Chemicals in the brain Flashcards by Holly O'Flanagan

Synaptic vesicle release and recycling

Pool of vesicles anchored to cytoskeleton by synapsin

AP causes voltage gated Ca2+ channels to open so influx

Ca2+ activates CaMKII which phosphorylates synapsin

P-synapsin no longer binds to cytoskeleton so vesicles dock to active zone

SNARE complex at active zone docks vesicles to plasma membrane

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Mechanisms of exoctyosis during neurotransmitter release

Vesicle docks
SNARE complexes form to pull membranes together
Entering Ca2+ binds to synaptotagmin
Ca2+ bound synaptotagmin catalyses membrane fusion by binding to SNAREs and the plasma membrane

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Synaptic recycling

Vesicle membrane rapidly recovered via endocytosis

New vesicles bud off and are refilled with transmitter

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Cleavage of SNARE proteins by clostridial toxins

Sites of proteolysis that blocks neurotransmitter release

Botulinum toxin reduces neuromuscular transmission ACh

Tatanus toxin reduces interneurones at spinal cord GABA Gly

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Botox and tetanus

Prevent transmitter release

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Botulinum and tetanus toxins

From bacteroa Clostridium botulinum and tetani

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Botox

Acts directly at the neuromuscular junction

Muscle lose all input and so become permanently relaxed

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Tetanus toxin

Inhibits release of glycine and GABA at inhibitory neurones

Results in dis-inhibition of cholinergic neurones which causes permanent muscle contraction

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Diseases that affect presynaptic terminal

Congenital myasthenic syndromes result in impaired vesicle recycling

Latrotoxin triggers vesicle fusion

Botulinum and tetanus affect SNARE protein in fusion

Cognitive disorders impair transsynaptic signaling

LEMS attack presynaptic Ca2+ channels

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Vesicular transporters powered by proton gradient

ATPase proton pump loads up vesicles with H+

Makes vesicle acidic compared to neutral pH of cytoplasm

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Plasma membrane transporters powered by electrochemical gradient

Na+ higher outside, K+ higher inside

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Glia

Astrocytes have extensions that wrap around synapses

One neurone signals to another by releasing neurotransmitters

These transmitters also taken up by astrocyte

Once activated, astrocytes experience increase in intracellular Ca2+ and release own transmitters into synapse

Transmitters enhance or inhibit synaptic activity

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Categories of neurotransmitters

Amino acids: synthesised locally in presynaptic vesicle

Monamines: stored in synaptic vesicle

Acetylcholine: released in response to local increase in Ca2+

Neuropeptides: synthesised in cell some and transported to terminal; stored in secretory granules; released in response to global increase in Ca2+

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Fast transmitters

Stored in synaptic vesicles

Close to voltage gated calcium channels in membrane of nerve terminal

Released in short bursts when membrane is depolarised

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Slow transmitters

Stored in separate vesicles further from the membrane

Must first migrate to the membrane and occurs only when Ca2+ builds up sufficiently

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Excitatory NT in the CNS

Slightly depolarises the PostS membrane

Glutamate (CSNS)

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Inhibitory NT in the CNS

Slightly hyperpolarises the PostS membrane

GABA (brain)

Glycine (spinal cord and brain stem)

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Diffuse modulatory systems

Function in:

mood
sleep
pain
emotion
appetite

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Synthesis of glutamate

From glucose via the Krebs cycle

2. From glutamine converted to glutaminase into glutamate

Glutamate

Loaded and stored in vesicle by VGLUTs

Reuptake by excitatory amino acid transporters in plasma membrane of PreS cell and surrounding glia

Glial cells convert GLut to glutamine then transported back to nerve terminals back to glutamate

GABA synthesis

From glutamate in a reaction catalysed by glutaminc acid decarboxylase

GABA

Loaded and stored into vesicle by a vesicular GABA transporter

Cleared from synapse by reuptake using transporters on glia and neurones

Higher proportion of GABA is made de novo to refill vesicles rather than recycling

Too much Glu/ too little GABA

Hyper-excitability

Epilepsy

Excitotoxicity

Too much GAB

Sedation/ coma

Cerebral ischaemia

The metabolic events retain the electrochemical gradient are abolished Reversal of the Na+/K+ gradient Transporters release glutamate from cells by reverse operation Excitotoxic cell death (Ca+- enzymes- digestion)

GHB y-hydroxybutyrate (date rape drug)

A GABA metabolite that can be converted back to GABA Increases amount of available GABA Too much leads to unconsciousness and coma

Catecholamines

Dopamine Epinephrine (adrenaline) Norephineprhine

Indolamines

Serotonin

Catecholamine synthesis

Tyrosine--- (TH) L-Dihydroxy-phenylalanin--- (dopa decarboxylase) Dopamine--- (DBH) Noerepinephrine---(PNMT) Epinephrine

Catecholamine storage

Loaded into vesicles by VMATs

VMATs

Vesicular monoamine transporters

Modulation of catecholamine synthesis by drugs

L-DOPA - levodopa - the precursor of dopamine - used as treatment for Parkinson's disease - dopa decarboxylase converts it into dopamine increases pool of releasable transmitter

Catecholamine release and reuptake

Released by Ca2+ dependant exocytosis Binds and activates receptor Signal terminated by reuptake into axon terminal by transporters powered by EC gradient In cytoplasm - reloaded back into vesicle - enzymatically degraded by monoamine oxidase - inactivated by Catechol-O-methyl-transferase

Amphetamines

Reverses transporter so pumps out transmitter and blacks reuptake

Cocaine and methylphenidate

Blocks DA reuptake into terminals More DA in synaptic cleft Extended action of PostS neurone

Selegiline

MOA inhibitor found in dopaminergic nerve terminals Prevents degradation of DA More released on subsequent activations

Entacapone

COMT inhibitor Treatment of Parkinson's

Serotinin

Stored in vesicles Signal terminated by reuptake sertonin transporters on PreS membrane Destroyed by MAOs in cytoplasm

Fluoextine

Blocks reuptake of serotonin Treatment of - depression - OCD

Fenfluramine

Stimulates release of serotonin and inhibits its reuptake Appetite suppressant

MDMA

Causes NE and serotonin transporters to run backwards Release NT into synapse Assessed for therapeutic potential in PTSD

Achetylcholine

ChAT converts choline and acetyl-CoA to acetylcholine Packaged into vesicles by VAChT Rapidly degraded in cleft by AChE

AChE inhibitors

Blocks breakdown of ACh Prolongs its action in the cleft Neostigmine (treatment of myasthenia gravis)

Neuropeptides

Short polypeptide chains (3-36 aa) Vesicle fusion and exocytosis as result of global Ca2+ influx Neuropeptide vesicle membrane recycled by not refilled Bind to activate receptor Terminated by diffusion from site of release Degraded by proteases in extracellular environment Release is slower and signals last longer

Soluble gases

NO and CO 1. NO made in PostS neurone by NO synthase 2. Gas not stored but rapidly diffuses between cells 3. Activates guanylyl cyclase makes second messenger cGMP 4. After few seconds NO is converted to biologically inactive compound

Endocannabinoids

Small lipids mostly causes reduced GAB release at certain inhibitory terminals Active component of marijuana