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

LOCATION OF NICOTINIC ACIn the peripheral nervous systemp p y

CETYLCHOLINE RECEPTORSm

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 )

LOCATION OF MUSCARINIC AIn the peripheral nervous systemp p y

ACETYLCHOLINE RECEPTORS

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

LOCATION OF ADRENERGIC REIn the peripheral nervous systemp p y

ECEPTORS

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