Transcript Document

AP 151
• The Physiology of
Neurotransmitters
• An excellent resource for this unit can
be found at the following link:
• http://nba.uth.tmc.edu/neuroscience/index.htm
Synapses
• 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
1. Axodendritic synapse
2. Axosomatic synapse
3. Axoaxonic synapse
Figure 11.17
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.
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.
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, resynthesis and transport of
recycled NT my be unable to keep pace with demand for NT
• Synapse remains inactive until NT has been replenished
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.
Postsynaptic Potentials
• 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
Excitatory Postsynaptic Potentials
• 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
Inhibitory Synapses and IPSPs
• 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
Summation
• 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
Figure 11.21
Neurotransmitters
• Chemicals used for neuronal communication
with the body and the brain
• 50 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
Neurotransmitter Receptor
Mechanisms
• 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
Channel-Linked Receptors
• 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
Figure 11.23a
G Protein-Linked Receptors
• 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:
Mechanism
• 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
Figure 11.23b
G Protein-Linked Receptors:
Effects
• 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!!
Chemical Neurotransmitters
•
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Acetylcholine (ACh)
Biogenic amines
Amino acids
Peptides
Novel messengers: ATP and dissolved
gases NO and CO
Neurotransmitters: Acetylcholine
• 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
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.
Neurotransmitters:
Monoamines/Biogenic Amines
• Include:
– Catecholamines – dopamine, norepinephrine
(NE), and epinephrine (EP)
– Indolamines – serotonin and histamine
• Broadly distributed in the brain
• Cats. are important sympathetic NTs
• Play roles in emotional behaviors and our
biological clock
Synthesis of Catecholamines
• AA tyrosine is parent cpd
• Enzymes present in the
cell determine length of
biosynthetic pathway
• Norepinephrine and
dopamine are synthesized in axonal terminals
• Epinephrine is released
by the adrenal medulla
as a hormone
Figure 11.22
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 addictivedrugs 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 schizophrenia
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
Neurotransmitters:
Amino Acids
• Include:
– GABA – Gamma ()-aminobutyric acid
– Glycine
– Aspartate
– Glutamate
• Found only in the CNS
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!)
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
Neurotransmitters: Peptides
• 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: Novel Messengers
• 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 cerebrovasculature
– 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
Functional Classification of
Neurotransmitters
• 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)