diff --git a/2016-10-16-lecture08.md b/2016-10-16-lecture08.md index f1f5253..93fab82 100644 --- a/2016-10-16-lecture08.md +++ b/2016-10-16-lecture08.md @@ -1,49 +1,17 @@ ## Neurotransmitter receptors * Embedded in the plasma membrane of post-synaptic cell. - * Either are ion channels themselves (ionotropic, or ligand-gated ion channel) or interface with ion channels (metabotropic, or G-protein coupled receptors). - * Ultimately, the binding of neurotransmitter causes opening of channels and ion flux. This can lead to depolarization or hyperpolarization of the membrane potential depending on the ion concentrations and the particular ion species flowing in or out. -2016-02-01 16:12:13 - Note: - - - - - - - - - - - - - - Today we will dive a bit deeper into the structure and function of neurotransmitter receptors. - - - - --- ## Ionotropic neurotransmitter receptors -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - Neurotransmitter binds receptor Channel open allowing ions to flow through @@ -53,25 +21,12 @@ Channel open allowing ions to flow through Note: - - - The ionotropic receptors are the ones you’ve probably seen in our synaptic diagrams so far, where NT binds directly to an ion channel pore, causing it to open and allow ions to move through the pore. --- ## Ionotropic neurotransmitter receptors -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
Note: @@ -83,21 +38,10 @@ channel opens ions flow across membrane - --- ## Metabotropic neurotransmitter receptors -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
Note: @@ -113,21 +57,10 @@ ion channel opens ions flow across membrane - --- ## Title Text -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - [http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation05-03IonotropicandMetabotropicReceptors.mov](http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation05-03IonotropicandMetabotropicReceptors.mov)
@@ -141,13 +74,9 @@ Note: ## Nicotinic acetylcholine (nACh) receptors * Ion-channel receptor (ionotropic) - * ACh binds nACh receptor– opens up - * ACh causes nACh receptor 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 potential of the muscle, the EPP, which can trigger an action potential. Note: @@ -158,16 +87,6 @@ nACh Receptors are ionotropic receptors and are the receptor you’ve heard the ## Outside-out patch clamping showing ACh gated currents -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - Neuroscience 5e 5.17 Channels open for various amounts of time at a given potential. @@ -181,25 +100,10 @@ The binding of a neuro-transmitter to its receptor usually opens (sometimes clos The figure shows a simple case. In the absence of ACh, the channel is closed. In the presence of high ACh (the channel always has ACh bound), the channel opens and closes. These repeated breif openings are seen as downward deflections corresponding to inward current. - - - - - --- ## Activation of nACh receptors at neuromuscular synapses -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - post-synaptic muscle cell voltage clamped to look at currents not voltage clamped, inward EPC causes depolarizing EPP in the muscle cell @@ -214,18 +118,11 @@ Note: The traces show inward currents through these ionotropic ACh channels, showing the currents stemming from a single channel, 10 channels, and a million channels. - - 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. - - - - [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. --- @@ -233,15 +130,10 @@ As we will learn in a few minutes, the channel opened by ACh lets mostly Na+ thr ## How do we figure out what ions flow through the nACh receptor? * From Nernst equation– the equilibrium potential of a cell is the potential at which there is a balance between the concentration gradient and the electrochemical gradient. - * In other words– 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 potential that current flow was 0. This is called the reversal potential or Erev. - * The end plate current (EPC) is therefore IACh and is equal to the driving force on an ion multiplied by its permeability (remember Ohms 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. Note: @@ -264,28 +156,10 @@ This would then predict that current will be inward at potentials more negative * - Predicts that current will be negative (inward) at potentials more negative than Erev, becomes small at potentials approaching Erev, and becomes positive (outward) at potentials more positive then Erev. - - - - - - - - --- ## Influence of the postsynaptic membrane potential on end plate currents -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
Note: @@ -293,59 +167,29 @@ Note: A postsynaptic muscle fiber is voltage clamped to control the muscle fiber’s membrane potential, while the presynaptic neuron is stimulated to cause ACh release at the end plate synapse. - --- ## Hypothetical ion channel selectivities and the reversal potential -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
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 a non-selective cation channel (passing both K and Na) than - - - - - - - - 11Na, 12Mg, 17Cl, 19K, 20Ca - - - - --- ## What ions flow through the nACh receptor? * Voltage clamping experiments show that there are large inward currents at -110 mV, smaller currents at -60 mV and no current at 0 mV. Outward currents at +70 mV. Therefore Erev = 0. - * Erev is not at any of the equilibrium potentials for a single ion, lies in between K+ (-100 mV) and Na+ (+70 mV). - * Altering the K+ concentration or the Na+ concentration will change the membrane potential. Therefore both Na+ and K+ are permeable through the nACh receptor. - * nACh receptor can conduct both Na+ and K+ ions. The direction of flow is dependent on the membrane potential. The normal resting state of muscle is -100 mV, well below 0 mV (Erev) therefore normally at rest Na+ rushes in with very little K+ rushing out. Note: @@ -358,49 +202,21 @@ Furthermore, altering… Therefore we can conclude that the nAChR can conduct both Na and K ions. - - - - --- ## Influence of the postsynaptic membrane potential on end plate currents -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
Note: - - --- ## The effect of ion channel selectivity on the reversal potential -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - K+ only permeable channel -Cl– only permeable channel - -Na+ only permeable channel +Cl– only permeable channelNa⁺ only permeable channel
@@ -408,22 +224,10 @@ Na+ only permeable channel Note: - - --- ## Influence of the postsynaptic membrane potential on end plate currents -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
Note: @@ -434,16 +238,6 @@ So it seems that the ACh activated ion channels are equally permeable to Na and ## Na+ and K+ movements during EPCs and EPPs -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - -90 typical resting potential of a muscle depolarization @@ -464,16 +258,6 @@ Even though these ionotropic channels opened by ACh are permeable to both Na and ## Na+ and K+ movements during EPCs and EPPs -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - EPC: in or out EPP:depolarzing or @@ -488,14 +272,8 @@ Note: Here is the key: you get inward currents at potentials more negative the Erev and you get outward currents at potentials more positive than Erev. - - The resulting EPPs depolarize postsynaptic cell at potentials more negative than Erev and potentials more positive than Erev hyperpolarize the cell. - - - - --- ## Na+ and K+ movements during EPCs and EPPs @@ -507,35 +285,24 @@ The resulting EPPs depolarize postsynaptic cell at potentials more negative than Note: - --- ## Think about it * At normal resting potentials as the nACh receptor opens, many Na+ ions rush in and a few K+ rush out. This causes the cell to depolarize. As the potential goes toward Erev, as many K+ go out as Na+ goes in. Therefore the nACh receptor if open long enough would drive the potential to Erev. If Erev is above threshold, the probability of an action potential happening is increased and is called an excitatory postsynaptic potential (EPSP) - * If Erev is below threshold the probability of an action potential is decreased. Called an inhibitory postsynaptic potential (IPSP). Note: - - - - - - [http://www.nature.com/nrd/journal/v1/n6/full/nrd821.html: ](http://www.nature.com/nrd/journal/v1/n6/full/nrd821.html) >In the case of this modified muscle nAChR, the conductance of the pore is sensitive to the presence of negative charge at three locations that form three negatively charged rings in and near the M2 domain56. So, intensive studies of the M2 segment have been carried out to determine the amino acids that are responsible for the cationic or anionic selectivity of receptors. - - --- ## Postsynaptic potentials between neurons * Excitatory postsynaptic potentials (EPSP) increases the likelihood that an action potential will be initiated in the post synaptic cell. - * Inhibitory postsynaptic potentials (IPSP) decreases the likelihood that an action potential will be initiated in the post synaptic cell.
@@ -544,32 +311,21 @@ Note: In fact we can generalize the properties that we’ve learned about EPCs through ionotropic AChR and their effects on EPPs at the neuromuscular junction to the general case of chemical synapses between pairs of neurons. - - Instead of so called EPPs, the postsynaptic potentials between neurons we call excitatory if it increases the likelihood of an AP firing in a postsynaptic cell and inhibitory if it decr the probability of an AP occurring in a postsynaptic cell. - - This plot shows two pretend neurotransmitters D and H that can depolarize or hyperpolarize the cell and their corresponding Erevs. This one causes an EPSP and inward current from Vrest, whereas this one causes an IPSP and an outward current from Vrest. - - --- ## Similar mechanisms exist at all chemical synapses * Instead of end plate current called postsynaptic current (PSC). - * Instead of end plate potential called post synaptic potential (PSP). - * excitatory PSP– EPSP increases likelihood of an action potential - * inhibitory PSP– IPSP decreases likelihood of an action potential Note: - - --- ## EPSP summation @@ -578,8 +334,6 @@ Note: Note: - - --- ## EPSP @@ -593,21 +347,16 @@ Neuroscience 5e 5.21 Note: - --- ## IPSP #1 * Here is an IPSP mediated by GABA activating Cl- selective channels. - * The reversal potential for the Cl current is negative to the resting potential and threshold. - * Activation of Cl channels hyperpolarizes the neuron. ECl - - Neuroscience 5e 5.21 Time (ms) @@ -615,19 +364,15 @@ Time (ms) Note: - --- ## IPSP #2 * The reversal potential for the Cl– current is positive to the resting potential but negative to threshold. - * Activation of Cl– channels depolarizes the neuron. Stabilizes membrane potential below threshold. ECl - - Neuroscience 5e 5.21 Time (ms) @@ -635,27 +380,15 @@ Time (ms) Note: - - - Also called shunting inhibition. Na+ channels persistently in state of inactivation due to small depolarizing pulses. - - So just remember if the Erev for the neurotransmitter receptor is more positive than threshold than it is excitatory. If it is more negative than threshold than it is inhibitory. - - - - - - >Blocking NKCC1 with bumetanide disrupts excitatory synapse development in the cortex Bumetanide, a selective NKCC1 inhibitor, has been demon- strated to suppress certain forms of epileptiform activity in vitro and in vivo, presumably by attenuating the depolarizing effect of GABA (Dzhala et al., 2005; Kilb et al., 2007) - >effect of GABA on membrane polarity depends on the Cl gradient created by the expression of Na -K -2Cl cotrans- porter (NKCC) and K -Cl cotransporter (KCC). NKCC1 im- ports Cl and is expressed from the embryonic stage until the first postnatal week, whereas KCC2 exports Cl and is weakly expressed at birth and upregulated as the brain matures (Plotkin et al., 1997; Rivera et al., 1999; Li et al., 2002). The temporal expression patterns of these two transporters correspond to the switch of GABA from being excitatory to inhibitory during the first few weeks of rodent postnatal life (Delpire, 2000). --- @@ -663,9 +396,7 @@ Bumetanide, a selective NKCC1 inhibitor, has been demon- strated to suppress cer ## Remember in neurons an EPSP is not driven from one pulse * Activation of ionotropic receptors opens nonselective cation channels. - * The first stimulation does not reach threshold. - * More intense stimulation yields a larger EPSP and an AP.
@@ -673,35 +404,21 @@ Bumetanide, a selective NKCC1 inhibitor, has been demon- strated to suppress cer Note: - --- ## IPSP * Activation of ionotropic receptors opens Cl- channels. - * The first stimulation does not reach threshold. - * More intense stimulation yields a longer IPSP but not a larger one. Note: - --- ## Summation of postsynaptic potentials -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - Neuroscience 5e 5.22
@@ -711,19 +428,14 @@ Neuroscience 5e 5.22 Note: - --- ## Summation * In general EPSPs in neurons are small 0.2–0.4 mV. - * 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. Note: @@ -734,16 +446,6 @@ Of course we are greatly simplifying everything here, a single neuron may have a ## Neural integration -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
Note: @@ -755,47 +457,21 @@ Note: ## Neural integration * How does a neuron integrate all the information it is getting? - * In most motor neurons and interneurons the decision to initiate an action potential is at the axon hillock. Contains a high density of voltage dependent Na+ channels. 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 mostly due potentials that spread passively. - * Temporal summation, process by which consecutive synaptic potentials at the same site are added together. Different synapses will have different time constants. - * 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. - * Some dendrites even have voltage gated Na+ channels, these can amplify inputs. Note: - - - - - - some neurons in the globus pallidus have voltage gated Na channels. - - - - --- ## Title Text -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - [http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation05-02SummationofPostsynapticPotentials.mov](http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation05-02SummationofPostsynapticPotentials.mov)
@@ -803,41 +479,19 @@ some neurons in the globus pallidus have voltage gated Na channels. Note: - --- ## Events from neurotransmitter release to postsynaptic excitation or inhibition -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
Note: - --- ## Ionotropic neurotransmitter receptors -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - Note: neurotransmitter binds @@ -847,21 +501,10 @@ channel opens ions flow across membrane - --- ## Metabotropic neurotransmitter receptors -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - Note: neurotransmitter binds @@ -880,16 +523,6 @@ ions flow across membrane ## Metabotropic neurotransmitter receptors -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - Ligand binding site G-protein binding site @@ -915,23 +548,16 @@ ions flow across membrane ## 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. Nicotine is not cleared very well so receptor stays open longer which leads to larger EPSPs - * 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 --- @@ -945,19 +571,14 @@ As we’ve shown in our examples earlier the nAChR receptor is a non-selective c Note: - --- ## 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 2 α, β,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.
@@ -971,37 +592,28 @@ The alpha subunits bind ACh. ## Muscle nAChR * Pentamers of 2α1, ß1, γ, δ in fetal mammals vs. 2α1, ß1, 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 .3 nm) - -
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
@@ -1009,69 +621,42 @@ curare is a competitive antagonist. Note: - --- ## Muscarinic ACh receptors -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
Note: - --- ## Muscarinic ACh receptors * Muscarine, a poisonous mushroom alkaloid, is an agonist. - * Metabotropic, mediates most of ACh effects in the brain. - * 5 or so isoforms - * mACh blockers are used for pupil dilation (atropine), motion sickness (scopolamine) and asthma treatment (ipratropium). Note: - seven transmembrane spanning domains. - - coupled to G proteins - -cause variety of slow postsynatpic responses. - -highly expr in sttiatum 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 +- cause variety of slow postsynatpic responses. +- highly expr in sttiatum 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 in hippocampus mAChRs are excitatory, acting by closing KCNQ type K+ channels * 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) - - 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. --- @@ -1079,87 +664,51 @@ Also found in ganglia of PNS. Mediate peripheral cholinergic responses of autono ## Muscarinic ACh receptors * Muscarine, a poisonous mushroom alkaloid, is an agonist. - * Metabotropic, mediates most of ACh effects in the brain. - * 5 or so isoforms - * mACh blockers are used for pupil dilation (atropine), motion sickness (scopolamine) and asthma treatment (ipratropium). - * [Also used for bad things http://www.rense.com/general38/frug.htm](http://www.rense.com/general38/frug.htm) Note: - --- ## Glutamate receptors * Both ionotropic and metabotropic - * Ionotropic– NMDA receptors, AMPA receptors, and Kainate 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 many subunits, that can combine to create many isoforms. Note: tetramers - - 3 classes, 8 subunits - - - - 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 receptors -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
Note: - - --- ## AMPA/Kainate receptors * glutamate receptors that allow Na+ or K+ ions across. - * multi-subunit channels - * evoke EPSPs that are large and fast - * AMPA receptors are more common than Kainate receptors
@@ -1167,45 +716,27 @@ Note: Note: - --- ## 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. - * 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: - - - - - - - - PCP “angel dust” binds and clogs channel. Get symptoms similar to schizophrenia. Some hypothesize NMDA receptor is involved in this disease. - - --- ## NMDA receptor currents requires glutamate, glycine, and removal of voltage-gated Mg2+ block * Glycine is a co-agonist-no glycine no current. - * Mg2+ blocks pore-is removed by depolarization. - * This can happen because AMPA and NMDA receptors are often in the same synapse. Neuroscience 5e 6.6 @@ -1220,46 +751,18 @@ Note: ## NMDA receptor currents require glycine and removal of Mg2+ block -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
Note: - - - - - - fig from: [http://www.bris.ac.uk/synaptic/info/glutamate.html](http://www.bris.ac.uk/synaptic/info/glutamate.html) - - --- ## The NMDA receptor channel can open only during depolarization -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
Note: @@ -1267,17 +770,13 @@ Note: chp 8 more on NMDA-R mediated mechanisms involved in learning and memory, adv neuroscience. - --- ## Building a brainier mouse * NMDA receptor consists of four subunits, each constructed separately. - * Receptors with NR2B subunits stay open longer than those with NR2A. - * Genetically engineered mice to produce NR2B receptors, the DOOGIE mouse. - * The genetically engineered mice showed stronger synaptic connections, faster fear learning, and better water maze learning. Tsien, J.Z (2000) Building a brainier mouse. @@ -1296,16 +795,6 @@ Conductances during early infancy and as an adult ## Neurobiology: Young receptors make smart mice -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - Figure 1 Object-recognition task. a, In an initial training session the mouse explores two objects in a box, devoting roughly equal time to each. @@ -1325,35 +814,26 @@ subunit NR2A in adults subunit NR2B during development Note: - --- ## 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: - --- ## 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 have generally the same properties as GABA receptors Note: @@ -1364,16 +844,6 @@ Note: ## Ionotrophic GABA Receptors -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
Note: @@ -1382,30 +852,16 @@ In this example Erev>Vm so chloride goes from inside to outside - - [from: https://en.wikipedia.org/wiki/Picrotoxin](https://en.wikipedia.org/wiki/Picrotoxin) 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. - - --- ## Ionotrophic GABA Receptors -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - current due to many channels opening @@ -1426,32 +882,14 @@ In this example Erev>Vm so chloride goes from inside to outside - - --- ## Examples of GABA receptor-mediated IPSPs recorded at different membrane potentials -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - - - - - Reversal potential is at the Nernst potential for Cl- ions. (In this case about –78 mV) - - Figure from Coombs et al. 1955)
@@ -1459,21 +897,10 @@ Figure from Coombs et al. 1955) Note: - --- ## GABA induced IPSPs -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - Stimulate GABA producing interneuron- record from post-synaptic neuron
@@ -1481,55 +908,32 @@ Stimulate GABA producing interneuron- record from post-synaptic neuron Note: - --- ## The GABA receptor binds many interesting things -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five - [http://www.youtube.com/watch?v=L6dzUOYTQtQ-](http://www.youtube.com/watch?v=L6dzUOYTQtQ-)
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. --- @@ -1537,91 +941,56 @@ Note: ## 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 - * A2A adenosine receptor (blocked by caffeine) - * Generally excitatory in nature - * Used in spinal cord, motor neurons, and other ganglia. Note: Another neurotransmitter that we didn’t talk about last time is - - - - 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. @@ -1630,41 +999,22 @@ One class of purinergic receptors for ATP and adenoscie are P2X-receptors which ## Title Text -* Body Level One - -* Body Level Two - -* Body Level Three - -* Body Level Four - -* Body Level Five -
Note: - - --- ## Summary * Neurotransmitter receptors bind neurotransmitters. Tremendous diversity but with commonalities. - * Two types– ionotropic (ligand-gated ion channel) and metabotropic (G-protein coupled receptor). - * Both types lead to opening or closing of ion channels. These conductance changes can either increase or decrease the probability of firing an action potential. - * 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: - --- - ---- -