Week of 10/19
Week of 10/19 NSCI 3310
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This 19 page Class Notes was uploaded by Emma Notetaker on Friday October 23, 2015. The Class Notes belongs to NSCI 3310 at Tulane University taught by Jeffrey Tasker in Summer 2015. Since its upload, it has received 48 views. For similar materials see Cellular Neuroscience in Nutrition and Food Sciences at Tulane University.
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Date Created: 10/23/15
Neurotransmitters 102315 832 PM 0 criteria 0 1 synthesized and stored in presynaptic terminal 0 immunohistochemistry use of antibody to identify where neurotransmitters are determines whether nt in vesicle main technique for nt location and whether or not chemical is neurotransmitter generate antibody for chemical by injecting animal with chemical to make antibodies will stick to antigen sites when applied to brain slice 0 2 released from terminals with stimulation 0 chemical assay take up ECF assay for chemical 0 determined by chemical response 0 3 specific receptors on postsynaptic cells 0 neuropharmacology using agonists or antagonist to stimulate or block receptors 0 autoradiography using radiotagged or fluorescenttagged neurotransmitters to see where it sticks to find receptors 0 discovery of neurotransmitters 0 transmission of nerve signal electrical or chemical experiment by Otto Loewi 1921 confirms neuron doctorine o 2 hearts in separate chambers connected by tube so ONLY fluid could flow no electrical connection 0 stimulation of vagus nerve of 1 0 transfer of medium to 2nd 0 results 1St heart decreased rate and contraction vagus nerve stimulated 2nd heart ALSO decreased after first one SO chemical connection between chambers through fluidnot electrical chemical transmission of signal transmitter ACh vagusstoff 0 types 3 classes 0 1 small molecule nt 3 subgroups o 1 amino acids glutamate excitatory GABAglycine inhibitory o 2 ACh o 3 biogenic amines catecholamines a dopamine n norepinephrine n epinephrine serotonin histamine 2 neuropeptides all use Gprotein coupled receptors metabotropic o peptide packaged into vesicles and released by neurons 0 release from neurons near synapses acts as nt neurohumeral junctions synapses on blood vessels n acts as neurohormone a mostly contained in hypothalamus controls ANS and endocrine 0 types hypothalamic peptides opiates gut peptides 3 unconventional nt 0 gases I NO I CO 0 lipids endocannabinoids made in plasma membrane lipase converts lipid into endocannabinoid released during production 0 growth factorscytokines neurotransmitters are PROTEINS 3 classes 0 1 cytosolic synthesized by free ribosomes transported by slow axoplasmic fibrillar cytoskeleton and enzymes metabolic triggers where small molecule neurotransmitters come from u made from enzymes and precursors o 2 nuclear proteins 0 3 membrane associated proteins made by ribosomes stuck to RER types a 1 integral and peripheral proteins a 2 ER proteins a 3 vesicle associated proteins lysosomes secretory products enzymes synthesis transport packaging 1 small molecule 0 00000 synthesis of metabolic enzymes work on precursors cytosolic proteins taken transported into vesicles slow axoplasmic transport synthesis of transmitter uptake into synaptic vesicles release 0 2 neuropeptides O 0000 0 synthesis of precursor proteins packaging into vesicles into Golgi apparatus membrane proteins fast anterograde transport along microtubules gets to axon terminal peptides ready in vesicles ready for release not recycled or charged within vesicles cleavage of precursors by enzymes into final neurotransmitter product release neurotransmitter fate at synapse 0 can be uptake by presynaptic terminal or postsynaptic O uptake from presynaptic goes into repackaging of small molecule neurotransmitter to recycle 0 diffusion terminates response 0 exocytosis triggers endocytosis o reuptake of neurotransmitter or breakdown of neurotransmitter retransported by vesicular transporters on membrane put nt back into vesicles to recharge vesicles 0 neuropeptides usually packaged in densecore vesicles larger and more dense core than vesicles from small molecule transmitters 0 these vesicles are black under TEM o vesiclaes are off active site back a little further 0 released outside synapse farther back 0 responsible for volume transmission not at synapse but released into extracellular space add to volume and increase concentration in peptide in cytoplasm can be activating receptors anywhere in vicinity corelease of both types of transmitters peptides and small molecule 0 colocalization of nt 0 small molecule nt and neuropeptides often located in same terminals 0 corelease different locations of vesicles 0 synaptic vesicles small clocked at membrane 0 large densecore vesicles off membrane out of active zone takes priming to get them to move to membrane 0 different exocytosis conditions 0 low frequency firing 9 low calcium concentration 9 small molecule nt release readily releasable pool 0 high frequency firing 9 high ca concentration 9 small molecule AND neuropeptide release takes a lot of calcium to reach the area of neuropeptides because farther back often neuropeptides release modulates small molecule release slow response modulates fast response amino acids 0 packaged at axon terminal into vesicles 0 recycled at terminal into synaptic vesicles glutamate excitatory usually extrinsic projection project outside their area all over the brain principal neurons synthesis in terminal precursor glutamine catalyzed by glutaminase recognized by vesicular transporter release postsynaptic receptors n ionotropic AMPA kainite NMDA n metabotropic mGluRl mGluR8 termination of actions diffusion and uptake taken up by astrocytes EA39IT a broken down into precursor glutamine through glutamine synthetase n glutamine leaves astrocyte goes into axon terminal via glutamate transporters a recycled made into glutamate again GABA inhibitory 0 usually inhibitory interneurons intrinsic projections within a structure link up principal neurons synthesis in terminal glutamate is precursor catalyzed by glutamic acid decarboxylase GAD pyridoxal phosphate packaging in vesicles by vesicular transporter release receptors n ionotropic GABAA Cl channel a metabotropic GABAB K and Ca channels indirectly reuptake taken up into astrocytes and neurons GABA transporters take them back to recycle recycling breakdown ACh 0 synthesis in terminal 0 precursors acetyl CoA choline aa via choline acetyltransferase 0 release receptors 0 nicotinic ionotropic o muscarinic metabotropic termination breakdown o acetylcholinesterase acetate choline o uptake of choline choline transporter resynthesis of ACh transmitter recycling cholinergic systems 0 central ACh system diffuse system project axons out 3 sources a 1 PMT pontomesencephalotegmental complex basal forebrain projections n 2 basal nucleus of meynart cortical projections 0 higher forebrain n 3 medial septum corticalhippocampal projections ACh fibers lost in Alzheimer s 0 memory involvement attention 0 Ach in ANS o sympathetic ACh in preganglionic neurons 0 parasympathetic ACh in preganglionic and postganglionic catecholamines dopamine norepinephrine noradrenaline epinephrine adrenaline 0 synthesis 0 precursor tyrosine aa tyrosine hydroxylase 9 DOPA DOPA decarboxylase 9 dopamine dopamine B hydroxylase 9 norepinephrine PNMT 9 epinephrine OOOO mood stress fluidenergy homeostasis reward autonomic fx 0 receptors 0 dopamine D1D4 o norepinephrine metabotropic a B o epinephrine metabotropic a B o 1 dopamine o diffuse modulatory systems 0 3 sources 1 ventral tegmental area a cortex frontal lobe projections n schizophrenia a reward 2 substantia nigra n striatum projections n Parkinson s a motor 3 basal hypothalamus n neuroendocrine n regulates anterior pituitary n prolactin secretion central neuroendocrine systems 0 pons o locus coeruleus o dorsal noradrenergic bundle corticalcerebellar projections spinal projections medulla brainstem NE system 0 solitary tract nucleus 0 ventrolateral medulla o ventral noradrenergic bundle subcortical projections diffuse projections involved in arousal and mood NE in ANS sympathetic o postganglionic neurons norepinephrine B receptors serotonin 5HT 0 synthesis 0 precursos tryptophan aa o tryptophan5hydroxylase 9 5hydroxytryptamine 5HT serotonin 0 receptors metabotropic 5HT1 through 5HT7 5HT4 thought to NOT be in the brain 5HT3 IONOTROPIC 0 systems 0 brainstem Raphe nuclei n9 diffuse projections a brain arousal mood sleepwake cycle a spinal cordpain hypothalamic neuropeptides 0 control of o pituitary gland neuroendocrine system 0 ANS descending neuronal projections homeostasis control center Neuropeptides magnocellular neuroendocrine cells 0 posterior pituitary 0 part of brain 0 neuropeptide secretion directly into general circulation oxytocin a contraction of smooth muscle in mammary glands to eject milk milk ejection reflex n parturition child birth 0 contraction of smooth muscle cells in uterus vasopressin antidiuretic hormone ADH blood volumeosmolality a response to dehydration and drop in blood pressure a fluid homeostasis n BP regulation neuropeptides parvocellular neuroendocrine cells 0 anterior pituitary control 0 1 releasing hormones secreted from hypothalamus mainly neuropeptides n GnRH n TRH n CRH corticotropin releasing hormone 0 stress response HPA axis leads to corticosteroid secretion from adrenal glands n GHRH a dopamine inhibitory and excitatory o 2 pituitary hormones secreted from anterior lobe of pituitary prolactin FSH and LH TSH ACTH growth hormone 102315 832 PM 102315 832 PM Synaptic Modulation 102315 831 PM o synaptic shunting shunting inhibition 0 opening of ion channels independent of changing membrane potential 0 if EPSP charge goes through area of activated inhibitory open Cl channels draws Cl into cell negate that positive charge 0 positive charge shunted by negative charge being pulled in o negates EPSP 0 expressed by Ohm s law VIR resistance decreased when chloride channels open leads to proportionally smaller V o metabotropic receptors 0 Gprotein coupled receptors guanocine nucleotide binding protein 0 single subunit but can form and signal as dimers 7 transmembrane regions 0 associated with G protein GDP binding region 0 DO NOT form ion channels 0 2nd messenger system 0 intracellular messenger o indirect gating of channels targets of signal 0 sequence 0 receptor binding G protein activation 2nd messenger activation kinase activation phosphorylates target phosphorylation of channel protein ion channel 0 G protein activation 0 G protein 0 3 protein subunits alpha beta gamma By form one subunit 0 membrane associated o GDPbound guanosine diphosphate ligand binding to GPCR o activates G protein 0 G protein associates with receptor 0 GTP triphosphate substitutes for GDP on alpha subunit 0 a subunit dissociates from B and y 0000 O O O a and By can each signal ex trigger reactions a activates 2nd messenger system secondary effector By dimer can act directly on ion channels target protein 0 2nd messenger systems 0 activation of GPRC G protein coupled receptors 0 0 000 O 1 first messenger neurotransmitter binds to receptor 2 G protein activated GTP binding transducer G protein 9 signal transduction 3 primary effector enzyme activated 4 2nd messengers formed 5 secondary effector enzyme activated ex kinase 6 phosphorylation cAMP and phosphoinositol most common 2nd messengers CAMP Gs and GI stimulatory and inhibitory G proteins 0 different alpha subunits 0 GS stimulates adenylyl cyclase primary effector enzyme 0 O adrenaline noradrenaline epinephrine norepinephrine norepinephrine activates beta receptor coupled to GS protein when GTP added dissociates and has a positive regulation on adenylyl cyclase makes cAMP causes increase in cAMP production increase in pKA activity 0 GI inhibits adenylyl cyclase 0 receptor to norepinephrine and epinephrine recruits alpha I dissociation of alpha has inhibitory influence on adenylyl cyclase activity down regulates reduces cAMP production 0 cAMP activates cAMPdependent protein kinase proteinkinase A O PKA secondary effectory 9 phosphorylation of target proteins phosphoinositol precursor protein to UP3 and DAG 1 G protein GQ stimulates phospholipase C PLC 0 alpha Q subunit o PLC is enyme that acts on lipids 2 phosphatifylinositol diphosphate PIPZ membrane lipid precursor 3 PLC 9 IP3 and DAG production from PIPZ 4 IP3 9 release of calcium from intracellular stores and increases intracellular calcium concentration can increase activity in PKC 5 DAG 9 activates PKC calcium dependent all of these can signal to other proteins in cell 0 direct actions of G proteins via By inhibitory direct gating of channels WITHOUT second messenger intermediates ex in heart ACh muscarinic receptors slow heart rate ex GABAB receptors in brain activated by By subunit GIRK channels G protein gated inwardly rectifying potassium channels 0 inhibitory GPCR can open OR close ion channels ionotropic receptors activation leads to opening only 0 local actions ONLY ex at synapse signal can trael but initially only local metabotropic receptors activation can lead to both opening and closing 0 actions can occur distant from receptors diffusible messengers not local 0 amplification of signals 1 GPCR can signal to multiple G proteins each protein can act with multiple targets multiple signals diverge converge at end to amplify original signal 0 much slower rate longer lasting than ionotropic prolonged opening or closing modulates excitability of postsynaptic cell 0 changes in Vm o changed is R 0 changes in membrane responsivity based on Ohm s law 0 metabotropic receptors cause slow synaptic modulation modulation by G protein coupled receptors 0 in contrast to fast excitation and inhibition by glutamate and GABA 0 slow modulation 0 slow onset and offset 0 slowed by intracellular signal cascade Neurotransmitter G proteincoupled receptors Glutamate mGluR18 GABA GABAB 2 subtypes form dimers Acetylcholine muscarinic receptors M15 highlighted are GPCR postsynaptic modulation at dendrites or soma axosomatic axodendritic synapses works via metabotropic receptors 0 CAN affect neuron excitability spillover from axon into perisynaptic receptors on postsynaptic membrane 0 with high activity of that synapse so much nt that it cannot be taken up completely 0 increasing evidence that glia can release gliotransmitters 0 methods of modulation 2 o depolarization and hyperpolarization o increasedecrease in conductanceresistance openclose channels 0 ex glutamate and GABA o glutamate 9 mGluRs metabotropic glutamate receptors9 closing of voltagegated channels and K leak channels depolarizationexcitation o GABA 9 GABAB receptors metabotropic9 opening of K channels GIRK directly coupled to GABAB9 membrane resistance decreases more open channels hyperpolarization inhibition presynaptic modulation at axon terminal of presynaptic neuron due to metabotropic receptors activation of these receptors CANNOT affect excitability of neuron only influences neurotransmitter release at axon terminals 0 changes how much nt released per action potential changes probability of release at synapse axoaxonic caused by 0 1 retrograde messenger actions 0 2 also caused by neurotransmitter spillage from dendrites o 3 metabotropic receptors increases or decreases in neurotransmitter release glutamate INHIBITORY when acting at metabotropic glutamate receptors in presynaptic terminal 0 different from all other glutamate receptors 0 mGluR receptors 0 act on synaptic proteins that mediate exocytosis inhibit synaptic machinery resposible for exocytosis causes decrease in glutamate release causes decrease in GABA release 0 each spike in graph is vesicle of glutamate release causing inward current mGluR agonist causes decrease in frequency of EPSC because decrease in probability of release mGluR acting at glutamate synapse presynaptically to reduce frequency of vesicular release GABA via GABAB receptors inhibitory o modulate calcium influx decreaseinhibit voltagegated calcium channels decreases exocytosis because calcium dependent causes decrease in GABA release because calcium decreased causes decrease in glutamate release because calcium decreased outward current in graph 9 hyperpolarization application of norepinephrine causes increase in frequency of those events increases probability of release of GABA at GABA synapses by acting at presynaptic receptors 102315 831 PM 102315 831 PM