Download ANS NEURO-Transmitters Somatic NS ANS NEURO

ANS NEURO-Transmitters
Somatic NS
• There is only one place where neurotransmitters are
released since there is only one synapse ! ( Neuro muscular
junction)
ACh
• All somatic motor neurons release Acetylcholine at
their synapse with skeletal muscles.
• The effect is always excitatory ! ( EPSP’s )
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ANS NEURO-Transmitters
Autonomic NS
Since we have a two neuron system, we have two
synapses to deal with.
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ANS NEURO-Transmitters
Autonomic NS
Within the ganglion, the signal needs to be transmitted from
pre-ganglionic neuron to postganglionic neuron. This is
similar to the somatic system and thus requires a
neurotransmitter that is excitatory !
ACh
The neurotransmitter released in the synapse between
pre- and postganglionic neurons is always Acetylcholine. 3
ANS NEURO-Transmitters
The actual functional difference between Para Sympathetic
and Sympathetic Nervous system is thus at the level of the
postsynaptic neuron and synapse with the effector organ !
Parasympathetic postganglionic
neurons release Acetylcholine.
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ANS NEURO-Transmitters
Sympathetic postganglionic neurons release norepinephrine
Sympathetic activation of the adrenal medulla is a special case since
there is no postganglionic neuron.
The activated adrenal medulla releases epinephrine and
norepinephrine into the bloodstream.
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ANS NEURO-Transmitters
• Acetylcholine and Norepinephrine are thus the two major
neurotransmitters released by the ANS.
• ACh is released by all preganglionic neurons of PS + S
and by all postganglionic PS neurons.
• Postganglionic Sympathetic neurons release NE.
• Neurons that release ACh are called cholinergic fibers
• Neurons that release NE are called adrenergic fibers
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ANS NEURO-Transmitters
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ANS RECEPTORS
The receptor, located in the cell membrane of the target
cell, is a molecular transducer that sets in motion a
series of cellular effects.
The type of receptor determines the specificity
of cellular actions.
The neurotransmitter is the molecular trigger. It
requires binding to the receptor before the receptor
becomes activated.
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ANS RECEPTORS
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ANS RECEPTORS
The two primary ligands, agonists of the ANS are thus
AcetylCholine
Binds to
Cholinergic
Receptors
Norepinephrine
(Epinephrine )
Binds to
Adrenergic Receptors
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CHOLINERGIC RECEPTORS
They bind AcetylCholine
Two Kinds of Receptors
Nicotinic Receptors
also called nAChR
Muscarinic Receptors
also called mAChR
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Cholinergic Nicotinic Receptors
They are members of a superfamily of ligand-gated membrane
channels that mediate fast signal transmission at synapses.
All nicotinic AChRs are pharmacoligically identical
in that they bind nicotine as a ligand agonist.
Nicotinic receptors were the first kind to be
studied in detail, because they are present in
high concentrations in
the electrical organ that
the Torpedo stingray
uses to paralyze prey.
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Cholinergic Nicotinic Receptors
All nicotinic AChR’s are pentamers ;
they consist out of 5 polypeptide
subunits that are clustered around a
central receptor channel.
There are 2 ligand binding sites, formed by the alpha
subunits and an adjacent subunit
• Binding to both sites needed for channel to open
• Binding to only one site prevents channel activation
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Cholinergic Nicotinic Receptors
Binding of a ligand to the receptor causes conformational changes that
open the central channel to mostly Na+ and some K+ ions.
What is the normal physiological ligand in the body ?
AcetylCholine
What occurs in the cell that has this receptor when both binding sites
are occupied with ACh ?
The channel opens and Na+ rushes into the cell,
resulting in a depolarization !
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Cholinergic Nicotinic Receptors
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Cholinergic Nicotinic Receptors
Where do we find nicotinic Cholinergic Receptors (= nAChR)?
On post-synaptic cell-membranes of synpases that experience an exocytosis of
ACh from presynaptic vesicles and requiring fast depolarization of the
postsynaptic area.
• on the motor endplates of skeletal muscle (called somatic nAChR)
• on all cell bodies and dendrites of postganglionic neurons of
ParaSympathetic and Sympathetic system (called ganglionic nAChR)
• on the hormone producing cells of adrenal medulla
The effect of ACh on these receptors is thus always
stimulatory . It causes a depolarization of the cell !
This is your typical chemically gated Na channel !
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Cholinergic Nicotinic Receptors
Cholinergic nicotinic
Receptor
Skeletal muscle
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Cholinergic Nicotinic Receptors
Are the nACH receptors the same in the somatic system as the autonomic system ?
Yes, they are similar in structure but have different proteins that make up the
channel. Different proteins react differently to different drugs/toxins. So what does
this mean for your system with respect to this snake venom (bungarotoxin) ?
Somatic nAChR
Ganglionic nAChR
β4
α3
β4
Blocked by
α-bungarotoxin
α3
β4
Insensitive to
α-bungarotoxin
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Examples of nAChR effectors
Epibatidine :
• isolated from the skin of an Ecuadorian frog
(Epipedobates tricolor)
• exhibits very potent agonistic properties
• Thus would induce ANS potentiation
(hallucinations) and muscular spasms
Curare :
• isolated from the bark and leaves of the
tropical plant Strychnos toxifera
• it is a potent nAChR blocker in the NMJ but
affects ganglionic receptors as well
• the pure form is called tubocurarine ; mostly
used to create muscle paralysis
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Cholinergic Muscarinic Receptors
Where do we find muscarinic Cholinergic Receptors ?
On the target organs served by cholinergic postganglionic
neurons ( parasympathetic nerves) !
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Cholinergic Muscarinic Receptors
These receptors (mAChR) bind ACh as well, but the mechanism and response
elicited by these receptors differs from previousy discussed nAChR’s.
In contrast to nicotinic AChR’s, the muscarinic receptors bind
Muscarine, a component derived from the fly agaric mushroom
Amanita muscaria. (don’t eat the muschrooms)
Muscarinic Receptors operate as G-protein coupled receptors and
mediate their response by activating a variety of intra-cellular pathways.
ACh
+
+
mAChR
+
+
= activates
Enzyme
Intracellular product
G-protein
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Cholinergic Muscarinic Receptors
There are two Important G protein coupled systems, determined by the specific
enzyme that becomes activated ( and therefore different product produced)
Adenylate cyclase coupled receptors
ACh
AC = adenylate cyclase
+
mAChR
+
AC
+
ATP
Cyclic AMP
This is a very common pathway and is similar in for example smell and taste
activation.
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PLPc G-protein coupled Receptors
Phospholipase C coupled receptors
ACh
PLPc = Phospholipase C
+
mAChR
+
+
PLPc
PIP2
DAG
IP3
The concept of this pathway is the same, exept that a different enzyme is activated.
PLPc makes two products :
Diacylglycerol (DAG) and Inositol Triphosphate (IP3).
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G-protein coupled Receptors
• The purpose of these pathways is to generate intracelular signals to activate
specific tissues. Those intracellular signals are the product of the activated
enzymes (cAMP or DAG and IP3)
• Since we are covering the ANS, keep in mind the action of sympathetic versus
parasympathetic system. In this case, muscarinic receptors are typically found on
target tissues of the ParaSympathetic NS ( thus the opposite actions of the
Sympathetic NS).
• For example, if the receptors are located in smooth muscle, the purpose is to start
or inhibit smooth muscle contraction.
• If the receptors are located in glands, the purpose is to start or inhibit the
secretion of the glands.
• If they are located in important metabolic cels, the purpose is to start or inactivate
metabolic processes.
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Cholinergic Muscarinic Receptors
What effects do cAMP, DAG and IP3 have ?
cAMP and DAG
• They both activate Protein Kinases
• Protein kinases in turn will phosphorylate and activate/inactivate
proteins
• This would be a fast way of turning on/off proteins and turn on/off
a metabolic pathway
IP3
• Acts on the smooth ER
• Results is that calcium will be released into the cytoplasm
• Calcium in turn will bind to and activate a protein called calmodulin
• Activated calmodulin can now activate enzymes and other proteins
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Cholinergic Muscarinic Receptors
There are 5 different kinds of Muscarinic Receptors , named M1 to M5.
Always keep in mind that these receptors are typical for parasympathetic
target tissues.
Location
Action
M2
Heart
Inhibits Adenylate Cyclase
(thus decreases activities)
M3
Gut Smooth muscle,
glands
Activates PLP-C
(thus mediates contraction)
The M2 receptor, when it binds ACh (released from the vagus nerve), will stop production
of intracellular cAMP and this is the basis for reduced heart rate and heart contraction.
The M3 receptor, when it binds ACh will produce intracellular IP3 and this is the basis for
increased smooth muscle contraction. Found in the constrictor muscles of the iris and
smooth muscles of digestive system.
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Cholinergic Muscarinic Receptors
Muscarinic Antagonist: prevents activation of parasympathetic
target organs !
ATROPINE :
Atropa belladonna
Comes from the plant Atropa
belladonna.
The approximate lethal dose for an
adult is ten berries.
Symptoms of belladonna poisoning
are the same as those for atropine and
include :
• dilated pupils
• tachycardia
• dry throat
• constipation
• urinary retention
• hallucinations, a sense of suffocation
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Adrenergic Receptors
Adrenergic receptors, also called adrenoceptors, mediate the actions of
epinephrine (Adrenalin®), norepinephrine and related compounds.
Adrenergic receptors are found on the target organs of the sympathetic
nervous system.
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Adrenergic Receptors
Epinephrine and
norepinephrine belong
to the class of
catecholamines.
They are derivatives
from the amino acid
tyrosine !
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Adrenergic Receptors
These receptors also are coupled to G proteins which stimulate or inhibit intracellular signalling
pathways. The mechanism of signal transduction is thus very similar to the muscarinic receptors !
Epi, NorEpi
AC = adenylate cyclase
+
Ad. R
AC
+
+
ATP
Cyclic AMP
Epi, NorEpi
+
PLPc = Phospholipase C
Ad. R
+
+
PLPc
PIP2
DAG
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IP3
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Adrenergic Receptors Location-Action
Type
Location
Action
α1
Mostly smooth muscle of
Via PLPc , increases IP3 and thus free
peripheral blood vessels, eye, Ca2+
arrector pili
Results in excitation, vasoconstriction ,
pupil dilation
β1
Mostly cardiac muscle tissue
and kidney
β2
Smooth muscle of
coronaries, bronchi
β3
Adipose tissue
Via Ad. Cyclase and cAMP
Increased heart rate and contraction,
renin release
Via Ad. Cyclase and cAMP
Relaxation and vasodilation
Lipolysis
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Adrenergic Receptors
Alpha receptors
• when activated, generally produce excitatory responses
of smooth muscle in which they are located.
Beta receptors
• when activated, generally produce inhibitory responses
of smooth muscle in which they are located.
Complex physiological responses result from catecholamine
stimulation because there are multiple receptor types which
are differentially expressed in different tissues and cells.
In addition, many of these receptors are susceptible to up and
down regulation !
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