Download - 1 Cholinergic & Noradrenergic Transmission I
Cholinergic & NoradrenerCholinergic & NoradrenerCholinergic & NoradrenerCholinergic & Noradrener(Location / Funct
Dr. Eilí
rgic Neurotransmission I rgic Neurotransmission I rgic Neurotransmission I rgic Neurotransmission I tion / Receptors)
ís Dowd
FIRSTLY … OVERVIEW OF THE
Nervo
PNS
SomaticSomatic
Motor neurons
Sensory neurons
Paras
E NERVOUS SYSTEM
us systemy
CNS
AutonomicAutonomic
sympathetic Sympathetic
Enteric
NOTE ON CHOLINERGIC ANDNEUROTRANSMSSSION IN TNEU N M N N
1) Cholinergic and noradrenergic neurospinal cord) will not be studied in the
Main noradrenergic projections in the brain
D NORADRENERGIC THE CNSHE N
otransmission in the CNS (brain andese lectures
Main cholinergic projections in the brain
NOTE ON CHOLINERGIC NEURAT THE NEUROMUSCULAR JU
2) The neuromuscular junctionThis is the synapse between the so
HE NEU MU UL JU
- This is the synapse between the so- Cholinergic neurotransmission via
permits voluntary skeletal muscle c
ROTRANSMSSSION UNCTION
matic motor neurons and the muscles
UN N
matic motor neurons and the musclesnicotinic receptors at this synapse
contraction
OVERVIEW OF THE AUTONOM
1) The autonomic nervous systemh ll b h f f h l- This will be the focus of this lectu
PNS
Somatic
Motor Sensory Pneurons neurons
MIC NERVOUS SYSTEM
ure …
Autonomic
Parasympathetic Sympathetic
Enteric
FUNCTION OF THE AUTONOM
Th ANS ll f thThe ANS conveys all of thethe rest of the body (excinnervation of the skeletal m
The main processes regulated
The heartbeat
Contraction and relaxationContraction and relaxation
Hormonal (endocrine) and g
E lEnergy metabolism
MIC NERVOUS SYSTEM
t t f th CNS te outputs from the CNS tocept for the somatic motormuscle).
d by the ANS are:
)
n of smooth musclen of smooth muscle
glandular (exocrine) secretions
THE ANATOMY OF THE ANS
The ANS carries nerve impptarget via a series of two neu
Preganglionic neuron (before
Postganglionic neuron (after
CNS Ga
Note: A ganglion is a cluster of ne
ulses from the CNS to theurons:
e the ganglion)
r the ganglion)
anglion Target
erve cells located outside the CNS
THE ANATOMY OF THE ANS – The sympathetic nervous systemymp u y m
In the sympathetic nervous syy p ythe ganglia are located alothe vertebrae (paraversympathetic chain)sympathetic chain).
CNS Ganglion
ystem,y ,ongsidertebral
Target
THE ANATOMY OF THE ANS – The parasympathetic nervous systemp ymp u y m
In the parasympathetic nIn the parasympathetic nsystem, the ganglia areadjacent to or within the tarj
CNS Gangli
nervousnervouslocatedrgetg
ion Target
THE ANATOMY OF THE ANS – The sympathetic nervous system– The sympathetic nervous system
The sympathetic preganglionic neurons preganglionic neurons
leave the CNS via thoracic and lumbar
l spinal roots
Segments T1 – L3
THE ANATOMY OF THE ANS – The parasympathetic nervous system
Th th ti
p ymp u y m
The parasympathetic preganglionic neurons leave the
CNS via cranial and sacral NS v a cran al and sacral spinal roots
Oculomotor nerve (III)Facial nerve (VII)Glossopharyngeal nerve (IX)Glossopharyngeal nerve (IX)Vagus nerve (X)Sacral segments S2, S3, S4
THE FUNCTION OF THE ANS
The sympathetic nervous system:
Operates under normal conditions to
“Fight or flight” response
Prepares the body for activity
The parasympathetic nervous system:p ymp y m
Operates under normal conditions to
“Rest & digest” response
Acts to conserve energy
In most organs the sympathetic anIn most organs the sympathetic anopposing effects (except in adrenalsweat glands and spleen which only have
S
o maintain homeostatic tone
:
o maintain homeostatic tone
nd parasympathetic innervation exertnd parasympathetic innervation exertmedulla, blood vessels, liver, kidney,e a sympathetic innervation).
THE FUNCTION OF THE ANS
Dilates pupils
Sympathetic
Inhibits saliva flow
Increases heart rate and Increases heart rate and constricts blood vessels
Dilates bronchi
Inhibits stomach peristalsis & secretion
Conversion of glycogen to glucose in liver
p
Stimulates renin secretion
Reduces gut motility
Inhibits bladder contraction
g y
Stimulates ejaculation
S
Constricts pupils
Parasympathetic
Stimulates saliva flow
Decreases heart rateDecreases heart rate
Constricts bronchi
Sti l t t h Stimulates stomach peristalsis & secretion
Contracts bladder
Increases gut motility
Contracts bladder
Stimulates erection
THE NEUROTRANSMITTERS O– The sympathetic nervous systemymp u y m
Preganglionic neurons are cholinergili t i i ti i tganglia acts via nicotinic receptors
Postganglionic neurons are noradrenertargets acts via α or β adrenoceptorsg β p
Exception: The sympathetic innervpostganglionic neuron uses acetylcholine!
E h d l d ll h hException: The adrenal medulla whichneuron
SR
AL
NER
VOU
SSY
ETEM
CEN
TR
OF THE ANS
c and acetylcholine at sympathetic
rgic and noradrenaline at sympathetic
vation of sweat glands where thee!)h l h ‘ l ’ h lh only has a ‘preganglionic’ cholinergic
THE NEUROTRANSMITTERS O– The parasympathetic nervous systemp ymp u y m
Preganglionic neurons are cholinergicganglia acts via nicotinic receptors
Postganglionic neurons are alsoPostganglionic neurons are alsoparasympathetic targets acts via muscar
CN
SOF THE ANSmm
and acetylcholine at parasympathetic
cholinergic and acetylcholine atcholinergic and acetylcholine atrinic receptors
CHOLINERGIC AND NORADRENIn the peripheral nervous systemIn the peripheral nervous system
NERGIC TRANSMISSION
Cholinergic & NoradrenerCholinergic & NoradrenerCholinergic & NoradrenerCholinergic & Noradrener(Location / Funct
Dr. Eilí
rgic Neurotransmission II rgic Neurotransmission II rgic Neurotransmission II rgic Neurotransmission II tion / Receptors)
ís Dowd
CHOLINERGIC RECEPTORS
1. There are 2 types of ACh receptors
Nicotinic
(nicotinic actions of ACh can bi i k d b i ti )mimicked by nicotine)
MuscarinicMuscarinic
(muscarinic actions of Ach can bmimicked by muscarine (an extraf i h ))from a poisonous mushroom))
2. ACh is more potent at muscarinreceptors (i.e. larger doses arp ( grequired to activate nicotinreceptors)
:
be Nicotinic
bect
nicre
Muscarinic
nic
CHOLINERGIC RECEPTORS
1. There are 3 subtypes of nicotinic re
Muscle
Ganglion
CNS
2. There are 5 subtypes of muscarinic
M1 (neural)
M (h t)M2 (heart)
M3 (glandular/smooth muscle)
MM4
M5
ceptors
Nicotinic
receptors
Muscarinic
NICOTINIC ACETYLCHOLINE
1. All nicotinic acetylcholineyreceptors are ligand-gated ionchannel receptors
2 Therefore they mediate fast2. Therefore, they mediate fastexcitatory effects
RECEPTORS
4. They are pentameric (5 subunits)y p ( )
5. Each subunit is composed of 4membrane-spanning domains
6 h M d f h6. The M2 domains from eachsubunit form the ion channel pore
NICOTINIC ACETYLCHOLINE Overview of function
1. Function of the muscle type of nicotiLocated at the synapse between
Overview of function
Located at the synapse betweenskeletal muscles (the neuromusculaLocated on the muscle cellsMediates fast cholinergic contractMediates fast cholinergic contract
2. Function of the ganglion type of nicotL t d t th s s b tLocated at the synapse betweenneurons of the autonomic nervous sLocated on the postganglionic neurMediates fast cholinergic neurMediates fast cholinergic neurpostganglionic neuron
3 F ti f th CNS t f i ti i3. Function of the CNS type of nicotinicLocated at the synapse between neMediates fast cholinergic neurotra
RECEPTORS
inic receptorn the somatic motor neurons and then the somatic motor neurons and thear junction)
tion of the skeletal musclestion of the skeletal muscles
tinic receptorth li i d st li in the preganglionic and postganglionic
systemonotransmission between the pre andotransmission between the pre and
tc receptoreurons in the brainansmission in the brain
MUSCARINIC ACETYLCHOLINE
1 All muscarinic ACh 4 G pro1. All muscarinic AChreceptors are G-proteincoupled receptors
2 Th f th di t
4. G-profunctioprotei
5 Th G2. Therefore, they mediateslow excitatory orinhibitory effects
5. The Gthe re
6. The Gproteithe lwithin
E RECEPTORS
tein coupled receptors affect celltein-coupled receptors affect cellon indirectly by coupling to a G-n
G t i t b t li kiG-protein acts as a go-between linkingeceptor and a target proteins
G-protein interacting with the targetp g gn causes an increase or decrease inlevels of ‘second messenger’ signalthe cell
MUSCARINIC ACETYLCHOLINEOverview of signal transduction m
1 Signal transduction by the M M and
Overview of signal transduction m
1. Signal transduction by the M1, M3 andThese receptors are coupled to a G-The target for Gq is an enzyme callePhospholipase C is activated by intePhospholipase C is activated by inteThis causes the release of the 2nd mThis has excitatory effects on the
2. Signal transduction by the M2 and M4These receptors are coupled to a G-The target for Gi is an enzyme calleThe target for Gi is an enzyme calleAdenylate cyclase is inhibited by intThis reduces the amount of the 2nd
This has inhibitory effects on the cy
E RECEPTORSmechanisms
d M subtypes
mechanisms
d M5 subtypes-protein called Gqed phosplolipase Craction with the G-proteinraction with the G protein
messengers IP3 & DAGcell (e.g. see later slide)
4 subtypes-protein called Gied adenylate cyclaseed adenylate cyclaseteraction with the G-proteinmessenger cAMP in the cell
cell (e.g. see later slide)( g )
MUSCARINIC ACETYLCHOLIOverview of function – remember
1. Function of the M1 (neural) type of niLocated on CNS & peripheral neuron
Overview of function remember
Located on CNS & peripheral neuronMediates slow excitatory effects
2. Function of the M2 (heart) type of nicLocated on the heart (and presynapMediates slow inhibitory effects
di t ti )cardiac contraction)
3. Function of the M3 (glandular/smoothLocated on glands and smooth musclMediates slow excitatory effectsand contraction of smooth muscle)
4. Little is known about the M4 and M5 s
INE RECEPTORSr REST & DIGEST
icotinic receptorns (& gastric parietal cells)
r REST & DIGEST
ns (& gastric parietal cells)
cotinic receptortic terminals of CNS/peripheral neurons)(e.g. slows both the rate and force of
muscle) type of nicotinic receptorle(e.g. stimulation of glandular secretions
subtypes of muscarinic receptor
So which cholinergic recepmediates each of these pa
ptor subtype do you think arasympathetic effects?
Constricts pupils ……..
Stimulates saliva flow
Decreases heart rate
……..
……..
Constricts bronchi
Stimulates stomach l &
……..
peristalsis & secretion
l
……..
Contracts bladder
Increases gut motility ……..
……..
QUESTION
Bearing in mind the normal physiologg p y gfunctions of the parasympathetic nervous system …
In what clinical conditions would ywant to enhance cholinergic t i i f th ti itransmission for therapeutic gain
In what clinical conditions would yIn what clinical conditions would ywant to reduce cholinergic transmission for therapeutic gain
gical g
you
?n?
you you
n?
ADRENERGIC RECEPTORS
There are 2 types of adrenerypreceptors:
α-adrenoceptors&- α1 & α2
β-adrenoceptors- β1, β2 & β3
Distinction is based on agonist potenciesDistinction is based on agonist potencies
α-adrenoceptors- noradrenaline > adrenaline > isoprenaline
β-adrenoceptors- isoprenaline > adrenaline > noradrenaline
rgicg
α-adrenoceptors
s:β-adrenoceptors
s
ADRENERGIC RECEPTORS
1 All adrenergic receptors 4 G pro1. All adrenergic receptorsare G-protein coupledreceptors
2 Th f th di t
4. G-profunctioprotei
5 Th G2. Therefore, they mediateslow excitatory orinhibitory effects
5. The Gthe re
6. The Gproteithe lwithin
tein coupled receptors affect celltein-coupled receptors affect cellon indirectly by coupling to a G-n
G t i t b t li kiG-protein acts as a go-between linkingeceptor and a target proteins
G-protein interacting with the targetp g gn causes an increase or decrease inlevels of ‘second messenger’ signalthe cell
ADRENERGIC RECEPTORSOverview of signal transduction m
1. Signal transduction by the α1 subtyL k h M M M b
Overview of signal transduction m
Like the M1, M3, M5 subtypessubtype is also linked to Gq
2. Signal transduction by the α2 subtyLike the M2 and M4 subtypessubtype is also linked to Gi
3. Signal transduction by the β1, βreceptor
Th t l d tThese receptors are coupled to aLike Gi, the target for Gs is also aAdenylate cyclase is activated byThis increases the amount of theThis increases the amount of theThis has excitatory OR inhibitory
mechanisms
ype of adrenergic receptorf h h
mechanisms
of muscarinic ACh receptors, this
ype of adrenergic receptorof muscarinic ACh receptors, this
2 and β3 subtypes of adrenergic
G t i ll d GG-protein called Gsadenylate cyclaseinteraction with the G-protein2nd messenger cAMP in the cell2nd messenger cAMP in the celleffects on the cell
ALPHA ADRENERGIC RECEPTOROverview of function – rememberOverview of function remember
Subtype Locationα1 Vascular smooth muscle
Visceral smooth musclePupilsPupilsLiver
α2 Vascular smooth musclePupilsPupils
Pancreatic islets
RSr FIGHT or FLIGHTr FIGHT or FLIGHT
Physiological effectVasoconstriction
RelaxationDil t ti nDilatation
Glycogenolysis
VasoconstrictionDilatationDilatation
Inhibition of insulin release
BETA ADRENERGIC RECEPTORSOverview of function – rememberOverview of function remember
Subtype LocationSubtype Location
β1 Heart
β2 Bronchial smooth muscle
Visceral smooth muscle
Liver
Skeletal muscle
β3 Adipose tissue
Sr FIGHT or FLIGHTr FIGHT or FLIGHT
Physiological effectPhysiological effect
Increased cardiac rate and force
e Bronchial dilation
e Relaxation
Glycogenolysis
Tremor
Lypolysis
So which adrenergic recepmediates each of these
Dilates pupils……..
Increases heart rate……..
Dilates bronchi
Conversion of glycogen l i li
……..
Inhibits stomach peristalsis & secretion
to glucose in liver……..
……..
Inhibits bladder
Reduces gut motility……..Inhibits bladder
contraction……..
ptor subtype do you think sympathetic effects?
QUESTION
Bearing in mind the normal physiologig p y gfunctions of the sympathetic nervoussystem …
In what clinical conditions would yowant to enhance noradrenergic t i i f th ti i ?transmission for therapeutic gain?
In what clinical conditions would yoIn what clinical conditions would yowant to reduce noradrenergic transmission for therapeutic gain?
ical s
ou
ou ou
FUTURE LECTURES …
1) Cholinergic & Noradrenergic Transm) g gFurther reading Rang et al. : Chapter 9
Chapter 1Chapter 1
2) Cholinergic & Noradrenergic Trans
3) Cholinergic drugs I3) Cholinergic drugs I
4) Cholinergic drugs II
5) Noradrenergic drugsg g
mission I (Location/Function/Receptors)( p )9 (Chemical Mediators and the ANS)10 (Cholinergic Transmission)11 (Noradrenergic Transmission)
smission II