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What is a synapse?

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specialized junctions where neuronal axons contact another neuron or cell type

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Type I synapse

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-excitatory -axodendritic -round presynaptic vesicles -presynaptic specialization -large active zone -wide cleft -large postsynaptic density

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Type II synapse

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-inhibitory -axoaxonic -flat presynaptic vesicles -few presynaptic specializations -small active zone -narrow cleft -non-uniform postsynaptic density

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SNARE proteins

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expressed in membranes of neurotransmitter vesicles and axon terminals; facilitate docking

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synaptotagmine

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Ca2+ sensor protein in membrane of neurotransmitter vesicles

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synaptobrevin

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allows neurotransmitter vesicle to bind with cell membrane; interacts with syntaxin & SNAP-25

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G-alpha-s subunit

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activates adenylyl cyclase--> more cAMP--> more active PKA

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G-alpha-i/o subunit

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inhibits adenylyl cyclase--> less cAMP--> less PKA

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G-alpha-q subunit

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stimulates phospholipase C-beta--> breaks PIP2 into IP3 + DAG

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4 characteristics to be a neurotransmitter

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1. Produced & stored in vesicles in presynaptic neuron 2. Released in response to presynaptic depolarization; Ca-dependent 3. High-affinity receptors on post-synaptic cell 4. Mechanism to terminate activation

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3 mechanisms to terminate neurotransmitter action

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1. Diffusion away from receptor 2. Enzymatic degradation 3. Re-uptake

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choline acetyltransferase (ChAT)

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synthesizes acetylcholine from choline + acetyl CoA in presynaptic cell

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vesicular acetylcholine transporter

answer

transports ACh into vesicle for storage in presynaptic cell

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acetylcholine esterase (AChE)

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hydrolyzes acetylcholine--> choline + acetic acid *FASTEST enzyme in the body!

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choline transporter

answer

brings choline back into presynaptic cell so it can be used for synthesis of ACh

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agonists of muscarinic receptors

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acetylcholine, muscarine

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subtypes of muscarinic receptors

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*M1, M3, M5--> Gq --> PLC--> more Ca *M2, M4--> Gi--> inhibit adenylyl cyclase

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agonists of nicotinic receptors

answer

acetylcholine, nicotine

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alpha-bungarotoxin

answer

irreversibly binds & inhibits (competitive antagonist) activation of muscle nicotinic ACh receptors & alpha-7 nicotinic ACh receptors

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curare

answer

inhibits ALL nicotinic ACh receptors (competitive antagonist)

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nicotinic receptors

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ionotropic: non-selective cation channels 5 subunits, doughnut shape 2nd transmembrane domain of each subunit lines ion channel agonist binds N-terminal domain of alpha subunit

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What is the end plate potential (EPP)?

answer

Depolarization of skeletal muscle fibers caused by neurotrasmitters binding to post-synaptic receptors -always a multiple of mEPPs--> need MULTIPLE vesicles to release NT

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What is the miniature end plate potential (mEPP)?

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Depolarization of a skeletal muscle fiber resulting from the ACh released from ONE vesicle - happens spontaneously, even when there's no AP in pre-synaptic neuron

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Myasthenia gravis

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Organ-specific autoimmune disorder Usually auto-antibodies against muscle nAChRs Sometimes antibodies against MusK (stabilizes nAChR expression at NM junction) -muscle weakness starts at eyes--> moves down -gets worse with activity

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Pyridostigmine

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Reversible inhibitor of acetylcholinesterase--> increases lifetime of ACh in synaptic cleft Treat myasthenia gravis

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Lambert-Easton Myasthenic Syndrome (LEMS)

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Auto-antibodies against Ca channels in pre-synaptic motor neurons -muscle weakness starts at extremities--> moves up -gets better with activity

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Organophosphorus pesticide poisoning: Cholinergic crisis

answer

irreversible inhibition of acetylcholinesterase--> over-stimulation of muscarinic & nicotinic receptors Muscarinic syndrome: miosis (pupil contriction), profuse secretions, bradycardia, bronchoconstriction, hypotension, diarrhea Nicotinic syndrome: tachycardia, muscle weakness CNS: anxiety, confusion, tremors, seizures, cardiorespiratory paralysis

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What is the important structural difference between nAChR subunits and ionotropic glutamate subunits?

answer

nAChR subunits each have 4 transmembrane domains vs Ionotropic glutamate receptor subunits: 2nd "transmembrane" domain loops back inside, doesn't actually cross the cytoplasmic membrane

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3 functional classes of ionotropic glutamate receptors

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NMDA AMPA Kainate *All have 5 subunits, non-selective cation channels

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What is the major mechanism for terminating the action of GLUTAMATE in the synaptic cleft?

answer

Glial cells take up GLUTAMATE--> Glutamine synthase makes GLUTAMINE--> releases back to pre-synaptic cells

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How do Class II metabotropic glutamate receptors (mGluR2 & 3) lead to inhibition of the post-synaptic cell?

answer

These receptors are coupled to a Gi alpha subunit: bind Glu-->reduce adenylyl cyclase activity-->reduce PKA activity--> INCREASE K channel activity--> K flows out of cell--> HYPERPOLARIZATION = inhibition

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How do Class I metabotropic glutamate receptors (mGluR1 & 5) lead to plasticity in the post-synaptic cell?

answer

These receptors are coupled to Gq alpha subunits: bind Glu-->activate PLC-->increase DAG & IP3-->increase PKC & [Ca]-->modify translation and transcription = PLASTICITY

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How can metabotropic glutamate receptors lead to pre-synaptic inhibition of glutamate release?

answer

These receptors are bound to Gi alpha subunits: bind Glu-->inhibit adenylyl cyclase-->inhibit Ca influx via Ca channels-->prevent depolarization = INHIBITION

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What determines the calcium permeability of AMPA receptors?

answer

RNA editing of the GluR2 subunit: if arginine gets substituted for glutamine at a certain position, the channel will be IMPERMEABLE to Ca

question

What makes NMDA unique among ALL neurotransmitter receptors?

answer

To be activated, it requires simultaneous binding of: -primary agonist (glutamate, aspartate, or NMDA) -co-agonist (glycine, serine)

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What is the role of MAGNESIUM in NMDA receptor signaling?

answer

Extracellular concentration exerts a voltage-dependent block of the channel

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How is the Mg block of NMDA receptors removed?

answer

Membrane depolarization; usually accomplished by activation of AMPA receptors

question

Kynurenic acid

answer

competitive antagonist at the glycine site on NMDA receptors

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Non-competitive antagonists of NMDA receptors

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1. PCP (phencyclidine, drug of addiction) 2. Ketamine (anesthetic) 3. Ifenprodil 4. Memantine (Alzheimer's) 5. Lead (Pb2+)

question

How do extrasynaptic NMDA receptors differ from synaptic NMDA receptors?

answer

Synaptic--> turn on CREB pathways--> cell survival--> plasticity Extrasynaptic--> shut off CREB pathways--> cell death

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Memantine

answer

Non-competitive antagonist of EXTRASYNAPTIC NMDA receptors; prevent neuronal death in late-stage Alzheimer's *NOT for early disease b/c also blocks nicotinic receptors

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What are the 2 ways that GABA is re-uptaken from the synaptic cleft?

answer

1. Re-uptake by pre-synaptic neuron 2. Re-uptake by glial cells--> convert to Gln--> release back to pre-synaptic neuron

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Type of cell where GABA trasmission is mostly used

answer

Interneurons-- control activity of excitatory pathways in the brain

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Barbiturates

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Increase the DURATION of GABA-induced channel activation--> inhibition of other neurons *Anti-convulsant

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Benzodiazepines

answer

increase the FREQUENCY of GABA-induced channel activation--> inhibition of other neurons *Anti-convulsant

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Antagonists of GABA receptors

answer

Cause convulsions by relieving inhibition of excitatory neurons - Bicuculline - Picrotoxin - Dieldrin (organochlorine pesticide)

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Ionotropic GABA receptors

answer

GABA- A and C (C is only expressed in retina) Permeable to Cl- Just like nicotinic ACh receptors: 5 subunits with 4 transmembrane domains each, 2nd domain lines channel

question

When is GABA signaling excitatory instead of inhibitory?

answer

Developing brain: predominant expression of NKCC1--> high resting intracellular [Cl-]

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Why is GABA signaling inhibitory in the adult brain?

answer

KCC2 expression prevails over NKCC1--> low resting intracellular [Cl-]--> GABA stimulation makes Cl- flow in--> hyperpolarization

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Metabotropic GABA receptors

answer

GABA-B Coupled to Gi proteins--> inhibits adenylyl cyclase Beta-gamma dimer inactivates voltage-gated Ca channels, activates voltage-gated K channels

question

Baclofen

answer

Agonist of GABA-B receptors Treat muscle spasms

question

Major inhibitory neurotransmitter in the spinal cord

answer

Glycine

question

Inhibitory interneurons in spinal cord, feedback inhibition loop with motor neurons; use glycine as neurotransmitter

answer

Renshaw cells

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Serine hydroxymethyltransferase

answer

Serine-->Glycine in presynaptic terminal Needs folate as co-factor

question

Hyperekplexia

answer

Exaggerated startle response to acoustic & tactile stimuli Caused by mutation in glycine receptor alpha subunit

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Glycine receptors

answer

Ionotropic ONLY Permeable to Cl-

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Strychnine

answer

Inhibits glycine receptors--> excessive muscle contraction Rat poison

question

4 steps in catecholamine synthesis

answer

1. Hydroxylation: tyrosine--> DOPA 2. Decarboxylation--> dopamine 3. Hydroxylation--> norepinephrine 4. Methylation--> epinephrine

question

What is the rate-limiting step in catecholamine synthesis?

answer

Tyrosine hydroxylase: tyrosine--> DOPA

question

4 co-factors for tyrosine hydroxylase

answer

1. Fe2+ 2. Oxygen 3. Biopterin 4. NADPH

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2 ways to increase activity of tyrosine hydroxylase

answer

1. Phosphorylation of TH; mediated by increased intracellular cAMP 2. Phosphorylation of CREB (long-term, only after prolonged neuronal activation)

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2 feedback inhibitors of tyrosine hydroxylase

answer

Norepinephrine Dopamine (via autoreceptors)

question

Only enzyme in catecholamine synthesis that's located inside the NT vesicle

answer

Dopamine beta-hydroxylase (dopamine-->NE)

question

PNMT enzyme is expressed mostly in what tissue?

answer

Adrenal chromaffin granules (NE-->epi) A few neurons also do this

question

Controls uptake of monoamines into synaptic vesicles

answer

VNMTs (vesicular monoamine transporters)

question

Primary breakdown product of dopamine; low levels in CSF are diagnostic of___

answer

Homovanillic acid (HVA) Disorders of the basal ganglia

question

2 enzymes involved in breakdown of catecholamines

answer

Monoamine oxidase (MAO) Catecholamine-O-Methyl transferase (COMPT)

question

Primary breakdown product of norepinephrine; high levels in blood are diagnostic for ___

answer

Vanillylmandelic acid (VMA) Pheochromocytoma

question

Major means of terminating dopamine synaptic activity

answer

Reuptake into presynaptic cells by dopamine transporters

question

4 similarities between catecholamine and serotonin synthesis

answer

1. Dietary source 2. Hydroxylated by rate-limiting enzyme 3. Decarboxylated by AAD 4. Degraded by oxidation by MAO

question

Driving force for NT reuptake via SLC6 transporters

answer

Na (co-transport) or K (counter-transport) gradient

question

Alpha adrenergic receptors

answer

Excitatory Increase calcium or reduce cAMP

question

Beta adrenergic receptors

answer

Inhibitory Increase cAMP

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D1 receptors

answer

for dopamine increase cAMP not autoreceptors

question

D2 receptors

answer

for dopamine decrease cAMP can be autoreceptors targets for antipsychotics

question

2 norepinephrine pathways in the brain

answer

1. locus coeruleus--> cortex reticular formation--> NTS 2. spinal cord

question

2 dopaminergic pathways in the brain

answer

1. Nigrostriatal (substantia nigra--> striatum) 2. Mesolimbic (VTA--> frontal cortex & nucleus accumbens)

question

serotonergic pathways in the brain

answer

more diffuse that catecholaminergic pathways cell bodies in Raphe nuclei--> project to multiple areas throughout brain *Sleep, wakefulness, mood

question

Regulation of neuropeptide expression is largely ______.

answer

transcriptional (transcription factors, e.g. CREB, bind to response elements, turn transcription on/off)

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