CSB332 Midterm Notes.pdf

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Cell and Systems Biology
Francis Bambico

Ivan Tran CSB332 Notes CSB332 – Lecture 6 Notes Postsynaptic Potentials (end plate potentials [EEP], EPSP and IPSP) are produced by changes in the conductance of postsynaptic receptors (ionotropic receptors, which are ion channels + metabotropic receptors which lead to a cascade of reactionsG-protein coupled receptors [GPCR]) Ionotropic Receptors – Direct transmitter action  Transmitter binds to the ion channel, the channel is openedFast acting Metabotropic Receptors – Indirect transmitter action  Transmitter binds to the receptorSecond messenger triggers a cascade of reactionsIon channel opens Structure of a chemical synapse at the Neuromuscular Junction (NMJ):  Postsynaptic receptors are located on the sarcolemma of muscle fibers  These receptors are nicotinic acetylcholine (cholinergic) receptors (nAChR) o nAChR activation re+ults in EPPs that add up to threshold to generate APs via opening of voltage-gated Na channels  Was found that nAChR is permeable to cations in general  nAChR distribution at the skeletal neuromuscular junction in snakes were found that these receptors are localized postsynaptically and extrasynaptically  Other receptors are located presynaptically Structure of chemical synapse in the brain:  The CNS contains axospinous, axodendritic, axosomatic and axo-axonic synapses that are separated by a synaptic cleft  Some presynaptic axon varicosities are not closely apposed to the postsynaptic membrane o Still transmits chemical signals through large and far-reaching neurotransmitter release called volume transmission Transmission of electrochemical signal to the postsynaptic membrane is made through postsynaptic receptors whose activation leads to opening of ion channels and corresponding changes in the membrane potentialPostsynaptic potential or synaptic potential Iontophoresis (Ionophoresis, synonymous):  Electromotive drug administration o Uses electric current to deliver drugs and other agents into neural tissue o The ejecting current should have the same charge as the ionized drug molecule o These experiments can determine whether a receptor responds to certain drugs or chemical transmitters  This allows for knowledge on the receptors identity and the molecular/receptor composition of that synapse o Can also determine whether the receptor produces an EPSP (aka EPP) or an IPSP o Post synaptic potentials are graded or passive signals which can summate until they hit a threshold and produce an AP  This is spatial summation o Temporal summation is when AP are fired in close proximity or successive with respect to time, which means they essentially produce a larger AP together Ivan Tran CSB332 Notes CSB332 – Lecture 7 Notes Synaptic Delay:  Comparing the timing of AP arrival in the axon terminals and the registration of postsynaptic potential, we find that there is a 0.5 to 1ms delay  This delay would not occur if there is a mechanism that allows APs to passively diffuse through the synaptic cleft  Synaptic delay is not observed in electrical synapses and gap junctions BAPTA:  A calcium chelator - Exclusively binds to calcium to prevent generation of a post-synaptic potential because the calcium sensors is important for mobilizing the synaptic vesicle are not receiving any calcium, thus no neurotransmitter release from the pre-synaptic membrane o AP is still generated because BAPTA doesn’t bind to sodium, only calcium Calcium: 2+  Voltage-gated Ca channels are clustered on the axolemma of terminals  APs lead to their opening and to subsequent entry of Ca into the presynaptic neuron followed by exocytosis of neurotransmitters Aequorin:  Naturally produced by jelly fish  Pre-synaptic influx of calcium can be visualized using Aeqourin o Blue light is emitted when excited by calcium Mechanisms of Exocytosis – SNARE:  Exocytosis by SNARE is complete fusion exocytosis because the membrane and the vesicles are fused together o Opposite of this is exocytosis via Kiss and Run  Partial fusion of the vesicular membrane with a region on the presynaptic membrane called Porosomes  V-SNARE (Vesicle SNARE): o Synaptobrevin (VAMP)  Coils around Syntaxin from T-SNARE o Synaptotagmin (calcium sensor)  T-SNARE (target postsynaptic snare): o Syntaxin  Regulated by MUNC18-1  Directly promotes syntaxin stability and either controls the spatially correct assembly of core complexes for SNARE-dependent fusion, or acts as a direct component of the fusion machinery through the interaction with SNARE core o SNAP-25  Interacts with syntaxin  Together, the four SNARE proteins form a 4-helix bundleAnchors the two together o The bundle is stabilized by complexin  After fusion occurs, and calcium ions are released, calcium binds to Synaptotagmin and displaces Complexin  Active Zone: Region where vesicles cluster and are ready to release neurotransmitters  Clathrin: A triskelion shaped protein, causing reuptake of the vesicle membrane that fused, and encages the empty vesicle for recyclingRepacked in golgi bodies or hydrolyzed in lysosomes Ivan Tran CSB332 Notes CSB332 – Lecture 8 Notes Neurotransmitters are: 1. Synthesized in the neuron (rate-limiting enzyme) 2. Stored in synaptic vesicles 3. Released through a calcium-dependent process 4. May have exogenous analogues (drugs) Termination of Synaptic Transmission: 1. Neurotransmitters dissociate from receptors 2. Either pumped back into presynaptic terminal or broken down by enzymes while in the synaptic cleft 3. Breakdown products are taken up by the presynaptic neuron 4. Neurotransmitters are resynthesized in the presynaptic neuron 5. Neurotransmitters are repacked into synaptic vesicles Metabotropic (GPCR) Receptors:  Different neurotransmitters will bind to different receptors which will activate different GPCRs o This will change the effects that follow the activation of that G-protein  Gs:↑Adenylyl cyclase↑cAMP↑PKA  Gq: ↑Phospholipase Cinositol triphosphateCa DiacylglycerolPKC  Gi↓Adenylyl cyclas↓cAMP↑K channels openedInhibition o Results in hyperpolarization  Go: ↑Ca channels shut↓Transmitter release o Inhibitory in that they close Ca channels Neurotransmitters may bind synaptic receptors, extrasynaptic receptors, and presynaptic autoreceptors. Transmitter release is regulated by a number of mechanisms. These include presynaptic inhibition that may be mediated by transmitters activating presynaptic auto-inhibitory receptors or via retrograde messengers diffusing out of the postsynaptic neuron and activating presynaptic receptors Endocannabinoids:  Retrograde messengers acting on cannabinoid CB1 receptors and mediating depolarization- induced suppression of inhibition (DSI) or depolarization-induced suppression of excitation (DSE)  CB1 receptors can enhance or inhibit the activity of the post-synaptic membrane o Located above the presynaptic region of the neuron, near the end of the axon  When a post-synaptic neuron gets depolarized voltage gated calcium channels open and calcium enters the cell o Increases the affinity for certain enzymes that are responsible for synthesis of endogenous cannabinoids  Eg. Anandamide and 2-AG (2-Arachidonoyl glycerol)  Acts similarly to the way THC works on CB1 receptors  DSI via 2AG: o Influx of calcium causes downstream effects to generate 2AG o When 2AG accumulates in the post-synaptic membrane it will diffuse out  Not considered neurotransmitters since they are not stored within vesicles  “Neuromodulators” instead of neurotransmitters  Once diffused out, they will bind to CB1 receptors which are located near the presynaptic membrane Ivan Tran CSB332 Notes  CB1 receptors are GiG oassociated meaning inhibitory downstream effects o Thus the end effect is a decrease of influx in calcium from the presynaptic membrane and potassiumIncrease in influx of potassiumCausing hyperpolarization and blockage of calcium will inhibit release of GABA  This is DSIInhibition of GABA  The effect on the post-synaptic neuron is that there will be a lack of inhibition which leads to disinhibition of the post-synaptic neuron  DSE: o AP reaches presynaptic neuronIncreases glutamate presenceGlutamate activates receptors which are permeable to Calcium, Potassium and Sodium  Results in influx of calcium  Influx of calcium causes downstream effects to generate 2AG o 2AG will bind to CB1 receptors which will inhibit the influx of Calcium ions  No calcium ions means no release of excitatory neurotransmitters (glutamate) thus inhibition of the post-synaptic neuron Ivan Tran CSB332 Notes CSB332 – Lecture 9 Notes Endogenous Cannabinoids:  Eg. Anandamide and THC o Amplifies the effects of DSI/DSE because they’re agonists for CB1  Under the influence of THC, CB1 gets prolonged-activation  For DSI, this mean excitation in the post-synaptic neuron due to disinhibition Endocannabinoid-mediate DSE plays an important in habituation to stress Habituation is the progressive decrease in an emotional response or arousal after repeated exposure to the stressful stimulus/event  We do not get habituated to responding to our name  Mouse Restraining Experiment: o Day 1: Increase in activity of neurons (Fos expression)Focused on excitatory synapses o Day 5: Dramatic decrease in Fos expressionSuggests that the neurons are no longer over-activated  Because after prolonged exposure to the stressor, there is an accumulation of neuromodulators (eg. 2-AG)  Inability to Habituate: o OCD:  An anxiety disorder characterized by recurrent unwanted thoughts (obsessions) and or repetitive behaviours (compulsions)  There is a growing recognition that impairment of the endocannabinoid system
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