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Neurotransmitters (*GABA
(Gamma aminobutyric acid) (GABA Re-Uptake
the…
Neurotransmitters
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*Glutamate (Glu)
Glutamate
Receptors
- ALL main glutamate
receptors are ionotropic
AMPA Receptors
- allow in BOTH Na+ and K+ ions
--> think Glu main excitatory ion
--> Na+ and K+ main NTs for APs
--> only a small # of K+ actually pass through
- AMPA receptors are the main Glutamate receptors
- they give fast AP conduction
NMDA ligand gated (Mg+) Ion Receptors
- AMPA are the same as NMDA receptors since they allow both Na+ and K+
--> NMDA also allow Ca2+ though
- NMDA receptors are used to modulate AMPA receptors
- NMDA receptors are also needed in learning and memory
- note NMDA receptors are gated by Mg+ ions
--> the Mg+ doesn't move unless AMPA receptors on post synaptic cell have caused enough depolarization for the regulatory NMDA to kick in
- NMDA mneumonics
--> NM = need more ions = also let in Mg+ ions
--> NM = need memories
--> Need modulation
NMDA Glutamate receptors and LTP
- LTP = long term potentiation
- note by NMDA also allowing in Ca2+ in addition to Na+ and K+ from AMPA
--> think NM in NMDA = Need Memory!
- Ca2+ binds to calmodulin nd activates Ca2+/Calmodulin dependent protein kinase 2
- Ca2+ causes plasticity and strengthening of synapse
- Ca2+ also causes more AMPA receptors to go to the cell membrane to increase the response
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Glutamate synthesis
- amino acid NT
--> absorbed through diet
--> cannot pass the BBB
--> synthesized in the CNS by alpha-ketogluterate from Citric Acid Cycle = Krebb's Cycle
- note glutamate can be converted to GABA
--> this is a self regulating NT since if too much is made, it can be converted into GABA to inhibit itself
*ACh = Acetylcholine
ACh Synthesis
- ACh made in the brainstem
ACh Re-Uptake
#4 - VAT = Vesicular ACh Transporter
- VAT brings ACh into vesicles so it can be released at the terminal
#1 - ACh Esterase
- Acetyl choline esterase breaks down ACh in the synaptic cleft into:
--> Choline group + acetyl group
#2 - Na+/Choline Cotransporter
- Choline is brought back into the cell with Na+ that is in excess outside the cell
#3 - CAT enzyme = Choline Acetyl Transferase
- CAT enzyme transfers an acetyl group from the Citric acid cycle of mitochondria onto the choline
--> makes ACh
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ACh Receptors
nicotonic ACh receptors
- ionotropic receptors that are non-specific for cations
--> Ca2+, Na+, K+
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*Glycine
- inhibitory NT
- mainly in the brainstem and spinal cord
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Glycine Re-Uptake
#2 - SeTHM = serine transhydroxymethylase enzyme
- SETHM converts serine into glycine
#1 - GLAT
- GLAT = Glycine transporter
- transports Glycine directly back into the glycinegetic neuron
--> NO re-uptake intervention by glial cells like in Glutamate
#3 - VIAAT = vesicular inhibitory Amino acid transporter
- note VIAAT is the same transporter for vesicles as GABA since they are both inhibitory
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*Endocannabinoid
System (ECS)
- "endo" meaning endogenous
Anandamide
(mimetic = THC)
Receptor
- binds to ONLY CB1 receptors
Actions of Anandamide
- GABA normally released in CNS to inhibit DA release
- binds to CB1 receptors on Gabanergic neurons
- inhibits release of GABA
--> no inhibition of dopamine
Functions of Anandamide
- Anandamide supresses DA and other NTs to get rid of useless short term memories
- Anandamide also used to inhibit some movements to make us feel relaxed and calm
- Anandamide broken down very quickly in synaptic cleft
--> reason why anandamide doesn't give a high, but THC does
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*monoamines
- dopamine, NE, and 5 HT = serotonin
*Dopamine (DA)
- SIMPLE 2 step process like Serotonin
- also uses the same VMAT as serotonin
Dopamine Synthesis
- monoamine made from tyrosine
--> think of TYRONE the drug dealer
--> TYRONE sells dopamine
- tyrosine
--> L-DOPA
--> dopamine
--> NE = norepinephrine
--> Epi = epinephrine
- tyrosine hydroxylase converts tyrosine into dopamine
--> think TYRONE also sells alcohol
--> hydroxylase needed to form dopamine
Dopamine Re-Uptake
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#2 - VMAT
- VMAT = vesicular monoamine transport
- transports ALL monoamines into vesicles for release
--> dopamine
--> serotonin 5 - HT
--> NE = Norepinephrine
#1 - DAT
- DAT = dopamine transporter
- transports Dopamine directly back into the dopaminergic neuron
--> NO re-uptake intervention by glial cells like in Glutamate
Dopamine Receptors
- G protein coupled receptors
- allow in ALL cations?
4 Dopamine Pathways
Nigro-Striatum DA Pathway
- substantia nigra (midbrain) --> striatum (caudate + Putamen)
--> remember striatum as mix of a STRAIGHT CAUTIOUS DATER + PutaMEN
--> Striatum = Caudate + Putamen
MesoLimbic DA Pathway
- VTA = Ventral Tegmental Area (midbrain) --> Nucleus Accumbens (also to other limbic structures)
--> remember "V-TA DA-NA" song makes DANA very positive, happy and hallucinate
MesoCortical DA Pathway
- VTA = Ventral Tegmental Area (midbrain) --> Frontal cortex (mainly the prefrontal cortex)
Tuberoinfundibular --> Prolactin DA Pathway
- Infundibulum (= pituitary stalk of hypothalamus) --> anterior pituitary gland (causes release of prolactin)
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Dopamine/Catecholamine Breakdown
- MAO and COMT
- think that MAO is a COMMUNIST CAT
--> MAO is in the mitochondria
--> COMT is in the cytosol
MAO = Monoamine oxidase
- MAO breaks down catecholamines (NE mainly) in the mitochondria
- also breaks down these NTs:
--> histamine
--> serotonin
--> NE
- MAO inhibitors used to treat depression due to the monoamine theory of depression
--> note MAO inhibitors can cause hypertension since they stop NE breakdown in the periphery
MAO A
- mainly used for 5HT and NE breakdown
MAO B
- mainly used for Dopamine breakdown
COMT = catechol-o-methyl transferase
- COMT breaks down catecholamines (NE mainly) in the cytosol
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Serotonin = think of the turkey server RAPHE (5 HIAA 5s) and the Tyrant DOPES:"2 Tyrant DOPES at TABLE 4 TRY to TRYP Raphe the TURKEY SERVER while he gives 5 HIAA 5s to each table"
- 5 HIAA 5s = 5 HIAA = 5 - hydroxyindoleacetic acid
--> breakdown product of Serotonin
--> serotonin metabolized in the liver into 5 HIAA normally so would be in the liver
--> in Carcinoid Syndrome, mets to liver gives 5-HIAA in the urine insteads
- "TABLE 4 " = tetrahydrobiopterin
--> needed for both major NT monoamines serotonin and dopamine
--> deficiency leads to PKU and tryptophan build up
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Neurotrasnmitter Release and RecyclingH+ proton Gradient for loading vesicles with NTs
- NTs get pumped into secretory vesicles by antiporters
- think just like the ETC = Electron transport chain the secondary active transport is given by Hydrogen protons H+
--> H+ protons are pumped into the vesicles by ATP pumps
- Co-transporter then anti-ports H+ ions out and NTs in
Vesicle General cycle
- vesicles dock at active zones
--> active zones are areas where voltage-gated calcium channels are dense so the vesicles can be reached easily by calcium for release
- are primed for release
- then fuse withe the membrane
- then they bud off the membrane, fuse into endosomes, and again bud off endosomes to resume cycle
Distinct Pools of Vesicles
- Reserve Pool of vesicles
--> a reserve pool of vesicles are held away from the active zones by actin filaments
--> readily releasable pool are at the active zones and begin docking through the RAB- RIM proteins
SNARE Proteins, Docking and Release
- RAB- RIM proteins
--> initial docking starts when the Rab protein on vesicle binds to RIM protein on terminal membrane
--> think the vesicle wants to gRAB = RAB the RIM of the membrane
- V-SNARE protein = vesicle protein
--> synaptobrevin
- t-SNARE proteins = target proteins
--> syntaxin
--> SNAPP-25
- SNARE Complex
--> the SNARE complex is formed by the v-SNARE and t-SNARE proteins binding to form a helix
- Release TAG protein
--> synaptotagmin
--> note that synaptotagmin without bound calcium is slightly attracted to the t-SNARE proteins
--> Calcium binding to synaptotagmin increases the affinity of synaptotagmin for the t-SNARE proteins
--> Calcium enters through voltage gated calcium channel at the active zone
--> Ca2+ binds to synaptotagmin and the vesicle fuses with the plasma membrane
Recycling of the Vesicle
- NSF is special protein that disassembles the SNARE complex so the vesicle can be recycled
--> think of NSF = "NO SNARE FUSION"
Botulism and Tetanus
- both botulism and tetanus stop vesicle fusion and thus NT release
--> they selectively cleave SNARE proteins to stop vesicle docking
- both come from clostridium bacteria that release toxins
--> clostridium botulinum
--> clostridium tetani
- death comes from no NT release for muscles
--> mainly die from respiratory/diaphragmatic failure
- Botulism
--> cleaves SNARE proteins in motor neurons
--> facial BOTOX is Botox-type A
- Tetanus
--> cleaves SNARE proteins in inhibitory spinal cord neurons (Glycine mainly)
--> causes sustained contraction
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NOTES
Ionotropic and Metabotropic NT ReceptorsIntroductionfdIonotropic receptors = ion channel receptors
--> directly allow ions to pass through
- Metabotropic receptors = GPCR = G protein coupled receptors
--> have cascade signals that amplify
--> think GPCRs have long term effects and will effect metabolism = metabotropic
Classifying Ionotropic and Metabotropic Receptors
- the main excitatory and Inhibitory NTs and their main receptors are ionotropic with the lesser known ones being metabotropic
--> think that they are the main NTs for generating or stopping APs, thus they act directly through ions
- GABA receptors
--> GABA-a is ionotropic and allows in Cl- ions
--> GABA-b is metabotropic
- Glycine receptors are ionotropic
--> being the other inhibitory NT, Glycine receptors are similar to GABA-a in that they are also ionotropic and also let in Cl- ions to hyperpolarize
- Glutamate receptors
--> main Glutamate receptors: NMDA, AMPA, and Kainate are all ionotropic
--> lesser known mGluR is metabotropic
- Acetylcholine receptors are based off their names
- nicotinic ACh receptors
--> start with an N so they are Ionotropic
- muscarinic ACh receptors
--> start with an M so they are metabotropic
- Monoamine NTs and All Neuropeptides (opioid agonists)
--> ALL are metabotropic = GPCR
--> again think Monoamines start with an M
--> dopamine, serotonin = 5HT, NE
- the only exception is serotonin subtype 3 is ionotropic
Metabotropic = GPCR Receptors
- have 2 actions
--> modulate other ion channels
--> start cascade effects for protein synthesis, etc.
- Trimeric GTP binding proteins = alpha, beta, and gamma
- Alpha subunit
--> has a bound GDP to it
--> once NT binds to GPCR, Alpha unit replaces GDP with GTP
--> when GTP is bound to alpha, it disassociates from beta and gamma
--> alpha causes downstream effects and cascade
--> ex: Adenylate Cyclase
- bound beta and gamma subunits modulate other membrane proteins or ion channels
2 Most Common GPCR Pathways
- cyclic nucleotide pathways
--> cAMP or cGMP
- phosphoinositol pathway = Phospholipase C Pathway
- note it is the alpha subunit type that determines what "primary effector" a GPCR will effect
- Main GPCR types:
--> Gs = cAMP stimulation through Adenylate Cyclase
--> Gi = cAMP inhibition through inhibiting Adenylate Cyclase
--> Gq = Phospholipase C pathway
- note 2ndary effectors are always kinases
Gs cAMP GPCR Pathway
- primary effector = Adenylate Cyclase
- 2nd messenger = cAMP
- secondary effector = PKA = protein kinase A
- final effect = increase protein phosphorylation
--> since the 2nd or final effector is a kinase
Gq cAMP GPCR Pathway
- primary effector = Phospholipase C
--> note PhosphoLipase C stands for CHOPPER since this protein chops the head off of PIP2 = a lipid that makes DAG and IP3
- 2nd messenger = Diacylglycerol (DAG) and inositol triphosphate (IP3)
- secondary effector = PKC = protein kinase C and Ca2+ release
- final effect = increase protein phosphorylation due to kinase and also increase Ca2+ levels
--> note the C in Phospholipase C is for both the kinase and for the Calcium release
4 Ways Ca2+ levels are controlled and kept low in cell
- Ca2+ ATPase pumps calcium out of the cell
- Na+/Ca2+ exchanger at the cell membrane uses the sodium gradient to pump calcium out
- calbindin is a bufferring protein that bufffers Ca2+ in the cell
- Endoplasmic Reticulum stores intracellular calcium
3 effects of 2nd effectors (protein kinases) on ion channels
- Direct modualtion of ion channels by kinases
--> phosphorylating them modulates them
- Indirect modulation of ion channels by kinases
--> kinases may phosphorylate another protein that woul increase or decrease ion channel expression
- Transcriptional regulators of ion channels
--> may increase or decrease the production ion channels
- examples:
--> Beta NE GPCR Gs type --> PKA directly phosphorylates K+ channels
--> stops K+ from leaking out of the cell
Ionotropic and Metabotropic NT Receptors (cotinued)--> this lowers the threshold for APs in the heart to allow it to pump faster or harder
--> possible for weaker EPSPs = excitatory post synaptic potentials to give an action potential
- GABA-b GPCR receptors - 2 effects
beta gamma subunits directly activate K+ channels or deactivate Ca+ channels for inhibition
- PKA downstream casues dephosphorylation of NMDA glutamate receptors to stop allowing them to bring in Ca2+
--> recall the NM in NMDA stands for NEED MORE OR NEED MEMORY (more cations other than Na+ and K+ let in by AMPA glutamate receptors)
CREB protein
- CREB = cAMP response element binding protein
- transcription factor that becomes activated when phosphorylated by PKA
- CREB is a key protein in memory formation for long term potentiation
Main GPCRs types
- recall Glutamate, GABA-a, Glutamate, 5HT type3,nicotinic are ionotropic receptors
- All Monoamine (minus type 3 5HT) and neuropeptides are GPCRs
- Dopamine
--> D1,5 = excitatory = Gs
--> D2,3,4 = inhibitory = Gi
- NE
--> Beta 1,2 = Gs
--> Alpha 1 = Gq
--> Alpha 2 = Gi
- ACh Muscarinic
--> M1,3,5 = MNOPQ = Gq
--> M2,4 = Gi
