NEUROTRANSMITTER

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NEUROTRANSMITTER

• Sadiah Achmad Department of
  Biochemistry
• FACULTY OF MEDICINE UNIVERSITY OF PADJADJARAN
• BANDUNG

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NEUROTRANSMITTER

• Chemical substances that mediate signaling from
  neuron to another neuron or a muscle or gland
  cells through chemical synapses
• SYNAPSES
• Synapses junctions where neurons pass signals
  to a postsynaptic target cell
• Two types of synapses Electrical and Chemical
  

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Chemical synapses

• The majority of nerve to nerve signaling
• All nerve to muscle and nerve to gland signaling
• Impulses are transmitted by NTs which are
  released from the axon terminal of the
  presynaptic cell into the synaptic cleft and
  subsequently bound to specific receptors on the
  postsynaptic cell
• Impulse transmission occurs with a small time
  delay

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Chemical synapses
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Electrical synapses

• Much less common than chemical synapses
• Ions pass directly from the presynaptic cells to
  the postsynaptic cells through 2 nm gap junctions
• An action potential in one cell generates a local
  current that causes an action potential in an
  adjacent cell
• Impulse transmission is nearly instantaneous
• Found in cardiac muscle and in many types of
  smooth muscle

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Electrical synapses
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• TYPES OF NTs
• Acetylcholine
• Monoamines - catecholaminesdopamine,
  epinephrine
• 
  norepinephrine
• - serotonin
  (5-hydroxytryptamin, 5-HT)
• - histamine
• Amino acids - aspartate, glutamate, glycine,
  taurine
• GABA
• Neuropeptides- enkephalins, endorphins,
  substance P
• vasopressin,
  oxytocin, etc

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• The classic NTs
• Small molecules NTs
• Amino acids or derivatives, except acetylcholine
• Synthesized in the cytosol of axon terminals
• Stored in the synaptic vesicles and released by
  exocytosis
• Each neuron produces one type of classic NTs
• Neuropeptides are stored in a different type of
  vesicle.

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Small molecules neurotransmitters
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• NTs maybe excitatory or inhibitory
• Excitatory NTs - acetylcholine, catecholamines,
• serotonin,
  histamine, aspartate,
• glutamate,
  substance P
• Inhibitory NTs - GABA, glycine, taurine
• Excitatory NT increasing membrane permeability
  to Na,
• causes
  depolarization of the membrane
• Inhibitory NT increasing membrane permeability
  to Cl- or
• K, causing
  hyperpolarization

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PROCESS OF TRANSMISSION

• STEPS
• Arrival of an action potential opens
  voltage-gated Ca2 channels ? ?cytosolic Ca2
  levels
• The rise in Ca2 triggers exocytosis of the
  synaptic vesicles and release of NTs
• The NTs diffuse across the synaptic cleft, bind
  to receptors on the postsynaptic membrane ?
  change membrane potential
• Synaptic vesicles are endocytosed and recycled

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PROCESS OF TRANSMISSION

• Several inactivation mechanisms terminate the
  process
• - enzymatic degradation of NTs
• - reuptake of NTs by presynaptic neuron
• - diffusion of NTs from the synaptic cleft
• Signaling by most of the classic NTs is
  terminated by reuptake
• Signaling by acetylcholine and neuropeptides is
  terminated by enzymatic degradation

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SYNTHESIS OF NTs

• Nonpeptide NTs are synthesized in the cytosol of
  axon terminals
• Monoamine NTs are synthesized in a series of
  enzymatic steps from the precursor amino acids ?
  packaged into storage granules (synaptic
  vesicles).

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STORAGE OF NTs

• Small molecules NTs are imported from the cytosol
  into synaptic vesicles by a proton-coupled
  antiporters in the vesicle membrane and stored
• Synaptic vesicles 40-50 nm in diameter
• Synaptic vesicles membrane contains V-type ATPase
  (proton pumps) which maintains low intravesicular
  pH
• Synaptic vesicles membrane consist of at least
  eight types of membrane proteins that function in
  vesicle docking and fusion

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RELEASE OF NTs

• On stimulation of the nerve cells, NTs are
  released by exocytosis
• Exocytosis involves vesicle - targeting and
  fusion
• Synaptic vesicle fuse with axonal membrane
  releasing their contents into the synaptic cleft
• Synaptic vesicle are recycled locally to the axon
  terminus after fusion with the plasma membrane.

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• Cocaine inhibits the transporters for
  norepinephrine,
• serotonin, and dopamine.
• Binding of cocaine to dopamine transporter
  inhibits reuptake of dopamine ? prolonging
  signaling at key brain synapses.
• Dopamine transporter principal brain cocaine
  receptor.
• Antidepressant drugs
• fluoxetine (prozac) imipramine block
  serotonin uptake
• tricyclic desipramine blocks norepinephrine
  uptake

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• Fig. from Devlin 23.6a

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• Proteins of the synaptic vesicle membrane
• Synapsin- a fibrous P-protein that links
  synaptic vesicles
• - phosphorylated by
  c-AMP-dependent protein kinase
• and Ca-calmodulin (CaM)
  kinase ? regulates number
• of free or bound vesicles
• - bind to cytoskeletal proteins
  actin and spectrin
• VAMP (vesicle- associated membrane protein,
  synaptobrevin)
• - involved in vesicle
  transport and exocytosis
• Rab 3 (GTP-binding proteins)
• - involved in docking
  fusion of exocytosis.
• Synaptotagmin
• - contains four Ca2 binding
  sites
• - Ca2-sensing protein ?
  triggers vesicle exocytosis

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• Fig 23.8 Devlin

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• VAMP ? mechanism of action of botulinum-B toxin
• Botulinum B toxin
• - a bacterial protein
• - composed of 2 polypeptides
• one peptide binds to motor
  neuron that release
• acetylcholine at neuromuscular
  synapse
• the other, a protease, enter
  into the cytosol and
• destroy VAMP ? prevents
  acetylcholine
• release ? causing paralysis

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RECEPTORS OF NEUROTRANSMITTER

• Two classes of NT receptors
• Ligand-gated ion channels receptors
• mediate rapid postsynaptic responses (msec)
• contain 5 subunits, each has a transmembrane M2
  a- helix that lines the channel
• NT binding triggers a conformational change
  leading to channel opening and permit ion passage
• G-protein coupled receptors
• linked to a separate ion channel ? regulate ion
  channel indirectly
• mediate slow postsynaptic responses (seconds or
  more)

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RECEPTORS OF NEUROTRANSMITTER

• Depend on the specific R, the same NT can induce
  either excitatory or inhibitory response
• Stimulation of excitatory Rs causes
  depolarization of postsynaptic membrane ?
  generates an action potential
• Stimulation of inhibitory Rs causes
  hyperpolarization of postsynaptic membrane ?
  represses an action potential

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ACETYLCHOLINE

• Cholinergic neurons
• - projection neurons 2 clusters
• - basal forebrain complex
• - mesopontine complex
• interneurons - several brain regions including
  the
• striatum
• Periphery - preganglionic autonomic neurons
• - postganglionic parasympathetic
  neurons
• - neuromuscular junction

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ACETYLCHOLINE

• Cholinergic pathway in the brain memory
  formation.
• Alzheimers disease majority of nucleus basalis
  neurons in the basal forebrain are lost leading
  to impairments in the cortical cholinergic
  innervation ? correlate with the severity of
  dementia
• Dementia in Parkinsons disease due to
  degenerative process in the basal ganglia and
  other parts of the brain

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ACETYLCHOLINE

• SYNTHESIS, STORAGE AND RELEASE
• Synthesis transfer of acetyl group from acetyl
  CoA to choline,
• catalyzed by choline
  acetyltransferase
• Choline is derived from diet, transported from
  blood by high affinity transport mechanism.
• Choline availability is a rate limiting
  factor
• Stored into synaptic vesicles through vesicular
  H-acetylcholine antiporter
• Released from the vesicles into the synaptic
  cleft, reacts with the nicotinic-acetylcholine
  receptor on the postsynaptic membrane

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ACETYLCHOLINE

• The action of acetylcholine is terminated by
  acetylcholinesterase which hydrolyzes
  acetylcholine to choline and acetate.
• Choline is transported back into the nerve
  terminal by a H-choline symporter ? reuse
• Acetate is reabsorbed into the blood.
• Acetylcholinesterase inhibitors is used to treat
  dementia of Alzheimer (augment cholinergic
  transmission)
• Neurotoxins and nerve gasses inhibit
  acetylcholinesterase ? prolong the action of
  acetylcholine ? extending the period of membrane
  depolarization.
• Such inhibitors can be lethal if they prevent
  relaxation of the respiratory muscles

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• FIG.

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ACETYLCHOLINE RECEPTORS

• Two major classes - Muscarinic receptors
  G-protein coupled
• - Nicotinic
  acetylcholine receptors ligand-gated
• ion
  channels
• Muscarinic - implicated in learning memory,
  sleep regulation, pain
• perception and
  regulation of seizure susceptibility
• - 5 subtypes which are
  heterogenous
• - M1, M3, M5
  stimulate phosphoinositides
• - M2 M4 inhibit
  adenylate cyclase
• - M1 implicated in
  learning memory processes
• - M4 putative targets
  for anticholinergics used as
• 
  antiparkinson

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ACETYLCHOLINE RECEPTORS

• Muscarinic - in peripher - M2 regulate heart
  rate contractility
• 
  - M3 mediate smooth muscle contraction
• 
  glandular secretion
• - binding of
  acetylcholine to muscarinic Rs in heart
• muscle causes
  dissociation of G protein ? open K
• channels.
• Influx of K ions
  hyperpolarizes the cell membrane ?
• slowing heart
  contraction (fig. page )

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ACETYLCHOLINE RECEPTORS

• Nicotinic acetylcholine Receptor NAChR
• In the brain, NAChR are found at highest
  densities in the area implicated in cognitive
  function hippocampus, neocortex, substantia
  nigra, basal forebrain
• Admits both K Na
• Composed of pentameric protein radially arranged
  around a central ion pore subunits a2 ß ? d
  which are heterogenous
• The channel opens when R cooperatively binds two
  ACh molecules at the interfaces of the ad and a?
  subunits
• Its role is best known in synapses between motor
  neurons and skeletal muscle cells ? neuromuscular
  junction

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ACETYLCHOLINE RECEPTORS

• NAChR
• Binding of ACh to NAChR at neuromuscular junction
  triggers a rapid increase in permiability of the
  membrane to Na K ions, ?depolarization ?
  action potential ? contraction of the muscle
• Cortical NAChR
• - diminished in Alzheimers,
• Nicotine administration -improves
  attention defects in some
• 
  Alzheimer patients
• -
  improves measures of sensory gating
• 
  in some schizophrenia
• - Some rare familial epilepsy syndromes are
  associated with
• mutation of NAChR

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NICOTINIC ACETYLCHOLINE RECEPTOR
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NICOTINIC ACETYLCHOLINE RECEPTOR
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ACETYLCHOLINE RECEPTOR
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SEROTONIN

• Serotonin systems influence CNS activity at all
  levels of neuraxis
• Serotonergic neurons are clustered in midbrain,
  pons and medulla, project extensively throughout
  the brain and descend to the spinal cord
• Two types of fibres
• Fine with small varicosities dorsal raphe axons
• Beaded with large spherical varicosities median
  raphe axons
• Both type of fibres are found in the neocortex,
  which receive serotonergic innervation from both
  nuclei
• Caudal raphe serotonergic neurons project to
  medulla, cerebellum and spinal cord
• MDMA (methylene-dioxy-methamphetamine, ecstasy)
• produces selective loss of fine axons

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SEROTONIN

• SYNTHESIS
• Serotonin is synthesized from tryptophan.
• Brain uptake of tryptophan (active carrier
  mechanism) is determined by circulatory
  tryptophan by ratio of tryptophan to other
  large neutral amino acids
• Steps - hydroxylation of tryp by tryp
  hydroxylase ?
• 5-hydroxytryp (rate limiting)
• - decarboxylation of
  5-hydroxytryp by aromatic
• amino acid decarboxylase ?
  5-hydroxytryptamine
• (serotonin)

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SEROTONIN

• DEGRADATION
• - Mediated by monoamine oxidase type A (MAOA)
  which oxidizes amino group to form aldehyde
• - Further oxidation by aldehyde
  dehydrogenase ? 5-hydroxy-
• indolacetic acid (5-HIAA)
• Kidney, liver tissue, fecal bacteria convert
  tryptophan to tryptamine ? indole 3-acetate.
• Urinary catabolites 5-HIAA indole
  3-acetate
• - MAO inhibitors antidepressant effect ?
  elevation of serotonin

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SEROTONIN RECEPTOR

• Great diversity a single NT produce a wide
  variety of cellular
• effects in multiple neuronal systems
• Two types - G protein-coupled cAMP
  inositol-3P as 2nd
• 
  messengers
• - ligand-gated ion channels
• G-protein-coupled
• 5-HT1 - the largest subfamily with subtypes
• - inhibits adenylate
  cyclase ? ? cAMP
• - 5-HT1A
  postsynaptic presynaptic(autoR)
• Stimulation of
  autoR suppresses activity of
• serotonergic neuron
  

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SEROTONIN RECEPTOR

• 5-HT2 - stimulates phosphoinositide turnover ?
  ?IP3
• - antidepressant,
  antipsychotic antagonize 5-HT2C R
• - hallucinogen (LSD)
  agonist activity at 5-HT2 R
• 5-HT4, 5-HT6, 5-HT7 stimulate adenylate cyclase
  ? ? cAMP
• ?
  indirectly modulate K channel
• Ligand-gated ion channel
• 5-HT3 - passage Na K ? rapid excitatory
  effects in
• postsynaptic neurons

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Serotonin modulatory synapse
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CATECHOLAMINES

• DOPAMINE
• Dopamine neurons more widely distributed
• Three dopamine systems 1. nigrostriatal
• 
  2. mesocorticolimbic
• 
  3. tuberohypophyseal
• Nigrostriatal
• - cell bodies in the pars compacta
  substantia nigra
• - ascending projection to dorsal
  striatum modulate motor
• function
• - motor disturbances in Parkinsons
  disease degenerative
• disorder of nigrostriatal system
• - extrapyramidal adverse effects of
  antipsychotic drugs result
• from blockade of striatal receptors

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• DOPAMINE
• 2. Mesocorticolimbic
• - Ascending projection ?
  innervating limbic
• structures associated
  cortical structures
• - Regulate a wide variety of stimuli,
  including drugs of
• abuse
• - Target of antipsychotic drugs (dopamine
  R antagonist)
• 3. Tuberohypophyseal
• - dopaminergic neurons in hypothalamic
  arcuate
• periventricular nuclei.
• - projections to pituitary inhibitory
  regulation of prolactin
• release
• Administration of antipsychotic drugs ?
  galactorhea

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• NOREPINEPHRINE EPINEPHRINE
• Function as both systemic hormones NTs
• NE at synapses in CNS and peripheral neurons
• (synapses with smooth muscles
  innervated by
• sympathetic motor neurons)
• SYNTHESIS
• In adrenal medulla the brain
• Hydroxylation of tyrosine to dopa by tyrosine
  hydroxylase
• Decarboxylation of dopa to dopamine by dopa
  decarboxylase
• Hydroxylation of dopamine to NE by dopamine
  ß-hydroxylase,
• in catecholaminergic vesicles within
  adrenergic and
• noradrenergic neurons
• Conversion of NE to E by phenylethanolamin-N-methy
  l transferase (PNMT) in adrenergic neurons

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CATECHOLAMINES

• DEGRADATION
• The action of CA is terminated by reuptake into
  the presynaptic neuron ? repackaged into synaptic
  vesicles or metabolized
• Metabolism by - catechol-O-methyl transferase
  (COMT)
• - monoamine
  oxidase (MAO)
• COMT catalyzes transfer of a methyl group from
  S-adenosyl-
• methionine to a phenolic -OH group
• MAO catalyzes oxidative deamination of amines
  to aldehydes
• End product - dopamine homovanillic acid (HVA)
• - NE E
  3-methoxy-4-hydroxymandelic acid
• (MHMA)
• CA metabolites indicators of the activity of
  catecholaminergic
• systems

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• COMT - distributed throughout the brain
  peripheral tissues
• - wide substrate specifity
• - catalyzing transfer of
  methyl groups from S-adenosyl-
• methionine to hydroxyl
  group of catechol compouds
• MAO - located on the outer membrane of
  mitochondria
• - oxidatively deaminates
  catecholamines to aldehydes
• - two isoenzymes MAOA MAOB
• - MAOA preferentially
  deaminates serotonin NE
• - MAOB deaminates histamine,
  dopamine phenylethylamine
• - in peripheral tissues (GI
  liver) prevent accumulation of
• toxic amines
• MAO inhibitor - block MA catabolism ??
  monoamines in the brain
• - adverse
  effects ? peripheral amines

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CATECHOLAMINES RECEPTORS

• All known CA Rs are coupled to G proteins
• Different Rs are linked to different G pr ?
  different 2nd messengers
• DOPAMINE Rs D1-5
• D1 - stimulates - adenylate cyclase ? ? cAMP
• - phosphoinositide
  turnover ? ? IP3
• - not found on dopaminergic
  neuron ( not an autoR)
• - contribute to the effects of
  cocain in CNS
• - low affinity for
  antipsychotic (butyrophenones, halloperidol)
• D5 , D1-like - structural similarity
• - stimulates
  adenylate cyclase

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• DOPAMINE RECEPTOR
• D2 - interacts with a variety of G pr ?diverse
  2nd messenger ?
• - ? cAMP
• - modulates Ca2 K
  channel
• - alters phosphoinositide
  production
• - functions as postsynaptic or autoR on
  dopaminergic
• terminals, cell bodies dendrites of
  dopaminergic neuron
• - high affinity for antipsychotic drugs
• - in ant. pituitary inhibition of
  prolactin MSH release
• - in schizophrenia ? D2R
• - extrapyr adverse effects of
  antipsychotic block of striatal D2R
• D3,D4 , D2-like - similar in structure
  pharmacology
• - D4R more
  abundant in heart than in the brain
• - in schizophrenia
  ? D4R

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ADRENERGIC RECEPTORS

• Types a, ß , found in the brain in peripheral
  tissue
• a1 - stimulates phosphoinositide turnover
• - regulates smooth muscle
  contraction, control blood pressure,
• nasal congesion prostate function
• a2 - regulates cardio vascular function,
  autonomic NS arousal
• - postsynaptic presynaptic autoR
• - inhibit c-AMP formation
• - stimulation of a2R in brainstem
• - reduce sympathetic
  NS activity
• - augment
  parasympathetic NS activity
• - stimulation of a2 autoR inhibits
  firing of noradrenergic
• neurons implicated in arousal
  states

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ADRENERGIC RECEPTORS

• ß ß1, ß2,ß3
• ß1 regulate heart function
• ß2 regulate bronchial muscle contraction
• ß3 found in adipose tissue, stimulate fat
  catabolism

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AMINO ACID NEUROTRANSMITTER

• Several amino acids increase or decrease
  excitability of neurons
• Glutamate most important excitatory AA,
  widespread in CNS
• Glutamate is highly toxic to the brain in large
  quantities, mediated by Ca2 influx through NMDA
  R which are widespread in the cortex
• Aspartate potent stimulatory factor in CNS,
  its role is unclear
• No specific Rs, agonist at some types of
  glutamate Rs
• GABA glycine major inhibitory NTs in the
  CNS
• Glycine acts predominantly in the spinal
  cord brain stem
• GABA acts predominantly in all other parts
  of the brain
• Strychnine (CNS stimulant) binds to glycine
  R
• GABA R reacts with benzodiazepines
  barbiturates

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• GLUTAMATE
• The principle excitatory NT in mammalian CNS
• Most glutaminergic / glutamatergic neurons
• projection neurons pyramidal neurons in cerebral
  cortex
• project to various subcortical regions /
  other cortical area
• primary sensory afferents
• ganglion neurons in retina
• interneurons granule cells in cerebellum, in
  hippocampus
• (role in memory formation)
• Synthesis
• In neural tissues , include synaptic terminals
• Precursor glutamine, a- ketoglutarate, malate
• Involved synthesis of glutamate precursor in
  astrocytes
• Stored within vesicles by ATP-dependent specific
  transporters,
• present only on vesicles membrane in
  glutaminergic terminals

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Glutamate Receptors

• Found throughout the brain on neurons ganglia
• Two types
• ligand-gated ion channels - NMDA
• -
  non NMDA - AMPA
• 
  - Kainate
• -
  activated rapidly (mseconds)
• G protein coupled - L-AP4
• - ACPD
• - function
  more slowly (seconds)

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Glutamate Receptors

• NMDA - N-methyl-D-aspartate, excitatory
• - Influx of Ca2 Na
• - voltage
  dependent block by Mg2
• Abnormal functioning of NMDA R ? variety of
  neurological disorder
• Overactivation ischemic insults, head
  trauma, epileptic seizure triggering a cascade
  of cellular events ? neuronal cell death
• Hypofunction ? a psychosomatic state
  resemble schizophrenia
• AMPA a-amino-3-hydroxy -5-methylisoxazole-4-prop
  ionic acid
• Kainate agonist of AMPA
• L-AP4 L-2-amino-4-phosphonobutyrate, inhibitory
  autoR
• ACPD trans-1-aminocyclopentane-1,3-dicarboxylic
  acid

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Glutamate Receptors
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GABA

• Synaptic inhibition in CNS mediated primarily
  by GABA glycine
• Glycine major inhibitory NT in spinal cord
  and brain stem
• GABA predominates in the brain
• Both GABA glycine activate ligand - gated Cl-
  channels
• GABA is synthesized in GABAergic neurons
• a small interneurons with short axons
• projection neurons - Purkinje cells in the
  cerebellum
• -
  striatonigral pallidonigral in basal
• ganglia
• Function - focus refine firing pattern of
  projection neurons
• - facilitate the output of
  excitatory projection neurons by
• disinhibition
• - mediate presynaptic
  inhibition

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GABA

• SYNTHESIS
• GABA is synthesized degraded through GABA
  shunt
• Glu is the major precursor
• Glu by glu decarboxylase pyridoxal-P as
  co-enzyme ?GABA
• GABA glu share common routes of metabolism in
  astrocytes
• GABA glu taken up by astrocytes , converted
  to glutamine ? transported back into presynaptic
  neurons
• In excitatory neurons glutamine is converted to
  glu ? repackaged in synaptic vesicles
• In inhibitory neurons glutamine is converted to
  glu to GABA ? repackaged in synaptic vesicles
• In astrocytes most of GABA is converted to
  succinate by GABA transaminase
• Pool of GABA is replenished by glu a-KG which
  are supplied by astrocytes to GABAergic terminals
  

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GABA

• RELEASED INACTIVATION
• GABA is released from synaptic terminal similar
  to acetylcholine monoamines
• Inactivated by removal from synaptic cleft
• Diffuse into extracellular fluid adjacent to the
  synapse
• Reuptake into presynaptic terminal
• Uptake into postsynaptic neuron
• Vigorous uptake by astrocytes ? maintain low
  extracellular concentration ? removal of NTs from
  synaptic cleft rapidly

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Neuronal dendrite
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GABA RECEPTORS

• GABAA Rs
• Ligand-gated Cl- channels
• Heteropentameric protein complex
• Comprise of 4 types of subunit proteins a, ß,
  ?, d
• Regulated by phosphorylation of some serine
  hydroxyl residues in the inner loop of ß-
  subunits
• 5 separate drug binding sites
• Many drugs are known to bind to
  benzodiazepine or barbiturate sites, which are
  allosteric to the GABA binding site
• GABAB Rs
• G-protein coupled, of Gi subtype ? activates K
  channel
• Exert inhibitory effect on neuronal exitability
• Often located on presynaptic terminals ? inhibit
  NT release

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NEUROPEPTIDES

• Many small peptides released by neurons function
  as paracrine hormones as well as NTs
• Receptors G-protein coupled
• Neurohormones are used only once and degraded by
  extracellular protease ? not recycled
• Biosynthesis
• Precursor larger protein, cleaved by
  proteolysis
• Occurs in the cell body, not in the axon
• Travel along the axon to presynaptic terminal, by
  2 mechanism
• Fast axonal transport (400 mm/day)
• Slow axonal transport (1-5 mm/day)

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NEUROPEPTIDES

• SUBSTANCE P
• Excitatory NT
• Source hypothalamus, CNS, intestine
• Role in pain transmission, increases smooth
  muscle contraction of GI tract
• Endorphins (ß-endorphin)
• Hormone of pars intermedia anterior pituitary
• Acts on cells neurons to eliminate sensation of
  pain
• Product of proopiomelanocortin precursor of
  eight hormones from a single gene
• Enkephalins
• Secreted by chromaffin cells of adrenal medulla
• Pentapeptides met- leu- enkephalins
• Opioid activity
• A single gene encoded multiple copies of a single
  hormone

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REFERENCES

• Harpers Illustrated Biochemistry, 20th ed, 2003,
  p 266-267
• Textbook of Biochemistry with Clinical
  Correlation, Devlin TM, 5th ed, 2002, p 810,
  993-1001
• Molecular Cell Biology, Lodish et al, 4th ed,
  2000, p 935-950
• Comprehensive Textbook of Psychiatry, Kaplan
  Sadock, 7th ed, 2000, p 41-56