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NEUROTRANSMITTER. Sadiah Achmad : Department of Biochemistry FACULTY OF MEDICINE UNIVERSITY OF PADJADJARAN BANDUNG. NEUROTRANSMITTER :. Chemical substances that mediate signaling from neuron to another neuron or a muscle or gland cells through chemical synapses

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neurotransmitter
NEUROTRANSMITTER

Sadiah Achmad : Department of Biochemistry

FACULTY OF MEDICINE UNIVERSITY OF PADJADJARAN

BANDUNG

neurotransmitter2
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
chemical synapses
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
electrical synapses
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
slide7
TYPES OF NTs :
  • Acetylcholine
  • Monoamines: - catecholamines:dopamine, epinephrine

norepinephrine

- serotonin (5-hydroxytryptamin, 5-HT)

- histamine

  • Amino acids : - aspartate, glutamate, glycine, taurine

GABA

  • Neuropeptides:- enkephalins, endorphins, substance P

vasopressin, oxytocin, etc

slide8

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.
slide10
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

process of transmission
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
process of transmission12
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
synthesis of nts
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).
storage of nts
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
release of nts
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.
slide17
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
slide19
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

slide21
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

receptors of neurotransmitter
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 α- 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)
receptors of neurotransmitter23
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
acetylcholine
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

acetylcholine25
ACETYLCHOLINE
  • Cholinergic pathway in the brain : memory formation.
  • Alzheimer’s 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 Parkinson’s disease : due to degenerative process in the basal ganglia and other parts of the brain
acetylcholine26
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
acetylcholine27
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

acetylcholine receptors
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

acetylcholine receptors30
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 )

acetylcholine receptors31
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 α2βγδ which are heterogenous
    • The channel opens when R cooperatively binds two ACh molecules at the interfaces of the αδ and αγ subunits
    • Its role is best known in synapses between motor neurons and skeletal muscle cells  neuromuscular junction
acetylcholine receptors32
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 Alzheimer’s,

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

serotonin
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

serotonin37
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)

serotonin38
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

serotonin receptor
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

serotonin receptor41
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

catecholamines
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 Parkinson’s disease : degenerative

disorder of nigrostriatal system

- extrapyramidal adverse effects of antipsychotic drugs result

from blockade of striatal receptors

slide44
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

slide45
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 β-hydroxylase,

in catecholaminergic vesicles within adrenergic and

noradrenergic neurons

    • Conversion of NE to E by phenylethanolamin-N-methyl transferase (PNMT) in adrenergic neurons
catecholamines47
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

slide48
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

catecholamines receptors
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

slide50
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

adrenergic receptors
ADRENERGIC RECEPTORS
  • Types : α, β , found in the brain & in peripheral tissue
  • α1 : - stimulates phosphoinositide turnover

- regulates smooth muscle contraction, control blood pressure,

nasal congesion & prostate function

  • α2 : - regulates cardio vascular function, autonomic NS & arousal

- postsynaptic & presynaptic autoR

- inhibit c-AMP formation

- stimulation of α2R in brainstem :

- reduce sympathetic NS activity

- augment parasympathetic NS activity

- stimulation of α2 autoR inhibits firing of noradrenergic

neurons implicated in arousal states

adrenergic receptors52
ADRENERGIC RECEPTORS
  • β : β1, β2,β3
  • β1 : regulate heart function
  • β2 : regulate bronchial muscle contraction
  • β3 : found in adipose tissue, stimulate fat catabolism
amino acid neurotransmitter
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

slide54
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, α- 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

glutamate receptors
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)

glutamate receptors56
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 : α-amino-3-hydroxy -5-methylisoxazole-4-propionic acid
  • Kainate : agonist of AMPA
  • L-AP4 : L-2-amino-4-phosphonobutyrate, inhibitory autoR
  • ACPD : trans-1-aminocyclopentane-1,3-dicarboxylic acid
slide58
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

slide59
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 & α-KG which are supplied by astrocytes to GABAergic terminals
slide60
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
gaba receptors
GABA RECEPTORS

GABAA Rs

  • Ligand-gated Cl- channels
  • Heteropentameric protein complex
  • Comprise of 4 types of subunit proteins : α, β, γ, & δ
  • Regulated by phosphorylation of some serine hydroxyl residues in the inner loop of β- 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
neuropeptides
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)
neuropeptides64
NEUROPEPTIDES
  • SUBSTANCE P :
    • Excitatory NT
    • Source : hypothalamus, CNS, intestine
    • Role in pain transmission, increases smooth muscle contraction of GI tract
  • Endorphins (β-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
references
REFERENCES
  • Harper’s 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