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67 Cards in this Set

  • Front
  • Back
Furschpan and Potter
-found the existence of electrical synapses
-looking at escape response of cray fish-->too fast communication for chemical synapse
Martin and Pilar
-observed avian ciliary ganglian (sympathetic NS) and saw both electrical and chemical signaling occured.
-made up of 6 connexin
-many connexons make up a gap junction
-can be gated
neuromuscular junction
-synapse between motor neurons and muscle cells
-motor neurons fire an AP in a muscle fiber
motor unit
-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
Post-junctional folds
-allows AP to penetrate cell
-AP occur within them/carried through synaptic cleft
Neurotransmitter Vesicles+Katz
-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"
Necessary Proteins at Axon Terminal
-Na and K Channels
-Ca channels
Getting proteins/enzymes to terminal
-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
Types of Vesicle
-largo core dense vesicles (LCDV)
-small synaptic vesicles
Large Dense Core Vesicles
-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
Small Synaptic Vesicles
-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
-where the final sorting of proteins and formation of synaptic vesicles occurs
-structure from which new synaptic vesicles are formed
Small Synaptic Vesicle Reserve Pool
tethered to cytoskeleton away from PM and released during very high levels of activity
Small Synaptic Vesicle Releasable Pool
docked at PM and ready for release; continually recycled during regular activity
The 3 Molecules central to to exocytosis of synaptic vesicles
-synaptobrevin (vSNAREs)
-syntaxin (tSNAREs)
vesicular SNARE, synaptobrevin
-integral membrane protein
targets PM, syntaxin
-integral membrane protein
-not integral membrane protein
-contains a lipid group that tethers it to membrane
Steps forming SNARE complex
-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
MUNC proteins
-interact with SNAREs, preventing complex formation when bound to syntaxin (regulator protein)
-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.
-Rab3+GTP is bound to vesicular membrane
-when vesicle fusion occurs, GTP is hydrolyzed to GDP and Rab3 dissociates from vesicle membrane.
-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
Replenishing Vesicles with NT
-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
Calcium Domain Hypothesis
-must have domain of Ca near area of vesicular release
--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
Factors controlling how much Ca gets into Cell
-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.
increase in postsyn. response based on multiple stimuli
-due to NT release
decrease in postsyn. response based on activity
Post Tetanic Potentiation
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
Why do you get reduction in PSP?
-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
What could be causing enhanced response to stimuli of time?
-mitochondria have Ca pumps, so they can build up Ca, allowing another singal
-hypothetically, Ca can leak out of mito. allowing another release
Traditional NT similarities
-localize at axon terminal (vesicles)
-need to be released in Ca dependent manner
-there is some mechanism of termination (fast)
Types of NT
Low molecular weight (traditional)
-little larger than amino acid
-synthesized in terminals
High MW
-not synthesized in terminals
-mostly stored in LDCV
Acetylcholine synthesis and release
-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
Acetylcholine degradation and reuptake
-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
How we measured choline reuptake as a necessary step
-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
The Major Catacholamine
-dopamine-TH to dopa is rate limiting step
-norepi (sym. NS)
-epi (symp. NS)
ALL can inhibit TH
-all packaged into vesicles
Reuptake of Catacholamines
-slower than ACh
-removed by reuptake in presyn. cell
-sodium-dep. transport process
How to increase rate of catacholamine reaction
-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
--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
How do neurons react to long term stress?
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
Glycine NT
-don't need to synthesize, exists everywhere
-inhibitory in spinal chord
-product of intermediatory metabolism
-glia convert it to glatamine and then its passed back to terminals to make glutamate again
-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
-receive "things" (e.g. NT, ligands)
-usually two binding sites in LGIC and GPCR
Types of GlutamateR
-NMDA (NMDA-R: NMDAR1 (a-h) and NMDAR2A-D)
-KA/AMPA (KA-R: GlueR5-7, KA1,2) (AMPA-R: GluR1-4)
NE/epi Receptors
Acetylcholine Receptors
-Nicotinic (Ligand)
-Mucarinic (GPCR)
Ligand-gated Ion Channels (LGIC)
-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
G-Protein Coupled Receptors (GPCR)
-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
Ionotropic Glutamate Receptor
-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
Nicotinic AChR subunits from embryo to adult (and Muscarinic)
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
Examples of Ligand-Gated Ion Channels
-Nicotinic ACh R
-5-HT3 R
-Glycine R
Examples of GPCR
-Muscarinic ACh R
-Adrenergic (a, b)
-Peptide R
QRN Site
-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
AMPA-R and NMDA-R functioning together:
-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
-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)
GPCR Gs Family
-interact with adenylyl cyclase
-generally stimulatory towards activity
GPCR Gi Family
-primarily inhibitory
-some can inhibit andenylyl cyclase
-can activate OR inhibit channels but action will overall cause inhibition
GPCR Gq Family
-activates phospholipase C which activates IP3
The Two Types of GPCR Mediated Events
1. direct modulation of ion channels
2. indirect modulation
Direct modulation of mAChR
-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
Modulation of alpha2-adrenergic R
-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
Activation/Inhibition of adenylate cyclase/cyclic AMP-dependent protein kinase system
-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)
G-Protein Coupled Phospholipase C actions
-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)
How do we know GPCR are involved?
-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)
How do we know if GPCR are acting directly or indirectly?
-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