Neuron types and Neurotransmitters -...
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Neuron types and Neurotransmitters
Faisal I. Mohammed. PhD, MD
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Transmission of Receptor Information to the Brain
the larger the nerve fiber diameter the faster the rate of transmission of the signal
velocity of transmission can be as fast as 120 m/sec or as slow as 0.5 m/sec
nerve fiber classification
type A - myelinated fibers of varying sizes, generally fast transmission speed
subdivided into a, b, d, g
type C - unmyelinated fibers, small with slow transmission speed
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Types of Nerve Fiber
-Myelinated fibers –
Type A (types I, II and III)
- A α
- A β
- A γ
- A δ
-Umyelinated Fibers-
Type C (type IV)
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Neuron Classification
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5
Structural Classification of Neurons
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NeurotransmittersChemical substances that function as synaptic transmitters
1. Small molecules which act as rapidly acting transmitters
acetylcholine, norepinephrine, dopamine, serotonin, GABA, glycine, glutamate, NO
2. Neuropeptides
more potent than small molecule transmitters, cause more prolonged actions
endorphins, enkephalins, VIP, ect.
hypothalamic releasing hormones
TRH, LHRH, ect.
pituitary peptides
ACTH, prolactin, vasopressin, ect.
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Neurotransmitters
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Comparison between Small Molecules and
Neuropeptides Neurotramsmitters (NT)
Small molecules NT are rapidly acting as compared to slowly acting neuropepides
Neuron has only one NT but may have one or more NP
Small molecules NT have short lived action compared to prolonged time of action for neuropeptides
Small molecules NT are excreted in larger amounts compared to smaller quantities of neuropeptide
Small molecules NT vesicles are recycled but neuropeptide ones are not
Neuropeptides are co-secreted with small molecules NT
Neuropeptides are synthesized at the soma while small molecules could be formed at the presynaptic terminals
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Removal of Neurotransmitter
Diffusion
move down concentration gradient
Enzymatic degradation
Acetylcholinesterase for (Ach),
peptidases for neuropeptides
Uptake by neurons or glia cells
neurotransmitter transporters
Prozac = serotonin reuptake inhibitor
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Transmitter Inactivation:
reuptake and enzymatic breakdownReuptake by
transporters
(glial cells)
Enzymatic
breakdown
Neurotransmitter can be recycled in presynaptic terminal
or can be broken down by enzymes within the cell
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II Neurotransmitters and receptors
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Basic Concepts of NT and receptor
Neurotransmitter: Endogenous signaling
molecules that alter the behaviour of neurons
or effector cells.
Neuroreceptor: Proteins on the cell membrane
or in the cytoplasm that could bind with
specific neurotransmitters and alter the
behavior of neurons of effector cells
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•Vast array of molecules serve as neurotransmitters
•The properties of the transmitter do not determine its effects on the postsynaptic cells
•The properties of the receptor determine whether a transmitter is excitatory or inhibitory
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A neurotransmitter must (classical definition)• Be synthesized and released from neurons
• Be found at the presynaptic terminal
• Have same effect on target cell when applied externally
• Be blocked by same drugs that block synaptic transmission
• Be removed in a specific way
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Agonist
A substance that mimics a specific
neurotransmitter,
is able to attach to that neurotransmitter's
receptor
and thereby produces the same action that the
neurotransmitter usually produces.
Drugs are often designed as receptor agonists
to treat a variety of diseases and disorders
when the original chemical substance is
missing or depleted. University of Jordan 16
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Antagonist
Drugs that bind to but do not activate
neuroreceptors,
thereby blocking the actions of
neurotransmitters or the neuroreceptor
agonists.
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Receptor BReceptor A
• Same NT can bind to different -R
• different part of NT ~
NT
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NT
Specificity of drugs
Drug ADrug B
Receptor BReceptor A
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Five key steps in neurotransmission
• Synthesis
• Storage
• Release
• Receptor Binding
• Inactivation
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Synaptic vesicles
• Concentrate and protect
transmitter
• Can be docked at active
zone
• Differ for classical
transmitters (small,
clear-core) vs.
neuropeptides (large,
dense-core)
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Neurotransmitter Co-existence (Dale
principle)
Some neurons in both the PNS and CNS produce both
a classical neurotransmitter (ACh or a catecholamine)
and a polypeptide neurotransmitter.
They are contained in different synaptic vesicles that
can be distinguished using the electron microscope.
The neuron can thus release either the classical
neurotransmitter or the polypeptide neurotransmitter
under different conditions.
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Receptors determine whether:
• Synapse is excitatory or inhibitory
– NE is excitatory at some synapses, inhibitory at others
• Transmitter binding activates ion channel directly or indirectly.
– Directly
• ionotropic receptors
• fast
– Indirectly
• metabotropic receptors
• G-protein coupled
• slow
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Receptor Activation
• Ionotropic channel
– directly controls channel
– fast
• Metabotropic channel
– second messenger systems
– receptor indirectly controls channel ~
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(1) Ionotropic Channels
neurotransmitterNTChannel
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Ionotropic Channels
NT
Pore
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Ionotropic Channels
NT
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Ionotropic Channels
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Metabotropic Channels
• Receptor separate from channel
• G proteins
• 2nd messenger system
– cAMP
– other types
• Effects
– Control channel
– Alter properties of receptors
– regulation of gene expression ~
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G protein: direct control
• NT is 1st messenger
• G protein binds to channel
– opens or closes
– relatively fast ~
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G protein: direct control
R
G
GDP
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G protein: direct control
R
G
GTP
Pore
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G protein: Protein Phosphorylation
RG
GDP
A
C
PK
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G protein: Protein Phosphorylation
R
A
C
PK
G
GTPATP
cAMP
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G protein: Protein Phosphorylation
R
A
C
PK
G
GTP
ATP
cAMP
P
Pore
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Transmitter Inactivation
• Reuptake by presynaptic terminal
• Uptake by glial cells
• Enzymatic degradation
• Presynaptic receptor
• Diffusion
• Combination of above
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Summary of
Synaptic
Transmission
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Some Important Transmitters
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(1) Acetylcholine (ACh) as NT
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Acetylcholine Synthesis
choline + acetyl CoA ACh + CoA
choline
acetyltransferase
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Acetylcholinesterase (AChE)
• Enzyme that
inactivates ACh.
– Present on
postsynaptic
membrane or
immediately outside
the membrane.
• Prevents continued
stimulation.
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The Life Cycle of Ach
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Ach - Distribution
• Peripheral N.S.
• Excites somatic skeletal muscle (neuro-muscular
junction)
• Autonomic NS
Ganglia
Parasympathetic NS--- Neuroeffector junction
Few sympathetic NS – Neuroeffector junction
• Central N.S. - widespread
Hippocampus
Hypothalamus ~
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•ACh is both an excitatory and inhibitory NT, depending on organ involved.
–Causes the opening of chemical gated ion channels.
•Nicotinic ACh receptors:
–Found in autonomic ganglia (N1) and skeletal muscle fibers (N2).
•Muscarinic ACh receptors:
–Found in the plasma membrane of smooth and cardiac muscle cells, and in cells of particular glands .
Ach Receptors
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Acetylcholine Neurotransmission
• “Nicotinic” subtype Receptor:
– Membrane Channel for Na+ and K+
– Opens on ligand binding
– Depolarization of target (neuron, muscle)
– Stimulated by Nicotine, etc.
– Blocked by Curare, etc.
– Motor endplate (somatic) (N2),
– all autonomic ganglia, hormone producing cells of adrenal medulla (N1)
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Acetylcholine Neurotransmission
• “Muscarinic” subtype Receptor: M1
– Use of signal transduction system
• Phospholipase C, IP3, DAG, cytosolic Ca++
– Effect on target: cell specific (heart , smooth muscle intestine )
– Blocked by Atropine, etc.
– All parasympathetic target organs
– Some sympathetic targets (endocrine sweat glands, skeletal muscle blood vessels - dilation)
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Acetylcholine Neurotransmission
• “Muscarinic” subtype: M2
– Use of signal transduction system
• via G-proteins, opens K+ channels, decrease
in cAMP levels
– Effect on target: cell specific
– CNS
– Stimulated by ?
– Blocked by Atropine, etc.
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Cholinergic Agonists
• Direct
– Muscarine
– Nicotine
• Indirect
– AChE Inhibitors ~
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Cholinergic Antagonists
• Direct
Nicotinic - Curare
Muscarinic - Atropine
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Ligand-Operated ACh Channels
N Receptor
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G Protein-Operated ACh Channel
M receptor
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(2) Monoamines as NT
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Monoamines
• Catecholamines –
Dopamine - DA
Norepinephrine - NE
Epinephrine - E
• Indolamines -
Serotonin - 5-HT
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Tyrosine
L-Dopa
Dopamine
tyrosine
hydroxylase
Norepinephrine
dopa decarboxylase
dopamine b -
hydroxylase
Dopaminergic
Neurons
Adrenergic
Neurons
Epinephrine
phenylethanolamine-
N-methyltransferase
Adrenal Glands
Synthesis of Monoamine NT
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Mechanism of Action (b receptor)
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Norepinephrine (NE) as NT
• NT in both PNS and CNS.
• PNS:
– Smooth muscles, cardiac muscle and glands.• Increase in blood pressure, constriction of arteries.
• CNS:
– General behavior.
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Adrenergic Neurotransmission
• a1 Receptor
– Stimulated by NE, E,
– blood vessels of skin, mucosa, abdominal viscera, kidneys, salivary glands
– vasoconstriction, sphincter constriction, pupil dilation
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Adrenergic Neurotransmission
• a2 Receptor
– stimulated by, NE, E, …..
– Membrane of adrenergic axon terminals (pre-synaptic receptors), platelets
– inhibition of NE release (autoreceptor),
– promotes blood clotting, pancreas decreased insulin secretion
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Adrenergic Neurotransmission
• b1 receptor
– stimulated by E, ….
– Mainly heart muscle cells,
– increased heart rate and strength
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Adrenergic Neurotransmission
• b 2 receptor
– stimulated by E ..
– Lungs, most other sympathetic organs, blood vessels serving the heart (coronary vessels),
– dilation of bronchioles & blood vessels (coronary vessels), relaxation of smooth muscle in GI tract and pregnant uterus
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Adrenergic Neurotransmission
• b 3 receptor
– stimulated by E, ….
– Adipose tissue,
– stimulation of lipolysis
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(3) Amino Acids as NT
• Glutamate acid and aspartate acid:
– Excitatory Amino Acid (EAA)
• Gamma-amino-butyric acid (GABA) and glycine:
– Inhibitory AA
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(4) Polypeptides as NT
• CCK:
– Promote satiety following meals.
• Substance P:
– Major NT in sensations of pain.
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(5) Monoxide Gas: NO and CO
• Nitric Oxide (NO)
– Exerts its effects by stimulation of cGMP.
– Involved in memory and learning.
– Smooth muscle relaxation.
• Carbon monoxide (CO):
– Stimulate production of cGMP within neurons.
– Promotes odor adaptation in olfactory neurons.
– May be involved in neuroendocrine regulation in hypothalamus.
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THANK YOU