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67 Cards in this Set
- Front
- Back
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Furschpan and Potter
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-found the existence of electrical synapses
-looking at escape response of cray fish-->too fast communication for chemical synapse |
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Martin and Pilar
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-observed avian ciliary ganglian (sympathetic NS) and saw both electrical and chemical signaling occured.
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connexons
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-made up of 6 connexin
-many connexons make up a gap junction -can be gated |
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neuromuscular junction
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-synapse between motor neurons and muscle cells
-motor neurons fire an AP in a muscle fiber |
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motor unit
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-a motor neuron and all the muscle fibers it innervates
--a single neuron innervates many muscle fibers but muscle fibers only have one neurons innervating them |
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Post-junctional folds
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-allows AP to penetrate cell
-AP occur within them/carried through synaptic cleft |
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Neurotransmitter Vesicles+Katz
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-Katz figured out that they must be quantal (packets)-->about 5000 Ach molecules in one
-need extracellular Ca and VG Ca channels -1 pack will give a MEPP -about 100-300 packets released in normal circumstances-->"safety factor" |
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Necessary Proteins at Axon Terminal
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-SNAP, SNARE
-Na and K Channels -Ca channels -transporters -auto-receptors -pumps |
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Getting proteins/enzymes to terminal
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-proteins synthesized in rough ER
-newly synthesized proteins enter golgi apparatus -proteins then transferred to vesicles which bud off of golgi -vesicles transported on microtubules by kinesin -At PM, vesicles can be stored for later, secreted for ECM, or inserted into membrane |
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Types of Vesicle
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-largo core dense vesicles (LCDV)
-small synaptic vesicles |
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Large Dense Core Vesicles
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-about 200nm in diamter
-package peptides, hormones, NTs very densely -released under high level of stimulus -need high sensitivity to Ca -synthesized in cell body and transported |
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Small Synaptic Vesicles
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-about 40nm in diamter
-contain classical NTs (NE, dopamine, ACh, GABA, glutamate) -Docked and released at membrane (low to moderate stimulation) -Located very close to Ca channels so not highly sensitive to Ca -come in 2 pools: reserve pool and releasable pool |
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Endosome
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-where the final sorting of proteins and formation of synaptic vesicles occurs
-structure from which new synaptic vesicles are formed |
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Small Synaptic Vesicle Reserve Pool
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tethered to cytoskeleton away from PM and released during very high levels of activity
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Small Synaptic Vesicle Releasable Pool
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docked at PM and ready for release; continually recycled during regular activity
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The 3 Molecules central to to exocytosis of synaptic vesicles
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-synaptobrevin (vSNAREs)
-syntaxin (tSNAREs) -SNAP-25 |
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vSNARES
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vesicular SNARE, synaptobrevin
-integral membrane protein |
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tSNAREs
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targets PM, syntaxin
-integral membrane protein |
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SNAP-25
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-not integral membrane protein
-contains a lipid group that tethers it to membrane |
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Steps forming SNARE complex
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-synaptobrevin, syntaxin, and SNAP-25 come together and form the loose SNARE complex
-synaptotagmin (Ca sensor on vesicle membrane) binds two Ca molecules -Binding of Ca causes the tight SNARE complex, initiating fusion event |
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MUNC proteins
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-interact with SNAREs, preventing complex formation when bound to syntaxin (regulator protein)
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Rab3
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-G-protein
Docking: -Rab3 is anchored to the membrane of synaptic vesicles (only when bound to GTP) and is then bound to rabphilin which is bound to Rim, associated with the PM. Exocytosis -Rab3+GTP is bound to vesicular membrane -when vesicle fusion occurs, GTP is hydrolyzed to GDP and Rab3 dissociates from vesicle membrane. |
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Endocytosis
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-as membrane containing the synaptic vesicle proteins begins to bud off from PM, dynamin (needs GTP) forms a collar of proteins around the neck of the newly budding vesicles
-Collar allows pinching off of the membrane -clathrin coats the membrane -vesicle moves to early endosome and fuses -retrieved synaptic vesicle proteins are then ready to be reorganized into new vesicles, budding off from endosome |
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Replenishing Vesicles with NT
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-new vesicles bud off from endosome
-interior of vesicle gets acidified by activity of proton pump which uses ATP to pump protons across membrane into vesicle -acidic environment drives uptake and storage of NT |
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Calcium Domain Hypothesis
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-must have domain of Ca near area of vesicular release
-predictions: --1. will get locally high Ca by the release sites (dramatic rise in NT release in narrow range of Ca concentrations) --2. NT release should response rapidly to rise in Ca --3. Level of presyn. depol. is important for NT release |
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Factors controlling how much Ca gets into Cell
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-how many channels are open (Gca)
-driving force (I=G(V-E)) --depol. actually brings Vm closer to Eca (less driving force) by need depol to open channels-->need a good in between -with a small depol., will open few channels but will have large DF -some presyn. terminals have other inputs on them (something inhibitory) that sum (open K channels), making AP more hyperpol. |
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Facilitation
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increase in postsyn. response based on multiple stimuli
-due to NT release -plasticity |
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depression
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decrease in postsyn. response based on activity
-plasticity |
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Post Tetanic Potentiation
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enhancement of postsyn. response but longer term than facilitation
-pumps on presyn. get rid of calcium at slower rate than channel, sp residual Ca gets added to next wave of AP, adding to summation and increase in NT release -time frame of 10s of minutes--seconds to form, minutes to go away |
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Why do you get reduction in PSP?
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-depletion of NT pool (less vesicles)
-low population of vesicles to begin with -large amount of vesicular release after initial stimulus, not as much released the next time -corelease of NT |
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What could be causing enhanced response to stimuli of time?
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-mitochondria have Ca pumps, so they can build up Ca, allowing another singal
-hypothetically, Ca can leak out of mito. allowing another release |
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Traditional NT similarities
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-localize at axon terminal (vesicles)
-need to be released in Ca dependent manner -there is some mechanism of termination (fast) |
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Types of NT
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Low molecular weight (traditional)
-little larger than amino acid -synthesized in terminals High MW -not synthesized in terminals -mostly stored in LDCV |
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Acetylcholine synthesis and release
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-in peripheral NS
-synthesized at nerve terminals from acetyl-CoA and choline in a reaction catalyzed by the enzyme choline acetyltransferase (CAT) -Acetylcholine packaged in synaptic vesicles and released arrival of AP -some acetylcholine in the cytoplasm can also be released |
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Acetylcholine degradation and reuptake
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-can bind to receptor molecules on postsynaptic membrane
-acetylcholinesterase is a powerful hydrolytic enzyme that destroys acetylcholine, producing Acetyl and Choline very quickly -choline is taken back up in the nerve terminal by a Na pump and used again |
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How we measured choline reuptake as a necessary step
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-used HC-3, a choline reuptake inhibitor
-saw an initially good release of ACh but then release stops being able to occur, since no reuptake -conclusion: substrate limited mechanism |
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The Major Catacholamine
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-dopamine-TH to dopa is rate limiting step
-norepi (sym. NS) -epi (symp. NS) ALL can inhibit TH -all packaged into vesicles |
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Reuptake of Catacholamines
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-slower than ACh
-removed by reuptake in presyn. cell -sodium-dep. transport process |
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How to increase rate of catacholamine reaction
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-package dopamine in vesicles to maintain its production (is highly inhibitory otherwise)
-long term: --increase amount of TH --bipass rate limiting step by increasing DOPA --stimulation --phosphorylation of TH (inc. in Ca (long term) activttes a kinase that does this) and phosphorylated Th drives faster reaction but less reactity for end product |
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How do neurons react to long term stress?
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transynaptic regulation (not always presyn. mediated)
-postsyn. cells will sense enhance NE release -postsyn. cell releases nerve growth factor (NGF) -NGF taken up by neuron, transported up axon to nucleus -NGF stimulates gene transcription to enhance TH making |
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Glycine NT
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-don't need to synthesize, exists everywhere
-inhibitory in spinal chord |
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Glutamate
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-product of intermediatory metabolism
-glia convert it to glatamine and then its passed back to terminals to make glutamate again |
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GABA
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-primary inhibitory NT in brain
-gabanergic neurons are the only cells that have GAD (breaks down glutamic acid into GABA) -classified as an amino acid NT but is not actually an aa |
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receptor
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-receive "things" (e.g. NT, ligands)
-selective -saturability -usually two binding sites in LGIC and GPCR |
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Types of GlutamateR
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-NMDA (NMDA-R: NMDAR1 (a-h) and NMDAR2A-D)
-KA/AMPA (KA-R: GlueR5-7, KA1,2) (AMPA-R: GluR1-4) -Metabotropic |
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NE/epi Receptors
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-alpha-adrenergic
-beta-adrenergic |
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Acetylcholine Receptors
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-Nicotinic (Ligand)
-Mucarinic (GPCR) |
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FMRFamide
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?????
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Ligand-gated Ion Channels (LGIC)
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-have 5 subunits (2alpha, beta, gamma, delta) around a central pore
-alpha sites bind ACh -4 membrane crossing domains (m2 is portion lining pore-defines gating and selectivity) -extracellular N and C termini -primarily postsyn, and glia -very fast -short duration of action |
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G-Protein Coupled Receptors (GPCR)
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-7 transmembrane domains
-2 subunits -Extracelluar N terminus, intracellular C terminus -pre and postsyn. -slower speed of onset than LGIC -longer duration of action than LGIC |
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Ionotropic Glutamate Receptor
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-present in high [ ]s in electric eel tissues (torpedo)
-3 transmembrane domains --have a reentrant loop -4 subunits (not symmetrical although the subunits are pretty similar) -c-termini inside |
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Nicotinic AChR subunits from embryo to adult (and Muscarinic)
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2alpha, beta, gamma, delta-->2alpha, beta, epsilon, delta
-in neurons, still 5 subunits but up of only alphas and betas -in adults, openings shorter and less frequent -Neuronal receptors (adults):a2-9 and b while a7 makes homomeric receptor |
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Examples of Ligand-Gated Ion Channels
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-Nicotinic ACh R
-GABAa R -5-HT3 R -Glycine R -(Glutamate) |
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Examples of GPCR
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-Muscarinic ACh R
-GABAb R -5-HT1,2,4-7 -Adrenergic (a, b) -DA R -Peptide R |
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QRN Site
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-Presence of GluR2 subunit indicates no Ca flow
-RNA editing causes shift in amino acids (Q to R) --Q-glutamine, some Ca permeability --R-arginine, not permeable to Ca --N-asparigine, has very high Ca permeability |
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AMPA-R and NMDA-R functioning together:
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-in resting conditions, Mg bind to outside of NMDA-R channel, preventing glutamate from going through
-NMDA-R also need glycine (reuptook by glia-problems in schizophrenia)to bind with the two glutamates to be able to let Na/Ca through, but Mg needs to be removed first -When glutamates bind to AMPA-R, Na flows in and intracellular depol. kicks Mg out of NMDA-Rs and allows ion flow |
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GABAa R
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-subunits can be alpha, beta, gamma, delta, roe, pi
-5 subgroups (LGIC) -must have atleast one alpha and beta -binding subunit is beta -nonselective anion channel, but ultimately Cl goes through -primary inhibitory NT-->IPSP -If Vm is more negative than Ecl, then Cl moves out and it is then excitatory -Can be inhibitory axonic-axonically (inhibits or modulates) |
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GPCR Gs Family
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-interact with adenylyl cyclase
-generally stimulatory towards activity |
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GPCR Gi Family
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-primarily inhibitory
-some can inhibit andenylyl cyclase -can activate OR inhibit channels but action will overall cause inhibition |
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GPCR Gq Family
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-activates phospholipase C which activates IP3
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The Two Types of GPCR Mediated Events
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1. direct modulation of ion channels
2. indirect modulation |
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Direct modulation of mAChR
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-ACh binds to mAChR and activates G-protein
-Beta-gamma unit binds to potassium channel which opens and lets K leak out, hyperpolarizing the cell |
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Modulation of alpha2-adrenergic R
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-exocytosis of NE when Ca channels open at presyn. cell
-NE can bind to alpha2-adrenergic receptor on same presyn. cell which activates G protein -Ca influx decreases with binding of beta-gamma subunit --NE limits OWN activity |
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Activation/Inhibition of adenylate cyclase/cyclic AMP-dependent protein kinase system
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-cAMP is synthesized from ATP by the enzyme adenylate cyclase (AC) which is coupled to a few different receptors via a G protein (alpha-s activates AC)
-cAMP activates cAMP Kinase-->can catalyze serine or threonine phophorylation of target proteins -cAMP is broken down by phosphodiesterase (PDE) Gs proteins cause this while Gi do exact opposite, inactivating cAMP formation (alpha-i) |
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G-Protein Coupled Phospholipase C actions
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-Many receptors are coupled via a G protein to phospholipase c (PLC)--Gq protein.
-PLC acts as a phosphodiesterase to split PIP2 into IP3 and DAG (remains in the membrane) -AA can be released from DAG by another phospholipase --IP3, DAG, and AA all act as second messengers -IP3 goes into cytoplasm and binds to ER, opening Ca channels (can influence ion channel activity and more) -DAG remains in the membrane and translocates to protein kinase C (PKC) which can catalyze serine or threonin (some ion channels) |
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How do we know GPCR are involved?
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-GPCR require GTP so see if this is involved.
--use whole cell patch clamp (outside out) with NT in bath and control 0GTP vs. GTP --use inside out with 0GTP vs. GTP in bath and NT in clamp (can also add activated Gproteins instead of GTP, in absence of NT) |
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How do we know if GPCR are acting directly or indirectly?
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-use cell attached technique (no access to interior), only measuring channels in patch
-any affect seen will be indirect since membrane loses its fluidity in this technique and membrane associated movement cant have access |
