Download Adrenergic Transmission

Saquiba Yesmine, PhD
1
Major Neurotransmitters in the Body
Neurotransmitter
Role in the Body
Acetylcholine
A neurotransmitter used by the spinal cord neurons to control muscles and
by many neurons in the brain to regulate memory. In most instances,
acetylcholine is excitatory.
Dopamine
The neurotransmitter that produces feelings of pleasure when released by
the brain reward system. Dopamine has multiple functions depending on
where in the brain it acts. It is usually inhibitory.
GABA
(gamma-aminobutyric acid)
The major inhibitory neurotransmitter in the brain.
Glutamate
The most common excitatory neurotransmitter in the brain.
Glycine
A neurotransmitter used mainly by neurons in the spinal cord. It probably
always acts as an inhibitory neurotransmitter.
Norepinephrine
Norepinephrine acts as a neurotransmitter and a hormone. In the
peripheral nervous system, it is part of the flight-or-flight response. In the
brain, it acts as a neurotransmitter regulating normal brain processes.
Norepinephrine is usually excitatory, but is inhibitory in a few brain areas.
Serotonin
A neurotransmitter involved in many functions including mood, appetite,
and sensory perception. In the spinal cord, serotonin is inhibitory in pain
pathways.
NIH Publication No. 00-4871
Cholinergic Transmission
Adrenergic Transmission
Cell Signaling and Synaptic Transmission
Most cell-to-cell communication in the CNS involves chemical transmission.
Chemical transmission requires several discreet specializations:
• Transmitter synthesis. Small molecules like ACh and NE are synthesized in
nerve terminals; peptides are synthesized in cell bodies and transported to nerve
terminals.
• Transmitter storage. Synaptic vesicles store transmitters, often in association
with various proteins and frequently with ATP.
• Transmitter release. Release of transmitter occurs by exocytosis. Depolarization
results in an influx of Ca2+, which in turn appears to bind to proteins called
synaptotagmins. An active zone is established to which vesicles dock and then
fuse with scaffolding proteins on the presynaptic membrane. After fusing with the
membrane and exocytotic release of their contents, synaptic vesicle proteins are
recycled through endocytosis.
Cell Signaling and Synaptic Transmission
•Transmitter recognition. Receptors exist on postsynaptic cells, which recognize
the transmitter. Binding of a neurotransmitter to its receptor initiates a signal
transduction event, as previously described.
•Termination of action. A variety of mechanisms terminate the action of
synaptically released transmitter, including hydrolysis (for acetylcholine and
peptides) and reuptake into neurons by specific transporters such as NET, SERT,
and DAT (for NE, 5-HT, DA). Inhibitors of NET, SERT, and DAT increase the dwell
time and thus the effect of those transmitters in the synaptic cleft. Inhibitors of the
uptake of NE and/or 5-HT are used to treat depression and other behavioral
disorders
Cell Signaling and Synaptic Transmission
A cholinergic neuroeffector junction showing features of the
synthesis, storage, and release of acetylcholine (ACh) and
receptors on which ACh acts. The synthesis of ACh in the
varicosity depends on the uptake of choline viaa sodiumdependent carrier. This uptake can be blocked by
hemicholinium. Choline and the acetyl moiety of acetyl
coenzyme A, derived from mitochondria, form ACh, a
process catalyzed by the enzyme choline acetyl transferase
(ChAT). ACh is transported into the storage vesicle by
another carrier that can be inhibited by vesamicol. ACh is
stored in vesicles along with other potential cotransmitters
(Co-T) such as ATP and VIP at certain neuroeffector
junctions.
Cell Signaling and Synaptic Transmission
Release of ACh and the Co-T occurs on depolarization of the
varicosity, which allows the entry of Ca2+ through voltagedependent Ca2+ channels. Elevated [Ca2+]in promotes fusion
of the vesicular membrane with the cell membrane, and
exocytosis of the transmitters occurs. This fusion process
involves the interaction of specialized proteins associated with
the vesicular membrane (VAMPs, vesicle-associated
membrane proteins) and the membrane of the varicosity
(SNAPs, synaptosome-associated proteins). The exocytotic
release of ACh can be blocked by botulinum toxin. Once
released, ACh can interact with the muscarinic receptors (M),
which are GPCRs, or nicotinic receptors (N), which are ligandgated ion channels, to produce the characteristic response of
the effector. ACh also can act on presynaptic mAChRs or
nAChRs to modify its own release.
Cholinergic Transmission
Choline is transported into the presynaptic nerve terminal by
a sodium-dependent carrier (A).
This transport can be inhibited by hemicholinium drugs.
ACh is transported into the storage vesicle by a second
carrier (B) that can be inhibited by vesamicol.
Release of transmitter occurs when voltage-sensitive
calcium channels in the terminal membrane are opened,
allowing an influx of calcium.
The resulting increase in intracellular calcium causes fusion of vesicles with the surface
membrane and exocytotic expulsion of ACh into the junctional cleft. This step is blocked by
botulinum toxin.
Acetylcholine's action is terminated by metabolism by the enzyme acetylcholinesterase.
Receptors on the presynaptic nerve ending regulate transmitter release.
Cholinergic Transmission
The terminals of cholinergic neurons contain large numbers of small membrane-bound
vesicles concentrated near the synaptic portion of the cell membrane as well as a smaller
number of large dense-cored vesicles located farther from the synaptic membrane.
The large vesicles contain a high concentration of peptide cotransmitters, while the smaller
clear vesicles contain most of the acetylcholine. Vesicles are initially synthesized in the neuron
soma and transported to the terminal. They may also be recycled several times within the
terminal.
Acetylcholine is synthesized in the cytoplasm from acetyl-CoA and choline through the
catalytic action of the enzyme choline acetyltransferase (ChAT). Acetyl-CoA is synthesized in
mitochondria, which are present in large numbers in the nerve ending.
Choline is transported from the extracellular fluid into the neuron terminal by a sodiumdependent membrane carrier (carrier A). This carrier can be blocked by a group of drugs
called hemicholiniums. Once synthesized, acetylcholine is transported from the cytoplasm
into the vesicles by an antiporter that removes protons (carrier B). This transporter can be
blocked by vesamicol.
Acetylcholine synthesis is a rapid process capable of supporting a very high rate of
transmitter release. Storage of acetylcholine is accomplished by the packaging of "quanta" of
acetylcholine molecules (usually 1000–50,000 molecules in each vesicle).
Continuation of Cholinergic Transmission
Release of transmitter is dependent on extracellular calcium and occurs when an action
potential reaches the terminal and triggers sufficient influx of calcium ions.
The increased Ca2+ concentration "destabilizes" the storage vesicles by interacting with
special proteins associated with the vesicular membrane. Fusion of the vesicular membranes
with the terminal membrane occurs through the interaction of vesicular proteins (vesicleassociated membrane proteins, VAMPs), eg,
synaptotagmin and synaptobrevin, with several proteins of the terminal membrane
(synaptosomeassociated proteins, SNAPs), eg, SNAP-25 and syntaxin.
Fusion of the membranes results in exocytotic expulsion of — in the case of somatic motor
nerves—several hundred quanta of acetylcholine into the synaptic cleft.
The amount of transmitter released by one depolarization of an autonomic postganglionic
nerve terminal is probably smaller. In addition to acetylcholine, several cotransmitters will be
released at the same time.
The ACh vesicle release process is blocked by botulinum toxin through the enzymatic
removal of two amino acids from one or more of the fusion proteins.
Continuation of Cholinergic Transmission
•The final step in the synthesis occurs
within the cytoplasm, following which
most of the ACh is sequestered within
synaptic vesicles.
• Moderately potent inhibitors of choline
acetyltransferase exist, they have no
therapeutic utility, because the uptake
of choline is the rate-limiting step in
ACh biosynthesis.
Continuation of Cholinergic Transmission
•After release from the presynaptic terminal,
acetylcholine molecules may bind to and activate
an acetylcholine receptor (cholinoceptor).
Eventually (and usually very rapidly), all of the
acetylcholine released will diffuse within range of
an acetylcholinesterase (AChE) molecule.
•AChE very efficiently splits acetylcholine into
choline and acetate and terminates the action of
the transmitter. Most cholinergic synapses are
richly supplied with acetylcholinesterase; the halflife of acetylcholine in the synapse is therefore
very short.
Continuation of Cholinergic Transmission
Two pools of acetylcholine appear to exist:
- One pool, the "depot" or "readily releasable"
pool, consists of vesicles located near the
plasma membrane of the nerve terminals; these
vesicles contain newly synthesized transmitter.
Depolarization of the terminals causes these
vesicles to release ACh rapidly or readily.
- The other pool, the "reserve pool,“ replenish
the readily releasable pool and may be required
to sustain ACh release during periods of
prolonged or intense nerve stimulation
Adrenergic Transmission
Adrenergic Transmission
Adrenergic neurons transport a precursor molecule into the
nerve ending, then synthesize the catecholamine transmitter,
and finally store it in membrane bound vesicles.
In most sympathetic postganglionic neurons, norepinephrine is
the final product.
In the adrenal medulla and certain areas of the brain,
norepinephrine is further converted to epinephrine.
Synthesis terminates with dopamine in the dopaminergic
neurons of the central nervous system.
Several important processes in these nerve terminals are
potential sites of drug action.
Adrenergic Transmission
Adrenergic Transmission
Tyrosine is transported into the noradrenergic ending by a
sodium-dependent carrier (A).
Tyrosine is converted to dopamine, which is transported into
the vesicle by a carrier (B) that can be blocked by reserpine.
The same carrier transports norepinephrine (NE) and several
other amines into these granules.
Dopamine is converted to NE in the vesicle by dopaminehydroxylase.
Release of transmitter occurs when an action potential opens
voltage-sensitive calcium channels and increases intracellular
calcium. Fusion of vesicles with the surface membrane
results in expulsion of norepinephrine, cotransmitters, and
ATP
Catecholeamines biosynthesis
•The conversion of tyrosine to dopa, is the rate-limiting
step in catecholamine transmitter synthesis. It can be
inhibited by the tyrosine analog metyrosine.
•A high-affinity carrier for catecholamines located in
the wall of the storage vesicle can be inhibited by the
reserpine alkaloids.
• Another carrier transports norepinephrine and similar
molecules into the cell cytoplasm (reuptake 1). It can
be inhibited by cocaine and tricyclic antidepressant
drugs, resulting in an increase of transmitter activity in
the synaptic cleft.
Continuation of Adrenergic Transmission
In addition to the primary transmitter (norepinephrine), ATP,
dopamine- -hydroxylase, and peptide cotransmitters are also
released into the synaptic cleft.
Indirectly acting sympathomimetics—eg, tyramine and
amphetamines—are capable of releasing stored transmitter
from noradrenergic nerve endings.
These drugs are taken up into noradrenergic nerve endings by
uptake 1.
In the nerve ending, they may displace norepinephrine from
storage vesicles, inhibit monoamine oxidase, and have other
effects that result in increased norepinephrine activity in the
synapse.
Biosynthesis of catecholamines
•The rate-limiting step,
conversion of tyrosine to
dopa,
•It can be inhibited by
metyrosine (amethyltyrosine).
• TH deficiency has been reported in
humans.
• Characterized by generalized rigidity,
hypokinesia, and low cerebrospinal fluid
(CSF) levels of NE and DA metabolites
homovanillic acid and 3-methoxy-4hydroxyphenylethylene glycol.
•DβH deficiency in humans is characterized by
orthostatic hypotension, ptosis of the eyelids,
retrograde ejaculation, and elevated plasma levels
of dopamine.
•In the adrenal medulla, catecholamines are stored
in chromaffin granules. These vesicles contain
extremely high concentrations of catecholamines
(21% dry weight), ascorbic acid, and ATP, as well
as specific proteins such as chromogranins,
The adrenal medulla has two distinct catecholaminecontaining cell types:
a. those with NE and
b. those with primarily epinephrine.
The b cell population contains the enzyme
phenylethanolamine-N-methyltransferase (PNMT). In
these cells, the NE formed in the granules is
methylated in the cytoplasm to epinephrine.
Epinephrine then reenters the chromaffin granules, stored
until released.
In adults, epinephrine accounts for 80% of the
catecholamines of the adrenal medulla, with NE
making up most of the remainder.
The adrenal medulla has two distinct catecholaminecontaining cell types:
a. those with NE and
b. those with primarily epinephrine.
The b cell population contains the enzyme
phenylethanolamine-N-methyltransferase (PNMT). In
these cells, the NE formed in the granules is
methylated in the cytoplasm to epinephrine.
Epinephrine then reenters the chromaffin granules, stored
until released.
In adults, epinephrine accounts for 80% of the
catecholamines of the adrenal medulla, with NE
making up most of the remainder.
•A major factor that controls the rate of synthesis of
epinephrine, is the level of glucocorticoids secreted
by the adrenal cortex.
•The intra-adrenal portal vascular system carries the
corticosteroids directly to the adrenal medullary
chromaffin cells, where they induce the synthesis of
PNMT.
•The activities of both TH and DβH also are
increased in the adrenal medulla when the secretion
of glucocorticoids is stimulated.
•Thus, any stress that persists sufficiently to evoke
an enhanced secretion of corticotropin mobilizes and
release epinephrine.
Metabolism of catecholamines by catechol-Omethyltransferase (COMT) and monoamine oxidase (MAO).
Norepinephrine and
epinephrine
metabolized by -
MAO and COMT
Termination of the Actions of Catecholamines
The actions of NE and epinephrine are terminated
by:
- reuptake into nerve terminals by NET
- dilution by diffusion out of the junctional cleft and
uptake at extraneuronal sites by ENT, OCT 1, and
OCT 2
Following uptake, catecholamines can be
metabolized or re-stored in vesicles.
Two enzymes –
monoamine oxidase (MAO) and
catechol-O-methyltransferase (COMT).
Termination of the Actions of Catecholamines
• The inhibitors of neuronal reuptake of catecholamines
potentiate the effects of the neurotransmitter; e.g.,
cocaine and imipramine.
• Inhibitors of MAO and COMT have relatively little effect.
However, MAO metabolizes transmitter that is released
within the nerve terminal.
• COMT, particularly in the liver, plays a major role in the
metabolism of endogenous circulating and administered
catecholamines.
Termination of the Actions of Catecholamines
Adrenergic Transmission
Nicotinic Ach Receptors