Post on 24-Oct-2014
Neurotransmitters and Synapses
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NEUROTRANSMITTERS
DEFINITION: Are chemical transducers which are released by electrical impulse into the synaptic cleft from presynaptic membrane from synaptic vesicles. It then diffuse to the postsynaptic membrane and react and activate the receptors present leading to initiation of new electrical signals.
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Discovery of neurotransmitters
• Loewi, 1921
• frog hearts in saline solution
• Stimulation of vagus nerve results in lower heart rate
– gave long vagal nerve stimulation
• Heart #2:
– Exposed to saline solution from heart #1
– Slowed heart rate
• Conclusion: Neurotransmission is
chemical
– nerve releases chemical that can influence other cells
Fig 8.1, Zigmond “Fundamental Neuroscience”
Neurotransmitters
• substances that mediate chemical
signaling between neurons.
• criteria for a substance to be
considered a neurotransmitter.
– they must be demonstrated to be present
in the presynaptic terminal
– they must be synthesize by the presynaptic
cell.
– they should be released on depolarization
of the terminal
– there should be specific receptors for them
on the postsynaptic membrane or other
sites outside the synapse
• A junction that mediates information transfer from one neuron: – To another neuron
• Called neuro-synapses or just synapse
– To an effector cell • Neuromuscular synapse if muscle involved
• Neuroglandular synapse if gland involve
• Presynaptic neuron – conducts impulses toward the synapse
• Postsynaptic neuron – transmits impulses away from the synapse
• Two major types: – Electrical synapses
– Chemical synapses
Synapses
Synapses
Figure 11.17
1. Axodendritic synapse 2. Axosomatic synapse 3. Axoaxonic synapse
Electrical Synapses • Pre- and postsynaptic neurons
joined by gap junctions
– allow local current to flow between adjacent cells. Connexons: protein tubes in cell membrane.
• Rare in CNS or PNS
• Found in cardiac muscle and many types of smooth muscle. Action potential of one cell causes action potential in next cell, almost as if the tissue were one cell.
• Important where contractile activity among a group of cells important.
Chemical Synapses
• Most common type
• Cells not directly coupled as in electrical synapses
• Components – Presynaptic terminal
– Synaptic cleft
– Postsynaptic membrane (PSM)
• Chemical neurotransmitters (NT‟s) released by presynaptic neuron
• NT binds to receptor on PSM
Chemical Synapse Events at a chemical synapse 1. Arrival of action potential on presynaptic
neuron opens volage-gated Ca++ channels. 2. Ca++ influx into presynaptic term. 3. Ca++ acts as intracellular messenger stimulating synaptic vesicles to fuse with membrane and release NT via exocytosis. 4. Ca++ removed from synaptic knob by mitochondria or calcium-pumps. 5. NT diffuses across synaptic cleft and binds to receptor on postsynaptic membran 6. Receptor changes shape of ion channel opening it and changing membrane
potential 7. NT is quickly destroyed by enzymes or taken back up by astrocytes or presynaptic membrane. Note: For each nerve impulse reaching the
presynaptic terminal, about 300 vesicles are emptied into the cleft. Each vesicle contains about 3000 molecules.
Types of Synaptic Transmission
Electrical
• occurs in gap junction
• by simple electrical
coupling
• usually bidirectional
• fast transmission
• (-) synaptic delay
Chemical
• occurs in synaptic cleft
• utilized a chemical
intermediaries
(neurotransmitter)
• unidirectional
• slow transmission
• (+) synaptic delay
Synaptic Delay
• 0.2-0.5 msec delay between arrival of AP at synaptic knob and effect on PSM
– Reflects time involved in Ca++ influx and NT release
– While not a long time, its cumulative synaptic delay along a chain of neurons may become important.
– Thus, reflexes important for survival have only a few synapses
Synaptic Fatigue • Under intensive stimulation, resysnthesis and transport of
recycled NT may be unable to keep pace with demand for NT
• Synapse remains inactive until NT has been replenished
Neurotransmitters
• more than 100 have been identified as potential
neurotransmitters or potential qualifiers.
• three major categories
– small molecule transmitters
• acetylcholine
• amino acids
• biogenic amines
• purines
– peptides
– gaseous transmitters
Neurotransmitters
• contained in synaptic vesicles.
• three kinds of synaptic vesicles
– small clear synaptic vesicle
• acethylcholine, glycine, GABA and glutamate
– small vesicle with dense core
• catecholamines
– large vesicle with dense core
• neuropeptides
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Fate of neurotransmitters
1. It is consumed ( broken down or used up) at postsynaptic membrane leading to action potential generation.
2. Degraded by enzymes present in synaptic cleft.
3. Reuptake mechanism( reutilization) this is the most common fate.
Removal of Neurotransmitter from Synaptic Cleft
• Method depends on neurotransmitter
• ACh: acetylcholinesterase splits ACh into acetic acid and choline. Choline recycled within presynaptic neuron.
• Norepinephrine: recycled within presynaptic neuron or diffuses away from synapse. Enzyme is monoamine oxidase (MAO). Absorbed into circulation, broken down in liver.
Receptor Molecules and Neurotransmitters
• Neurotransmitter only "fits" in one receptor.
• Not all cells have receptors.
• Neurotransmitters are commonly classified as excitatory or inhibitory.
• Classification is useful but not precise. For example: – ACh is stimulatory at neuromuscular junctions (skeletal)
– ACh is inhibitory at neuromuscular junction of the heart
• Therefore, effect of NT on PSM depends on the type of receptor, and not nature of the neurotransmitter
• Some neurotransmitters (norepinephrine) attach to the presynaptic terminal as well as postsynaptic and then inhibit the release of more neurotransmitter.
• NT affects the postsynaptic membrane potential
• Effect depends on:
– The amount of neurotransmitter released
– The amount of time the neurotransmitter is bound to receptors
• The two types of postsynaptic potentials are:
– EPSP – excitatory postsynaptic potentials
– IPSP – inhibitory postsynaptic potentials
Postsynaptic Potentials
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Types of responses on postsynaptic membrane
• Excitatory postsynaptic potential (EPSPs)
It is caused by depolarization.
• Inhibitory Postsynaptic potential (IPSPs)
It is caused by hyperpolarization.
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Fast & Slow Postsynaptic potentials
• Fast EPSPs & IPSPs work through ligand gated ion channels.eg. Nicotinic receptors(at the level of neuromuscular junction)
• Slow EPSPs & IPSPs are produced by multi step process involving G protein eg. Muscarinic receptors ( at the level of autonomic gangila)
• EPSPs are graded potentials that can initiate an action potential in an axon – Use only chemically gated channels
• Postsynaptic membranes do not generate action potentials
• But, EPSPs bring the RMP closer to threshold and therefore closer to an action potential
Excitatory Postsynaptic Potentials
• Neurotransmitter binding to a receptor at inhibitory synapses: – Causes the membrane to become more
permeable to potassium and chloride ions
– Leaves the charge on the inner surface more negative (flow of K+ out of the cytosol makes the interior more negative relative to the exterior of the membrane
– Reduces the postsynaptic neuron‟s ability to produce an action potential
Inhibitory Synapses and IPSPs
• A single EPSP cannot induce an action potential
• EPSPs must summate temporally or spatially to induce an action potential
• Temporal summation – one presynaptic neuron transmits impulses in rapid-fire order
• Spatial summation – postsynaptic neuron is stimulated by a large number of presynaptic neurons at the same time
• IPSPs can also summate with EPSPs, canceling each other out
Summation
Summation
Figure 11.21
• Chemicals used for neuronal communication with the body and the brain
• 100 different neurotransmitters have been identified
• Classified chemically and functionally
– Chemically:
• ACh, Biogenic amines, Peptides
– Functionally:
• Excitatory or inhibitory
• Direct/Ionotropic (open ion channels)
• Indirect/metabotropic (activate G-proteins) that create a metabolic change in cell
Neurotransmitters
• Direct: neurotransmitters that open ion channels – Promote rapid responses
– Examples: ACh and amino acids
• Indirect: neurotransmitters that act through second messengers – Promote long-lasting effects
– Examples: biogenic amines, peptides, and dissolved gases
Neurotransmitter Receptor Mechanisms
• Composed of integral membrane protein
• Mediate direct neurotransmitter action
• Action is immediate, brief, simple, and highly localized
• Ligand binds the receptor, and ions enter the cells
• Excitatory receptors depolarize membranes
• Inhibitory receptors hyperpolarize membranes
Channel-Linked Receptors
Channel-Linked Receptors
Figure 11.23a
• Responses are indirect, slow, complex, prolonged, and often diffuse
• These receptors are transmembrane protein complexes
• Examples: muscarinic ACh receptors, neuropeptides, and those that bind biogenic amines
G Protein-Linked Receptors
• Neurotransmitter binds to G protein-linked receptor
• G protein is activated and GTP is hydrolyzed to GDP
• The activated G protein complex activates adenylate cyclase
• Adenylate cyclase catalyzes the formation of cAMP from ATP
• cAMP, a second messenger, brings about various cellular responses
G Protein-Linked Receptors: Mechanism
G Protein-Linked Receptors: Mechanism
Figure 11.23b
• G protein-linked receptors activate intracellular second messengers including Ca2+, cGMP, and cAMP
• Second messengers:
– Open or close ion channels
– Activate kinase enzymes (phosphorylation rxn‟s)
– Phosphorylate channel proteins
– Activate genes and induce protein synthesis!!
G Protein-Linked Receptors: Effects
• Acetylcholine (ACh)
• Biogenic amines
• Amino acids
• Peptides
• Novel messengers: ATP and dissolved gases NO and CO
Chemical Neurotransmitters
• First neurotransmitter identified (by Otto Loewi) and best understood
• Synthesized and enclosed in synaptic vesicles
• Degraded by the enzyme acetylcholinesterase (AChE)
• Released by cholinergic neurons:
– All skeletal muscle motor neurons • Anterior horn motor neuron (= Lower motor neuron)
– Some neurons in the autonomic nervous system • All ANS preganglionic neurons (parasym. and sympathetic)
• All parasympathetic postganglionic neurons stimulating smooth muscle, cardiac muscle, and glands
• Symp. postganglionic neurons stimulating sweat glands
• Ach binds to cholinergic receptors known as nicotinic or muscarinic receptors
Neurotransmitters: Acetylcholine
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Nicotinic Muscarinic
1 Found at:
i. Neuromuscular junction of
skeletal muscle
ii. Postganglionic neurons of
parasympathetic nervous
system.
iii. Ventral tegmental area.
i. Glands
ii. Neuromuscular junctions of
cardiac and smooth muscle.
iii. Postganglionic neurons of
sympathetic nervous system.
2 Agonist Nicotine Muscarine ( a toxin produced by
certain mushroom)
3 Antagonist Curare ( paralyses skeletal
muscle)
Atropine
Acetyl Choline Receptors
Comparison of Somatic and Autonomic Systems
Figure 14.2
Cholinergic Receptors: Bind ACh
• Nicotinic receptors
- Are ion channels (rapid acting)
- On sarcolemma of skeletal muscle fibers
- On dendrites and cell bodies of ALL postganglionic
neurons of the ANS
- Excitatory (open Na+ channels fast EPSP)
• Muscarinic receptor
- Are G-protein couple receptors (complex intracellular
functions)
- On all parasympathetic target organs (cardiac and smooth muscle)
- Are excitatory in most cases; inhibitory in others
Acetylcholine
• Effects prolonged (leading to tetanic muscle spasms
and neural “frying”) by nerve gas and organophosphate insecticides (Malathion).
• ACH receptors destroyed by patients own antibodies in myasthenia gravis
• Binding to receptors inhibited by curare (a muscle paralytic agent
– blowdarts in south American tribes and some snake venoms.
• Include:
– Catecholamines – dopamine, norepinephrine (NE), and epinephrine (EP)
– Indolamines – serotonin and histamine
• Broadly distributed in the brain
• Cathecholamine are important sympathetic NTs
• Play roles in emotional behaviors and our biological clock
Neurotransmitters: Monoamines/Biogenic Amines
Synthesis of Catecholamines
• AA tyrosine is parent cpd
• Enzymes present in the cell determine length of biosynthetic pathway
• Norepinephrine and dopamine are synthe-sized in axonal terminals
• Epinephrine is released by the adrenal medulla as a hormone
Figure 11.22
41 MAO=monoamine oxidase ,COMT=catechole-o-methyle-transferase
BIOGENIC AMINES: Norepinephrine
• Norepinephrine (aka Noradrenaline) – Main NT of the sympathetic branch of autonomic nervous system
– Binds to adrenergic receptors ( or -many subtypes, 1, 2, etc)
– Excitatory or inhibitory depending on receptor type bound
– Very important role in attention and arousal - an organisms vigilance
– Also released by adrenal medulla as a hormone
– “Feeling good” NT
• Clinical Importance – Thought to be involved in etiology of some bipolar affective disorders
• Removal from synapse blocked by antidepressants and cocaine
• Levels lowers in depressed pts. and higher in manic phase of bipolar dis.
– Release enhanced by amphetamines
BIOGENIC AMINES: Dopamine
• Dopamine – Binds to dopaminergic receptors of substantia nigra of midbrain and hypothalamus
– Involved in important physiology functions including:
• Motor control
• Coordinating autonomic functions
• Regulating hormone release
• Motivational behavior and reward; i.e., a “feeling good” NT
– Hypothesized to be at the heart of the mechanisms of ALL addictive-
drugs and behaviors. For example,
• Release enhanced by amphetamines
• Reuptake blocked by cocaine
– Deficient in Parkinson‟s disease
– Receptor abnormalities have been linked to development of schizo-
phrenia
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Small Molecule Transmitters
• Biogenic Amines
– they have roles outside the nervous system as hormones.
– include
• catecholamines - epinephrine (adrenaline),
norepinephrine (noradrenaline) and dopamine
– from amino acid tyrosine
• serotonin (5 – HT)
– from amino acid tryptophan
• histamine
– from histidine
Biogenic Amines: Serotonin (5-HT)
• Synthesized from the amino acid tryptophan
– Since tryptophan not synthesized in humans, its levels available for synthesis of serotonin are dependent on diet.
• Diets high in tryptophan can markedly elevate serotonin levels
• May play a role in sleep, appetite, and regulation of moods (aggression)
• Low 5-HT levels associated with increased aggressiveness and risk taking
• Acts in a pathway that monitors carbohydrate intake, acting as a negative regulator of motivation to ingest carbohydrate
– Has led to the use of SSRIs (see below) as obesity pills (fenfluramine)
• Drugs that block its uptake relieve anxiety and depression and aggression
– SSRI‟s = selective serotonin reuptake inhibitors
– Include drugs such as Prozac, Celexa, Lexapro, Zoloft
• Ecstasy targets serotonin receptors
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Formation of serotonin =5-HT Hydroxy tryptamine HIAA=hydroxyindoleacetic acid
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Histamine
• Histamine forming cells are in posterior hypothalamus also found in gastric mucosa and in mast cells.
• Formed by decarboxylation of amino acid histidine with the help of enzyme histaminase.
• Three known types of histamine receptors in found e.g. H1, H2, H3.
• H3 receptors are presynaptic. Its function in brain is not very certain. Its main function is that it is excitatory.
BIOSYNTHESIS
OF
CATECHOLAMINES
Small Molecule Transmitters
• Biogenic Amines
– involved in setting the level of arousal (sleep and waking),
attention and mood.
– important in homoestatic functions (ANS) and motor
system.
• Catecholamines (NE and E)
– from the brainstem nuclei (locus ceruleus and nucleus subceruleus)
and postganglionic sympathetic cells.
• Serotonin (from midline of the brainstem (raphe nuclei)
• Histamine (from the hypothalamus)
• Dopamine (from substancia nigra and tegmental area)
Small Molecule Transmitters
• Purines --- ATP
– has potential to act as a transmitter or co-
transmitter in the CNS and PNS.
– has receptors coupled to an ion channel.
– can modify the action of other transmitters
with which it is co-released (NE, 5-HT etc)
• Include:
– GABA – Gamma ()-aminobutyric acid
– Glycine
– Aspartate
– Glutamate
• Found only in the CNS
Neurotransmitters: Amino Acids
Small Molecule Transmitters
• Amino acids --- Glutamate
– major excitatory CNS neurotransmitter
– present in all cells and has a key role in
multiple metabolic pathways.
– a precursor to GABA
– a potent neurotoxin at high concentrations
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Glutamic acid • It is the most commonly found neurotransmitter
in the brain. • It is always excitatory. • Glutamate is formed during Kreb‟s cycle for α –
ketoglutarate. • Glutamate is carried into astrocytes where it is
converted to glutamine and passed on to glutaminergic neurones.
• Glutamate is neurotoxic while glutamine is not. • There are two types of receptors e.g.
metabotropic and iontropic receptors.
Amino Acid Neurotransmitters • Excitatory Amino Acids
1. Glutamate • Indirect action via G proteins and 2nd messengers
• Direct action -- opens Ca++ channels (ionotropic)
– NMDA receptors (have a high permeability to Ca++)
• Widespread in brain where it represents the major excitatory neurotransmitter
• Important in learning and memory! • Highly toxic to neurons when present for extended
periods - “Stroke NT” -excessive release produces
excitotoxicity: neurons literally stimulated to death; most commonly caused by ischemia due to stroke (Ouch!) • Aids tumor advance when released by gliomas (ouch!)
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NMDA =N methyl-D-aspartate receptors, when glutamate & glycine bind to receptor ion channels open, Mg block channels
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Small Molecule Transmitters
• Amino acids --- Glycine
– an inhibitory neurotransmitter in a much
more restricted territories.
– predominantly found in spinal cord and
also present in lower brainstem,
cerebellum and the retina.
– acts as a co-transmitter at NMDA-type
glutamate receptors.
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Glycine
• It is simplest of all aminoacids, consisting of amino group and a carboxyl group attached to a carbon atom
C H3 N+
Coo-
H+
H+
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• Its an inhibitory neurotransmitter.
• It binds to a receptor which makes the post synaptic membrane more permeable to Cl- Ion and cause hyperpolarization (inhibition).
• The glycine receptor is primarily found in the ventral part of the spinal cord.
• Strychnine is glycine antagonist.
Glycine……..
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Gamma Aminobutyric acid (GABA)
• It is one of the inhibitory neurotransmitter of CNS and is also found in retina.
• It is formed by decarboxylation of glutamate. • The enzyme that catalyzes this reaction is
glutamate decarboxylase(GAD) • There are three types of GABA receptors e.g.
GABAA B & C.
• GABA A & B receptors are widely distributed in CNS.
• GABAC are found in retina only. • GABA B are metabotropic (G-protein) in
function.
Amino Acids
Inhibitory Amino Acids 1. GABA (Gamma aminobutyric acid)
• Direct or indirect action (depending on type of receptor
• Main inhibitory neurotransmitter in the brain - Selectively permeable to Cl- (hyperpolarizes memb.)
• Cerebral cortex, cerebellum, interneurons throughout brain and spinal cord
• Inhibitory effects augmented by alcohol and benzodiazepines (antianxiety drugs like Valium and Librium) and barbiturates - these drugs increase the number of GABA receptors
and thus enhance the inhibitory activity of GABA • Decreased GABA inhibition amy lead to epilepsy
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Neurotransmitter Postsynaptic
effect Derived from
Site of
synthesis
Postsynaptic
receptor Fate Functions
1.Acetyl choline
(Ach)
Excitatory Acetyl co-A +
Choline
Cholinergic
nerve endings
Cholinergic
pathways of
brainstem
1.Nicotinic
2.Muscarinic
Broken by acetyl
cholinesterase
Cognitive functions
e.g. memory
Peripheral action e.g.
cardiovascular
system
2. Catecholamines
i. Epinephrine
(adrenaline)
Excitatory in
some but
inhibitory in
other
Tyrosine
produced in
liver from
phenylalanine
Adrenal
medulla and
some CNS
cells
Excites both
alpha α &
beta β
receptors
1.Catabolized to
inactive product
through COMT &
MAO in liver
2.Reuptake into
adrenergic nerve
endings
3.Diffusion away
from nerve
endings to body
fluid
For details refer
ANS. e.g. fight or
flight, on heart,
BP, gastrointestinal
activity etc.
Norepinehrine
controls attention &
arousal.
ii.Norepinephrine Excitatory Tyrosine, found
in pons.
Reticular
formation, locus
coerules,
thalamus, mid-
brain
Begins inside
axoplasm of
adrenergic
nerve ending is
completed
inside the
secretary
vesicles
α1 α2
β1 β2
iii. Dopamine Excitatory Tyrosine CNS,
concentrated in
basal ganglia
and dopamine
pathways e.g.
nigrostriatal,
mesocorticolim
bic and tubero-
hypophyseal
pathway
D1 to D5
receptor
Same as above Decreased dopamine
in parkinson’s
disease.
Increased dopamine
concentration causes
schizophrenia
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Neurotransmitter Postsynaptic
effect Derived from
Site of
synthesis
Postsynaptic
receptor Fate Functions
6. Aspartate Excitatory Acidic amines Spinal cord Spinal cord Aspartate & Glycine form an excitatory /
inhibitory pair in the ventral spinal cord
7. Gama amino
butyric
acid(GABA)
Major
inhibitory
mediator
Decarboxylation
of glutamate by
glutamate
decarboxylase
(GAD) by
GABAergic
neuron.
CNS
GABA – A
increases the Cl - conductance,
GABA – B is
metabotropic
works with G –
protein GABA
transaminase
catalyzes.
GABA – C
found
exclusively in
the retina.
Metabolized by
transamination to
succinate in the citric
acid cycle.
GABA – A causes
hyperpolarization
(inhibition)
Anxiolytic drugs like
benzodiazepine cause
increase in Cl- entry
into the cell & cause
soothing effects.
GABA – B cause
increase conductance
of K+ into the cell.
8. Glycine Inhibitory
Is simple amino
acid having
amino group and
a carboxyl group
attached to a
carbon atom
Spinal cord
Glycine receptor
makes
postsynaptic
membrane more
permeable to Cl-
ion.
Deactivated in the
synapse by simple
process of
reabsorbtion by active
transport back into
the presynaptic
membrane
Glycine is inhibitory
transmitted found in
the ventral spinal
cord. It is inhibitory
transmitter to
Renshaw cells.
Peptides • more than 100 neuropeptides have been identified.
• co-released with classic neurotransmitters but can
function as a sole or primary neurotransmitter at a
synapse.
• synthesized in the cell body and transported to the
axon
• examples
– hypothalamic hormones, neuropeptide Y,
opioids, tachykinins, etc.
• Neuropeptide receptors are all G-protein linked – Alter levels of intracellular second messengers
• Include: – Substance P – mediator of pain signals
– Neuropeptide Y - stimulates appetite and food intake
– Beta endorphin, dynorphin, and enkephalins
– Opiods: include • Endorphins, Enkephalins, Dynorphin
• Act as natural opiates, reducing our perception of pain
• Found in higher concentrations in marathoners and women who have just delivered
– Bind to the same receptors as opiates and morphine
Neurotransmitters: Peptides
Gas Neurotransmitters
• neither packed into synaptic vesicles nor released
by exocytosis.
• synthesis is triggered by depolarization
• highly permeant and simply diffuse from the nerve
terminal to the neighboring cells.
• destroyed by diffusion or binding to superoxide
anions or various scavenger proteins.
• do not bind to a receptor
• examples: NO (inhibitory transmitter) and CO
• Nitric oxide (NO) – Same substance produced by sublingual nitroglycerin
produces to increase vasodilation in relief of angina
– A short-lived toxic gas; diffuses through post-synaptic membrane to bind with intracellular receptor (guanynyl cyclase)
• Is a free radical and therefore highly reactive compound
– Do not confuse with „laughing gas‟ (nitrous oxide)
– Is involved in learning and memory
– Important in control of blood flow through cerebro-vasculature
– Some types of male impotence treated by stimulating NO release (Viagra)
• Viagra NO release smooth muscle relaxation increased blood flow erection
• Can‟t be taken when other pills to dilate coronary b.v. taken
Neurotransmitters: Novel Messengers
Destruction of Small molecule Transmitters
• Acetylcholine
– enzymatic hydrolysis by acetylcholenesterase
– reuptake of choline at the presynaptic terminal
by Na+ symporter.
• Amino acid
– Reuptake into the neurons and glial cells
• Glutamate - Na+ - K+ transporter
• GABA - Na+– Cl- transporter
• Glycine - Na+– Cl- transporter
Destruction of Small molecule Transmitters
• biogenic amines
– Reuptake into the neuron and glial cells
• Na+– Cl- transporter
– enzymatic hydrolysis by MOA and COMT
• purines
– hydrolyzed by ATPase
Neurotransmitter Receptors
• small molecule transmitters
– biogenic amines (metabotropic receptors except 5 –
HT3)
• catecholamines (α1, α2, β1, β2, and β3)
• histamine (H1 and H2 )
• dopamine (D1, D2, D3, D4, and D5)
• serotonin (5HT1, 5HT2, 5HT3 and 5HT4)
– purines
• ionotropic (P2X) and metabotropic (P2Y)
• peptides
– neuropeptide receptors
MEDICAL PHYSIOLOGY 23TH EDITION by Ganong
RELESE OF NEUROTRANSMITERS
MEDICAL PHYSIOLOGY 23TH EDITION by Ganong
RELESE OF NEUROTRANSMITERS
• Two classifications: excitatory and inhibitory
– Excitatory neurotransmitters cause depolarizations (e.g., glutamate)
– Inhibitory neurotransmitters cause hyperpolarizations (e.g., GABA)
Functional Classification of Neurotransmitters
• Some neurotransmitters have both excitatory and inhibitory effects – Determined by the receptor type of the
postsynaptic neuron
– Example: acetylcholine • Excitatory at neuromuscular junctions with
skeletal muscle (nicotinic receptor)
• Inhibitory in cardiac muscle (muscarinic receptor)
Functional Classification of Neurotransmitters
Alzheimer’s Disease
• a form of dementia in which
memory function is
gradually and progressively
lost
• due to degeneration of
cholinergic neurons in the
basal forebrain areas,
neocortex, hippocampus and
amygdala (implicated in
memory function).
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RECEPTORS DYSFUNCTION
1. Presynaptic effect
i) Botulinum toxin: Its an exotoxin that binds to the presynaptic membrane and prevents the release of Ach resulting in weakness and reduction of tone. It is used to control dystonia in which body shows overactive muscular activity.
Clinical Correlation (fusion-exocytosis complex)
• Tetanus toxin – act on synaptobrevin (CNS) – spastic paralysis
• Botulinum toxins B, D, F and G – act on synaptobrevin (neuromuscular junction) – flaccid paralysis
• Botulinum toxin C – acts on syntaxin – causes flaccid paralysis
• Botulinum toxins A and B – act on SNAP-25 – Causes flaccid paralysis
• “Botox” (Botulinum toxin)
– local injection of small doses is effective in the treatment of conditions characterized by muscle hyperactivity.
– examples are
• achalasia (lower esophageal sphincter)
• used to remove wrinkles
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ii) Lumbert – Eaton syndrome
Antibodies directed against Ca++ channels located in presynaptic terminals and interfere with transmitter release causing weakness.
iii)Neuromyotonia
Patient complains of muscle spasm and stiffness resulting in continuous motor activity in the muscle. It is cased by antibody directed against the presynaptic voltage gated K+ channel so that the nerve terminal is always in a state of depolarization
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2. Effects at Postsynaptic level:
i) Curare binds to the acetylcholine receptor (AchR) and prevents Ach from acting on it and so that it induces paralysis.
ii) Myasthenia gravis: is caused by an antibody against the Ach receptors and Ach receptors are reduced hence the Ach released has few Ach receptor available to work and patients complain of weakness that increases with exercise.
Psychosis
• can be due to hyperactivity
of dopaminergic synapses
• can be treated by
dopamine antagonists
(chlorpromazine and other
antipsychotic drugs), which
inhibit dopamine receptors
in the postsynaptic
membrane.
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Synaptic strength
• Can be facilitated like long – term potentiation.
• Can be depressed ( inhibited) by long-term depression.
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Classification of Neurotransmitters
• Amines
A. Acetyl choline (Ach)
B. Monoamines
Catecholamines
– Epinephrine
– Nor epinephrine
– Dopamine (Substantia nigra, sympathetic ganglia)
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III. Purine derivatives
eg. Adinosine & ATP.
IV. Polypeptides ( a very long list of names)
eg. Enkephaline, hormones ( VIP etc)
( refer to the list in Ganong 21st edition pg.97)
V. Nonsynaptic transmitters
eg. Gases, nitric oxide & cabon mono oxide.
Excitatory neurotransmitters
• acetylcholine
• norepinephrine
• serotonin
• glutamate
Inhibitory neurotransmitters
• GABA
• glycine
• dopamine
CNS
Skeletal Muscle
Generation of AP in the motorneuron
Depolarization of the terminal buttons
Calcium influx (opening of voltage-gated channel)
Release of neurotransmitters (Ach) in NMJ
Binding of Ach with Ach receptors
Depolarization of motor end plate ( Na+ influx)
Generation of end plate potential (EPP)
Production of action potential
Generation of AP in the presynaptic neuron
Depolarization of the terminal buttons
Calcium influx (opening of voltage-gated channel)
Release of excitatory neurotransmitters in the synaptic cleft
Binding of excitatory NTA with its receptors
Depolarization of the postsynaptic cell ( Na+ influx)
Generation of excitatory post potential (EPSP)
Production of action potential
EXCITATORY CHEMICAL TRANSMISSION
Generation of AP in the presynaptic neuron
Depolarization of the terminal buttons
Calcium influx (opening of voltage-gated channel)
Release of inhibitory neurotransmitters in the synaptic cleft
Binding of excitatory NTA with its receptors
Depolarization of the postsynaptic cell ( Cl- influx and K efflux)
Generation of inhibitory post potential (iPSP)
Production of action potential
INHIBITORY CHEMICAL TRANSMISSION