neurotrans prep
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ackman678
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## Neurotransmitter receptors
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* Embedded in the plasma membrane of post-synaptic cell
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* Two classes of neurotransmitter receptors–
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* receptors that are ion channels themselves (**ionotropic** or 'ligand-gated' ion channel)
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* receptors that interface with separate ion channels (**metabotropic**, or G-protein coupled receptors)
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* 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**
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<div style="font-size:0.8em">
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<div></div>
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* Neurotransmitter receptors are embedded in the plasma membrane of the post-synaptic cell and are always one of the following:
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1. ion channels (**ionotropic** or 'ligand-gated' ion channel)
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2. receptors that interface with separate ion channels (**metabotropic**, or G-protein coupled receptors)
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* 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)
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* 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**
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</div>
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Note:
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Today we will dive a bit deeper into the structure and function of neurotransmitter receptors... last time was a warm up
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Diving a bit deeper into the structure and function of neurotransmitter (NT) receptors now...
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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*).
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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*).
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Two classes...
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Two classes of NT receptors.
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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)
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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)
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<!--
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--
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## Midterm 1
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```r
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mean 84.4
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median 85.5
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std 7.8
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max 98
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min 58.5
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```
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-->
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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...
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---
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@@ -54,6 +47,8 @@ The ionotropic receptors are the ones you’ve probably seen in our synaptic dia
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## Metabotropic neurotransmitter receptors
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* G-protein coupled receptor signalling results in modulation of nearby ion channels for metabotropic receptors.
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<figure><img src="figs/Neuroscience5e-Fig-05.16-2R_1f4ce78.jpg" height="300px"><figcaption>Neuroscience 5e fig. 5.16</figcaption></figure>
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@@ -68,7 +63,7 @@ Metabotropic transmitter receptors are G-protein coupled receptors, also known a
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* ions flow across membrane
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---
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--
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## Neurotransmitter receptors video summary
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@@ -76,14 +71,13 @@ Metabotropic transmitter receptors are G-protein coupled receptors, also known a
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Note:
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---
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## Nicotinic acetylcholine receptors (nAChR)
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* Ionotropic receptor
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* ACh binds the nAChR– opens the channel
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* ACh causes nAChR to open transiently and stochastically (patch clamp studies)
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* Acetylcholine (ACh) binds the nAChR– this opens the channel
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* ACh causes nAChR to open *transiently* and *stochastically* (patch clamp studies)
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* An action potential causes lots of ACh molecules to be released simultaneously, transiently opening many nACh receptors
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* 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
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@@ -93,14 +87,20 @@ So to understand the properties of ionotropic neurotransmitter receptors lets st
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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.
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ACh causes...
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stochastic
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: having a random probability distribution or pattern that may be analyzed statistically but may not be predicted precisely
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---
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## Patch clamping shows ACh gated currents through nicotinic ACh receptors
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<div><figcaption class="big">Patch clamp recording of current through single nAChR. Channels open for varying amounts of time while ACh is bound.</figcaption><img src="figs/Neuroscience5e-Fig-05.17-1R_copy_d0b6a64.jpg" height="500px"><figcaption>Neuroscience 5e Fig. 5.17</figcaption></div>
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<div>
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<figcaption class="big">Patch clamp recording of current through single nAChR.
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Channels open for varying amounts of time while ACh is bound.
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</figcaption>
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<img src="figs/Neuroscience5e-Fig-05.17-1R_copy_d0b6a64.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.17</figcaption>
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</div>
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Note:
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@@ -118,38 +118,41 @@ If this piece of membrane and channel is from a muscle cell than a bunch of thes
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## Activation of nAChR at neuromuscular synapses
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<div><figcaption class="big">end plate currents in a voltage-clamped muscle cell</figcaption><img src="figs/Neuroscience5e-Fig-05.17-2R_copy_fe44356.jpg" width="400px"><figcaption>Neuroscience 5e Fig. 5.17</figcaption></div>
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<div><figcaption class="big" style="width:500px">end plate currents in a voltage-clamped muscle cell</figcaption><img src="figs/Neuroscience5e-Fig-05.17-2R_copy_fe44356.jpg" width="400px"><figcaption>Neuroscience 5e Fig. 5.17</figcaption></div>
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<div>
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<figcaption class="big">
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depolarizing end plate potential recorded in muscle cell due
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to the inward end plate currents
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depolarizing end plate potential recorded
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in muscle cell due to the inward end plate currents
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</figcaption><img src="figs/Neuroscience5e-Fig-05.17-1_copy_fd2d12e.jpg" width="400px"><figcaption>Neuroscience 5e Fig. 5.17</figcaption></div>
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Note:
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Indeed imagine we are doing an experiment where we stimulate a motor neuron and we record end plate currents in a muscle cell...
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Imagine we are doing an experiment where we stimulate a motor neuron and we record end plate currents in a muscle cell...
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...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.
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...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.
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...and this panel on the right shows postsynaptic potential change or end plate potential produced by the EPC as we discussed previously
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...and the panel on the right shows postsynaptic potential change or end plate potential produced by the EPC as we discussed previously
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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.
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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.
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[from http://www.ncbi.nlm.nih.gov/books/NBK21586/](http://www.ncbi.nlm.nih.gov/books/NBK21586/):
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>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.
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* acetylcholine causes opening of a cation channel in the receptor capable of transmitting 15,000 – 30,000 Na⁺ or K⁺ ions a millisecond
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[from http://www.ncbi.nlm.nih.gov/books/NBK21586/: ](http://www.ncbi.nlm.nih.gov/books/NBK21586/)
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* *acetylcholine causes opening of a cation channel in the receptor capable of transmitting 15,000 – 30,000 Na⁺ or K⁺ ions a millisecond*
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* - >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.
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---
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## How do we figure out what ions flow through the nicotinic ACh receptor?
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## What ions flow through the nicotinic ACh receptor?
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<div style="font-size:0.8em;">
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<div style="font-size:0.7em;">
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<div></div>
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* 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 *E<sub>x</sub>*)
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* Thus if one measured the ACh dependent current flow at different potentials, one could determine the membrane potential (*V<sub>m</sub>*) where current is 0. This is called the **reversal potential** or *E<sub>rev</sub>*
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* 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 *E<sub>x</sub>*)
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* Thus if one measured the ACh dependent current flow at different potentials, one could determine the membrane potential (*V<sub>m</sub>*) where there is no net ion flux (*I<sub>x</sub>* = 0). This is called the **reversal potential** or *E<sub>rev</sub>*
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* The end plate current (EPC) at the muscle cell must therefore be *I<sub>ACh</sub>* and is equal to the driving force on an ion multiplied by its permeability (remember Ohm's law: *I = gV*)
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* *I<sub>ACh</sub> = g<sub>ACh</sub>(V<sub>m</sub> – E<sub>rev</sub>)*
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* Predicts that current will be inward at potentials more negative than *E<sub>rev</sub>*, becomes small at potentials approaching *E<sub>rev</sub>*, and then becomes outward at potentials more positive then *E<sub>rev</sub>*
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@@ -172,7 +175,7 @@ This would then predict that current will be inward at potentials more negative
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---
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## Influence of the postsynaptic V<sub>m</sub> on end plate currents
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## Measure postsynaptic (end plate) currents while stimulating motor neuron
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<figure><figcaption class="big">voltage-clamping a postsynaptic muscle fiber</figcaption><img src="figs/Neuroscience5e-Fig-05.18-1R_copy_4d412d5.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.18</figcaption></figure>
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@@ -193,26 +196,32 @@ Note:
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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.
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If the channel was selective only to Na, than the E<sub>rev</sub> would be equal to ENa. Same for chloride.
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If the channel was selective only to Na, than the E<sub>rev</sub> would be equal to ENa. Same for chloride.
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If the channel was a non-selective cation channel (passing both K and Na) then the current-voltage relationship would look like...
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11Na, 12Mg, 17Cl, 19K, 20Ca
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*Ca2+ ions flow through CaV channels at a rate of ~106 ions s−1, but Na+ conductance is 500fold less through CaV channels*
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*extracellular [Na+] is nearly 70fold higher than Na+, thus Ca2+ selectivity is crucial*
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*Ca2+ and Na+ have nearly identical diameters (~2 Å)*
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*Ca2+ selectivity from high affinity binding, preventing Na+ permeability. Multi site pore, with knock on mechanism to push Ca2+ ions through* [#Tang:2014]
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*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]
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*extracellular [Na+] is nearly 70fold higher than Ca2+, thus Ca2+ selectivity is crucial* [#Tang:2014]
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*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).
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*Ca2+ selectivity is from high affinity binding, preventing Na+ permeability. Multi site pore, with knock on mechanism to push Ca2+ ions through* [#Tang:2014]
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[#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
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---
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## Influence of the postsynaptic V<sub>m</sub> on end plate currents
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## Postsynaptic V<sub>m</sub> affects the magnitude and direction of end plate currents
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<figure><figcaption class="big">Effect of V<sub>m</sub> on postsynaptic muscle fiber end plate currents</figcaption><img src="figs/Neuroscience5e-Fig-05.18-2R_copy_33e27e0.jpg" width="700px"><figcaption>Neuroscience 5e Fig. 5.18, Takeuchi J Physiol 1960</figcaption></figure>
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<figure>
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<figcaption class="big">
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Effect of V<sub>m</sub> on postsynaptic muscle fiber end plate currents.
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Inward current is down, outward current is up.
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*Notice the current reverses at 0 mV*
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</figcaption>
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<img src="figs/Neuroscience5e-Fig-05.18-2R_copy_33e27e0.jpg" width="700px"><figcaption>Neuroscience 5e Fig. 5.18, Takeuchi J Physiol 1960</figcaption></figure>
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Note:
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@@ -224,7 +233,7 @@ We already know that ACh is essential for the end plate currents-- therefore we
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---
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## Influence of the postsynaptic V<sub>m</sub> on end plate currents
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## Postsynaptic V<sub>m</sub> affects the magnitude and direction of end plate currents
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<div style="width:500px"><figcaption class="big">Expected E<sub>rev</sub> if nAChR permeable only to K⁺, Cl⁻, or Na⁺</figcaption><img src="figs/Neuroscience5e-Fig-05.18-4R_copy_a97bfef.jpg" width="300px"><figcaption>Neuroscience 5e Fig. 5.18</figcaption></div>
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<div><figcaption class="big">Observed E<sub>rev</sub> is in between E<sub>k</sub> and E<sub>Na</sub></figcaption><img src="figs/Neuroscience5e-Fig-05.18-3R_copy_3d4e047.jpg" width="300px"><figcaption>Neuroscience 5e Fig. 5.18, Takeuchi J Physiol 1960</figcaption></div>
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@@ -424,7 +433,7 @@ IPSP
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* 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
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* Not so simple. Some inputs are bigger than others, the inputs can be summed differently– spatially or temporally
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* 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
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* A neuron integrates all this information and either fires a spike or not
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* Integration of all the postsynaptic potentials determines whether the neuron fires an action potential
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Note:
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@@ -814,14 +823,18 @@ Chavas and Marty performed Gramacidin perforated patch recordings from young rat
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## GABA receptors bind many interesting things
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<!--
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<div style="width:430px; float:left;"><iframe src="https://www.youtube.com/embed/L6dzUOYTQtQ" width="420" height="315"></iframe><figcaption>A Biologist's St. Patrick's Day Song</figcaption></div>
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<div><img src="figs/ch16f2_ed1a4dc.jpg" height="200px"><figcaption>Basic Neurochemistry 6e Fig. 16.2</figcaption></div>
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Start at around 1:23
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-->
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<div><img src="figs/ch16f2_ed1a4dc.jpg" height="300px"><figcaption>Basic Neurochemistry 6e Fig. 16.2</figcaption></div>
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Note:
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Start at around 1:23
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[from: https://en.wikipedia.org/wiki/Barbiturate#Mechanism_of_action](https://en.wikipedia.org/wiki/Barbiturate#Mechanism_of_action)
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@@ -885,18 +898,19 @@ Opioid peptides distributed throughout the brain. Colocalize with GABA and 5-HT.
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* ATP is contained in all synaptic vesicles
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* Has specific receptors on post-synaptic cells
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* P2X
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* A2A adenosine receptor (blocked by caffeine)
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* Generally excitatory in nature
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* P2X– ionotropic non-selective cation channel
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* A2A– adenosine receptor (blocked by caffeine)
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* Used in spinal cord, motor neurons, and other ganglia
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Note:
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Another neurotransmitter that we didn’t talk much about last time is
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Another neurotransmitter that we didn’t talk much about last time is ATP.
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Receptors for ATP and adenosine are widely distributed through the nervous system as well as other tissues.
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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.
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One class of purinergic receptors for ATP and adenosine are P2X-receptors which are ionotropic non-selective cation receptors.
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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.
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---
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@@ -908,6 +922,3 @@ One class of purinergic receptors for ATP and adenoscie are P2X-receptors which
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* 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
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Note:
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---
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