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 vesamicolo 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).

Dense‐cored 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 Rate‐limiting 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 sodium‐dependent 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 ‐ dopamine‐β‐hydroxylase Fusion of vesicles with the synaptic membrane resuls in

the expulsion of NE, cotransmitters, and dopamine- β‐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 1o Partially responsible for the termination of

synaptic activityo Cytoplasmic pool of NE – not readily degraded

by MAO (in cytoplasm); in a protective stateo Vesicular pool of NE – NE is not degraded and

is insteado transported into the vesicleo 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 catechol‐O‐methyltransferase (liver and other tissues)

o Diffusion from receptor site Exam! Presynaptic receptors at the sympathetic nerve

terminalo Autoreceptor – (same) presynaptic alpha-2

receptors Produce a negative feedback

mechanismo 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)

Innervationso Single

Pilo erector muscles Most of the blood vessels are also

subserved by SNS Dualo Dual

Heart, bronchioles, bladder (also GIT and ciliary muscle of iris)

Antagonismo Effects of SNS and PNS are antagonistico 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.

Coordinationo 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

Dominationo 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 anti‐muscarinic 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 TRANSMISSIONAxonal 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

junctionTransmitter Release via Exocytosis

Mediated by Ca2+, antagonized by Mg2+o Ca2+ destabilizes vesicles → vesicles move

closer to presynaptic membrane → fusion of vesicular membrane and pre‐junctional 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)

Neurotransmitter‐Receptor 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 polarityo 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 noradrenalineo 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 actiono 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 ‐ extra‐neuronal uptakeo Transmitter substance diffuses into perisynaptic

glia and into the muscleo Simple diffusion into receptor sites – ultimately

goes back into circulation and is degraded by enzymes