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neurotransmitters1.md
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## Neurotransmitter receptors
## Neurotransmitters and receptors
<div style="font-size:0.8em">
<div></div>
* 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**
* Neurotransmitters, ligands for receptors; >100 molecules
* small molecule transmitters
- acetylcholine (ACh), amino acids, biogenic amines, purines
* neuropeptides
- various polypeptides, 3–36 amino acids in length
* Neurotransmitter receptors
1. **ionotropic**, 'ligand-gated' ion channels
2. **metabotropic**, G-protein coupled receptors that modulate separate ion channels
</div>
<div style="font-size:0.5em;">
<!-- date: -->
</div>
Note:
Diving a bit deeper into the structure and function of neurotransmitter (NT) receptors now...
@@ -54,7 +62,9 @@ The ionotropic receptors are the ones you’ve probably seen in our synaptic dia
Note:
Metabotropic transmitter receptors are G-protein coupled receptors, also known as seven-transmembrane domain receptors in you cell biology courses.
retinal vision reference for metabotropic modulation of ion channel function
Metabotropic transmitter receptors are G-protein coupled receptors, also known as seven-transmembrane domain receptors in your cell biology courses.
* neurotransmitter binds
* g protein binds and is activated
@@ -71,7 +81,7 @@ Effector enzymes for activated G-proteins include:
* 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)
* 3% of our genome is codes for protein phosphorylation 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
@@ -105,6 +115,78 @@ nACh Receptors are ionotropic or ligand-gated receptors where the ligand is ACh
stochastic
: having a random probability distribution or pattern that may be analyzed statistically but may not be predicted precisely
---
## nAChR
* Pentamer- 5 subunits to make a pore. Selective for cations
- Pore diameter 10x greater than voltage-gated Na⁺ channels (3 nm vs 0.3 nm)
* Nicotine mimics ACh to stimulate receptor, an agonist
* nicotinic ACh receptors (nAChR) produce excitatory postsynaptic potentials (EPSPs or EPPs)
* Many toxins specifically bind and block nAChR; these are 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+*
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).
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]
Most effects of nicotine go through nAChR
<!-- nAChR
* Green is motor axons, red is where Bungarotoxin binds, defines the endplates
<div><img src="figs/image2_a9b00a8.png" height="100px"><figcaption></figcaption></div> -->
---
## 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
<figure><img src="figs/Neuroscience5e-Fig-06.03-1R_copy_312f80c.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 6.3</figcaption></figure>
<figure><img src="figs/PN07100_copy_ba52d13.jpg" height="200px"><figcaption>Neuroscience 2e 2001</figcaption></figure>
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
Changes in subunit composition during development.
curare is a competitive antagonist.
---
@@ -466,11 +548,11 @@ Note:
<div></div>
* How does a neuron integrate all the information it is getting?
* In many neurons the decision to initiate an action potential is at the axon hillock. Contains a high density of voltage dependent Na^+^ channels and is contains membrane with lowest threshold
* Axon hillock is senses the local state of the cell, which is the combination of all the EPSPs and IPSPs going on at one time
* This is due graded potentials that spread passively
* Temporal summation, process by which consecutive synaptic potentials at the same site are added together.
* Spatial structure of the determines the degree to which a depolarization current decreases as it spreads passively. Easier to sum inputs on the same dendritic branch than on different branches
* For many neurons the axon hillock is where the decision to initiate an action potential is made. Contains a high density of voltage dependent Na^+^ channels; membrane with the lowest threshold
* Local state of the cell is sensed at the axon hillock. The bioelectrical state of the cell is a function of time, the combination of all the EPSPs and IPSPs going on at any moment
* The combined sub- or supra-threshold synaptic potential waveforms spread passively to the soma and axon hillock
* Temporal summation-- consecutive signals within a period of time are added together
* Spatial structure of the dendrites determines the degree by which a synaptic potential current decreases as it spreads passively. Summation of inputs is easier on same dendritic branch than on different branches
</div>
@@ -481,10 +563,10 @@ Note:
* Length constant of the cell determines the degree to which a depolarization current decreases as it spreads passively. Easier to sum inputs on the same dendritic branch than on different branches
Time constant
: time needed for for resistive current (I~r~, current due to ions flowing through channels) and membrane potential (V~m~) to reach **63%** of their *asymptotic values* is proportional to the combination of resistance and capacitance of the circuit in question (across the cell membrane)
: time needed for for resistive current (I~r~, current due to ions flowing through channels) and membrane potential (V~m~) to reach **63%** of their *asymptotic values* is proportional to the combination of resistance and capacitance of the circuit in question (across the cell membrane)
: membrane current (I~m~) is sum of I~r~ and the capacitive current (I~c~)
: I~m~ = I~r~ + I~c~
: capacitance of membrane: during change in applied voltage or current across membrane, positively charged ions pile on surface of one side of membrane and **electrostatically** interact with cations on the other side of membrane surface (membrane acts as thin impermeable surfaces in parallel, like a capacitor), repeling them and inducing immediate, fast capacitive current along membrane
: capacitance of membrane: during change in applied voltage or current across membrane, positively charged ions pile on surface of one side of membrane and **electrostatically** interact with cations on the other side of membrane surface (membrane acts as thin impermeable surfaces in parallel, like a capacitor), repeling them and inducing immediate, fast capacitive current along membrane
: capacitive current falls with an exponential time course. And the membrane potential rises with **same exponential** time course
: Relation of membrane potential at time *t* during charging of capacitance is given by V~t~ = V~inf~(1 - *e*^-t/RC^), where V~inf~ is the membrane potential at an infinite asymptotic value of the exponential curve. When t = RC, then we have V~t~ = V~inf~ ( 1 - *e*^-1^) ==> V~inf~ (0.63)
@@ -503,17 +585,3 @@ console.log( 1 - Math.E ** -1)
<div><video height=400px controls src="figs/Animation05-02SummationofPostsynapticPotentials_OC.mp4"></video><figcaption>Neuroscience 5e Animation 5.2</figcaption></div>
<!--
## Midterm 1
```
mean 83.15
std 9.11
max 100
min 55
median 84
```
<div><img src="figs/Midterm1-hist.png" height="400px"></div>
-->