked by Mg²⁺ in the pore during hyperpolarizing conditions. Depolarization can remove block. Needs either a bunch of presynaptic cells to fire at the same time or repeated firing of presynaptic cell to open channel
+* Key component of a model for learning
+* Evoke EPSPs that are slow and long lasting
+* PCP “angel dust” binds and clogs channel. Get symptoms similar to schizophrenia
+
+
+
+Note:
+
+* NR1 has the glycine agonist binding site
+* NR2 has the glutamate binding site
+* NR2B predominant in developing brain before switching to NR2B being predominant in adults
+* PCP “angel dust” binds and clogs channel. Get symptoms similar to schizophrenia. Some hypothesize NMDA receptor is involved in this disease.
+
+---
+
+## NMDA receptors require removal of a voltage-dependent Mg²⁺ block
+
+
+
+
+* Mg²⁺ blocks pore– removed by depolarization
+* This is possible because AMPA and NMDA receptors are often at the same synapse
+
+
+
+
Neuroscience 5e Fig. 6.6
+
+
+Note:
+
+
+
+---
+
+## NMDA receptors can open only during depolarization
+
+Neuroscience 5e Fig. 8.10
+
+
+Note:
+
+chp 8 more on NMDA-R mediated mechanisms involved in learning and memory, adv neuroscience.
+
+---
+
+## Metabotropic glutamate receptors (mGluRs)
+
+* Large class of receptor subtypes
+* G-protein coupled
+* Often leads to inhibition of postsynaptic Ca²⁺ and Na⁺ channels
+* But sometimes inhibitory sometimes excitatory
+
+Note:
+
+* group I (mGluR1, mGluR5) associated with IP3 signaling and ER Ca2+ channel opening. Also associated with Na+ and K+ channels. Can result in EPSPs but can also result in IPSPs.
+ * activated selectively by 3,5-dihydroxyphenylglycine (DHPG) (but not other groups)
+* group II mGluRs 2 and 3 prevent formation of cAMP (by activating Gi that inhibits adenylyl cyclase) and result in presynaptic inhibition (not apparently affecting PSPs directly)
+* group III, including mGluRs 4, 6, 7, and 8 prevent formation of cAMP and have similar functional pathway and consequences as group II
+
+---
+
+## GABA receptors
+
+* Three types of GABA receptors: A, B and C
+* A and C are ionotropic, B is metabotropic
+* A and C are inhibitory because their channels are permeable to Cl⁻. The flow of Cl⁻ into the cell lowers the potential. Erev is less than the threshold potential
+* Pentamers, subunit diversity as well as variable stoichiometry, allows for variable functions of GABA receptors
+* Glycine receptors generally have the same properties as GABA receptors
+
+Note:
+
+* pentameric
+* GABAB metabotropic receptors always inhibitory. Coupled indirectly to K+ channels and can decreased Ca2+ conductance resulting in less cAMP production. Baclofen is a potent and selective GABAB agonist. GABA responses that are insensitive to bicuculline and baclofen are termed GABAC responses.
+* GABAA: muscimol potent agonist from mushrooms. Bicuculline classical antagonist and convulsant.
+
+---
+
+## Ionotrophic GABA Receptors
+
+Neuroscience 5e Fig. 6.9
+
+Note:
+
+[picrotoxin](https://en.wikipedia.org/wiki/Picrotoxin)
+
+>Found primarily in the fruit of the climbing plant Anamirta cocculus, it has a strong physiological action. It acts as a non-competitive channel blocker for the GABAA receptor chloride channels.[3] It is therefore a channel blocker rather than a receptor antagonist.
+
+---
+
+## Examples of IPSPs recorded at different membrane potentials
+
+Erev is at the Nernst potential for Cl⁻ (e.g. –80 mV)Coombs et al., J Physiol 1955 Fig. 1
+
+
+Note:
+
+Coombs, Eccles, Fatt 1955: double barreled pipete, inject small currents through one barrel (for voltage clamp) in biceps motorneuron (crustacean) to hold Vm while stimulating afferent nerve inputs to get IPSPs. Erev was found to be close to ECl. Notice hyperpolarization when Vm was above -78 mV, small depolarizations when Vm below -80mV. They found that messing with Cl- concentrations would correspondingly alter the IPSPs but not when messing with Na or K concentrations. Thus Cl- ion flux is necessary for the IPSPs.
+
+[#Coombs:1955]: Coombs, J. S., Eccles, J. C., and Fatt, P. (1955). The specific ionic conductances and the ionic movements across the motoneuronal membrane that produce the inhibitory post-synaptic potential, J Physiol, 130(2), 326-74. PMID 13278905
+
+
+
+---
+
+## Ionotropic GABA receptor mediated IPSPs
+
+Stimulate GABA producing interneuron, record from post-synaptic neuronNeuroscience 5e Fig. 6.9
+
+
+Note:
+
+Chavas and Marty performed Gramacidin perforated patch recordings from young rat cerebellum interneurons and purkinje cells. *Interneurons had more depolarized GABAA reversal potentials than purkinje cells at matched ages (e.g. P12, likely from higher [Cl-]intra for interneurons compared to purkinje cells).*
+
+[#Chavas:2003]: Chavas, J. and Marty, A. (2003). Coexistence of excitatory and inhibitory GABA synapses in the cerebellar interneuron network, J Neurosci, 23(6), 2019-31. PMID 12657660
+
+
+---
+
+## GABA receptors bind many interesting things
+
+
+
+
Basic Neurochemistry 6e Fig. 16.2
+
+
+Note:
+
+
+[from: https://en.wikipedia.org/wiki/Barbiturate#Mechanism_of_action](https://en.wikipedia.org/wiki/Barbiturate#Mechanism_of_action)
+
+>Barbiturates act as positive allosteric modulators, and at higher doses, as agonists of GABAA receptors.
+
+[from: https://en.wikipedia.org/wiki/Benzodiazepine#Pharmacology](https://en.wikipedia.org/wiki/Benzodiazepine#Pharmacology)
+
+>Benzodiazepines work by increasing the efficiency of a natural brain chemical, GABA, to decrease the excitability of neurons.
+
+
+[from: http://thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03_m_par/i_03_m_par_alcool.html](http://thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03_m_par/i_03_m_par_alcool.html)
+
+
+>GABA’s effect is to reduce neural activity by allowing chloride ions to enter the post-synaptic neuron. These ions have a negative electrical charge, which helps to make the neuron less excitable. This physiological effect is amplified when alcohol binds to the GABA receptor, probably because it enables the ion channel to stay open longer and thus let more Cl⁻ ions into the cell.
+
+>Still other substances block a natural neuromediator. Alcohol, for example, blocks the NMDA receptors.
+
+>It has now been established that all substances that trigger dependencies in human beings increase the release of a neuromediator, dopamine, in a specific area of the brain: the nucleus accumbens.
+
+---
+
+## Serotonin receptors
+
+* Large family of receptors called 5-HT 1-7
+* 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
+
+Note:
+
+most receptors are metabotropic
+
+---
+
+## Catecholamine receptors
+
+* Act exclusively by activating G-protein coupled receptors. Contribute to complex behaviors
+* Norepinephrine and epinephrine each act on α and β adrenergic receptors
+* Mostly used to control smooth muscles, especially cardiovascular
+* B-blockers are used to treat hypertension, anxiety, and panic
+
+Note:
+
+
+---
+
+## Peptide receptors
+
+* Virtually all mediate their effects by activating G-protein coupled receptors
+* Neuropeptide-Y receptor important in food intake/obesity
+* Opiate receptors have been identified and shown to be important in addiction (e.g. µ-opioid receptor)
+
+Note:
+
+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.
+
+
+---
+
+## ATP and other purines (adenosine)
+
+* ATP is contained in all synaptic vesicles
+* Has specific receptors on post-synaptic cells
+ * P2X– ionotropic non-selective cation channel
+ * A2A– adenosine receptor (blocked by caffeine)
+* Used in spinal cord, motor neurons, and other ganglia
+
+Note:
+
+Another neurotransmitter that we didn’t talk much about last time is ATP.
+
+Receptors for ATP and adenosine are widely distributed through the nervous system as well as other tissues.
+
+One class of purinergic receptors for ATP and adenosine are P2X-receptors which are ionotropic non-selective cation receptors.
+
+Other purinergic receptors are metabotrobic GPCRs like A2A adenosine receptor throughout brain and heart, adipose tissue, and kidney. Xanthines (e.g. caffeine and theophylline) block adenosine receptors. This is thought to be the cause of its stimulant effects.
+
+---
+
+## Summary
+
+* Two types o neurotransmitter receptors– ionotropic (ligand-gated ion channel) and metabotropic (G-protein coupled receptor)
+* Both lead to opening or closing of ion channels. Ionic currents then either increase or decrease the probability of firing an action potential
+* Postsynaptic neurons are usually innervated by many different inputs– it is the combination of EPSP and IPSPs that determines if an action potential occurs
