SYNTHESIS OF ACETYLCHOLINE

One-step process:
o AcCoA + Choline produce ACh.
Choline transported into nerve
endings
Acetyl CoA synthesized in the
mitochondria
Ach is transported inside a vesicle via an active pump or
second carrier vesicle-associated transporter (VAT)
o Inhibited by vesamicol
o Peptides (P), adenosine triphosphate (ATP),
and proteoglycan are also stored in the vesicle.
o Vesicles:
Clear vesicles contain more of Ach
(found towards the synaptic
membrane).
Densecored vesicles contain more of
NANC transmitters (located farther
from the synaptic membrane).
o Each vesicle contains 1,000 50,000
molecules of Ach.
Ca2+ stimulates release when levels are increased,
which causes fusion of vesicles with the surface
membrane and exocytotic expulsion of acetylcholine and
cotransmitters into the junctional cleft.
o Can be blocked by botulinum toxin
recordingThe membrane of vesicle joins with the
membrane of the neuron leading to the release of
substances inside the vesicle.
The production, release, and degradation of the
substances are all very rapid
Released ACh are taken up by their respective
cholinoreceptors
Cholinoreceptors produce respective response
Previous transAction of Ach is terminated by:
o Enzymatic degradation by acetylcholinesterase
(AChE) Recording
RecordingAcetylcholinesterase (True/
Specific Cholinesterase) degrade
ACh and its analogs
Butyrylcholinesterase (Plasma/
Nonspecific Cholinesterase) -
degrade all types of esters
Choline is recycled. Previous trans
There are no therapeutic preparations
of Ach as degradation occurs almost
immediately hydrolysis occurs within
a fraction of a second (this is due to
the abundance of AChE in cholinergic
synapses).
AChE can also be found in other
tissues like RBCs.
o Diffusion from the receptor

SYNTHESIS OF NOREPINEPHRINE

Three-step process:
o Conversion of TYOSINE to DOPA
Enzyme: Tyrosine Hydroxylase
Ratelimiting step in catecholamine
synthesis
Inhibited by the drug METYROSINE
(not really given now; previously used
in the Tx of pheochromocytoma)
Tyrosine is transported into the
noradrenergic ending by a
sodiumdependent carrier.
o Conversion of DOPA to DOPAMINE
Enzyme: Dopa decarboxylase
Dopamine is taken up by VMAT
o Synthesis of norepinephrine (NE)
Occurs within the vesicle
Enzyme dopaminehydroxylase
Fusion of vesicles with the synaptic membrane resuls in
the expulsion of NE, cotransmitters, and dopamine-
hydroxylase through exocytosis.
Norepinephrine transporter (NET) carries NE and
similar molecules back into the cell cytoplasm from the
synaptic cleft
o A.k.a. uptake 1 or reuptake 1
o Partially responsible for the termination of
synaptic activity
o Cytoplasmic pool of NE not readily degraded
by MAO (in cytoplasm); in a protective state
o Vesicular pool of NE NE is not degraded and
is instead
o transported into the vesicle
o Inhibited by cocaine and tricyclic antidepressant
(TCA) drugs, resulting in an increase of
transmitter activity in the synaptic cleft
Termination of NE action:
o Neuronal uptake NE is taken back into the
cytoplasm
o Extra-neuronal uptake - degraded by enzymes
like monoamine oxidase (mitochondria) and
catecholOmethyltransferase (liver and other
tissues)
o Diffusion from receptor site
Exam! Presynaptic receptors at the sympathetic nerve
terminal
o Autoreceptor (same) presynaptic alpha-2
receptors
Produce a negative feedback
mechanism
o Heteroreceptor muscarinic receptors
Cocaine, tricyclic, and antidepressants (TCAs)
o inhibit neuronal uptake leading to more
norepinephrine that continuously activate the
receptors
o increase in sympathetic activity

PHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM
The ANS controls smooth muscle
Visceral & vascular
Exocrine (and some endocrine) secretion are increased
o Increased lacrimation, sweating, gastric
secretion
Rate and force of contraction affected by both PNS and
SNS
Certain metabolic processes (e.g. glucose utilization, fat
metabolism)
Innervations
o Single
Pilo erector muscles
Most of the blood vessels are also
subserved by SNS Dual
o Dual
Heart, bronchioles, bladder (also GIT
and ciliary muscle of iris)
Antagonism
o Effects of SNS and PNS are antagonistic
o In those organs that are dually innervated
especially if they are antagonistic to one
another, there is one division that becomes
more dominant.
o Examples:
Heart rate accelerated by SNS and
diminished by PNS
GIT
PNS increase tone or
motility
SNS decrease motility;
relaxation of GIT smooth
muscle
Gut
PNS walls contract; trigone
and sphincter relax
SNS sphincter contraction
Exception salivary glands stimulation
by both PNS and SNS will result in
increase salivation.
Coordination
o When a number of organs are involved to affect
a physiological function in a coordinated way,
the two divisions are called to act in a
coordinated or orchestrated manner.
o Examples:
Vomiting
Male reproductive system
PNS - erection
SNS - ejaculation
Domination
o In an organ that receives dual innervations from
the two opposing divisions, one of them usually
plays a dominant role in controlling the function.
o PNS is generally more dominant because it is
responsible for homeostasis, except in
vasomotor tone (SNS dominant).
o Antagonism of the dominant division produces
effects very similar to stimulation of the other
more submissive division.
Examples:
o PNS dominant in eyes pupillary constriction
(miosis); if PNS is blocked pupillary dilation
(mydriasis), a SNS effect
o PNS dominant in GIT causing increased motility
giving antispasmodic or antimuscarinic
diminishes GIT activity
o PNS dominant in heart (bradycardia)
Atria are more affected than the
ventricles (recording)
blocking will produce tachycardia
Sympathetic activity increases in stress (fight or flight
response), whereas parasympathetic activity
predominates during satiation and repose (maintain body
homeostasis). Both systems exert a continuous
physiological control of specific organs under normal
condition, when the body is at neither extreme.
AUTONOMIC NERVOUS SYSTEM IMPORTANT REFLEX
MECHANISMS (The following comes from the missing ppts that
dean reyes mentioned)*

Barostatic Reflex
ANS activity can be initiated or modified by impulses
from higher centers.
Changes in arterial pressure detected by
baroreceptors in carotid and aortic arch
Impulses from baroreceptors (located in carotid
sinus) via afferents (cranial nerve IX) signal
vasomotor center (VMC) to counteract original
change in BP
Example:
o Increase peripheral resistance (PR)
causes IX nerve firing:
Inhibit VMC decrease firing of
neurons in VMC decrease VMT
blood vessels (relayed thru S ganglia)
decrease BP
Excites vagal nucleus in medulla
reflex bradycardia
If you have orthostatic hypotension,
reflex mechanism is reflex tachycardia.
Spinal Micturition
Accumulation of urine increase in intravesical
tension activates sensory neurons in urinary
bladder wall sends afferents to spinal cord
efferent impulses from spinal cord activate
detrusor muscle and inhibit sphincter
micturition reflex
STEPS IN NEUROHORMONAL TRANSMISSION
Axonal Conduction
Passage of impulse along the axon or muscle fiber
Ca2+ and Na+ dependent opening of Na+ channels
influx of Na+ membrane depolarization response
(e.g. muscle contraction)
Increased permeability to Na+ depolarization

o Synthesis and storage of transmitter
substances in their respective vesicles
o Axonal conduction is produced upon arrival of
an action potential.
o Stimulation of nicotinic receptor muscle
contraction prolonged stimulation
depression of depolarization block leads to
flaccid paralysis
By blocking the Na+ channels, action potential
propagation can be inhibited by:
o Saxitoxin (red tide toxin)
Neurotoxin caused by dinoflagellates
Responsible for paralytic shellfish
poisoning (PSP)
Can block conduction by blocking Na+
channels; causes muscle paralysis
Tetrodotoxin (puffer fish toxin)
Local anesthetics
Transmission across Junctions
Passage of the impulse across synaptic or neuroeffector
junction
Transmitter Release via Exocytosis
Mediated by Ca2+, antagonized by Mg
2
+
o Ca2+ destabilizes vesicles vesicles move
closer to presynaptic membrane fusion of
vesicular membrane and prejunctional
membrane occurs with interaction of specific
membrane proteins (vesicular proteins and
proteins associated with terminal membrane
e.g. VAMP, synaptosomes) release of
transmitters
Certain toxins may inhibit neurotransmitter release (e.g.
botulinum toxin (Botox) inhibits Ach release, causing
muscle relaxation)
NeurotransmitterReceptor Combination and Interaction
Change in permeability of receptor membrane
o Generalized increased permeability to all ions
(e.g. K+, Na+, Ca2+ depolarization)
o Selective permeability to small ions (e.g. K+
causes hyperpolarization)
Change in polarity
o Before transmission, transmitter substances are
synthesized in the synaptic vesicle.
o Arrival of the action potential (AP) destabilizes
synaptic vesicle which causes fusion of the
presynaptic membranes with the synaptic
vesicle release of neurotransmitter (NT)
Generalized increased permeability
depolarization excitatory
postsynaptic potential (EPSP)
increased activity (e.g. muscle
contracts)
Selective permeability
hyperpolarization (opening of K+
channels) inhibitory postsynaptic
potential (IPSP) decreased activity
(e.g. muscle relaxes)
Repolarization return to resting stage
ready for another AP
Enzymatic Destruction
Acetylcholine (Ach)
o Degraded by acetylcholinesterase (major
pathway) also known as true or specific
cholinesterase
o Found in cholinergic nerve synapse, RBC,
platelets, as well as in some vascular tissues
o Plasma/butyryl/pseudo cholinesterase has a
broader function.
NE or noradrenaline
o Degraded by catechol O methyl transferase
(COMT) which is found in liver and muscle, and
monoamine oxidase (MAO) which is found in
the mitochondria, cytoplasm, in the nerve
terminal itself, liver, and intestine
Uptake
UPTAKE 1 neuronal uptake
o Major pathway for termination of NE action
o NE goes back into cytoplasm via an active
pump that requires a carrier and also goes back
into vesicle.
o Also true for Ach choline (product of
degradation) goes back into cytoplasm for
synthesis of Ach
o Site of action of tricyclic antidepressants and
procaine (prevent the uptake of NE back to the
cytoplasmic pool)
UPTAKE 2 extraneuronal uptake
o Transmitter substance diffuses into perisynaptic
glia and into the muscle
o Simple diffusion into receptor sites ultimately
goes back into circulation and is degraded by
enzymes