Cholinergic & Noradrener rgic Neurotransmission I (Location / Funct tion / Receptors)

Dr. Eil Dowd s

FIRSTLY OVERVIEW OF THE NERVOUS SYSTEM E Nervous system y

PNS

CNS

Somatic

Autonomic

Motor neurons

Sensory neurons

Paras sympathetic Enteric

Sympathetic

NOTE ON CHOLINERGIC AND NORADRENERGIC D NEU NEUROTRANSMSSSION IN THE CNS N M N N THE N

1) Cholinergic and noradrenergic neuro otransmission in the CNS (brain and spinal cord) will not be studied in the lectures ese

Main noradrenergic projections in the brain

Main cholinergic projections in the brain

NOTE ON CHOLINERGIC NEUR ROTRANSMSSSION AT THE NEU MU UL HE NEUROMUSCULAR JU UN UNCTION N

2) The neuromuscular junction - This is the synapse between the somatic motor neurons and the muscles - Cholinergic neurotransmission via nicotinic receptors at this synapse

permits voluntary skeletal muscle c contraction

OVERVIEW OF THE AUTONOM MIC NERVOUS SYSTEM

1) The autonomic nervous system - This will b the f h ll be h focus of this l f h lectu ure

PNS

Somatic

Autonomic

Motor neurons

Sensory neurons

Parasympathetic P Enteric

Sympathetic

FUNCTION OF THE AUTONOM MIC NERVOUS SYSTEM

The Th ANS conveys all of the outputs f ll f the t t from th CNS t the to the rest of the body (exc cept for the somatic motor innervation of the skeletal m muscle). ) The main processes regulated by the ANS are: d The heartbeat Contraction and relaxation of smooth muscle n Hormonal (endocrine) and g glandular (exocrine) secretions Energy metabolism E l

THE ANATOMY OF THE ANS The ANS carries nerve impulses from the CNS to the p target via a series of two neu urons: Preganglionic neuron (before the ganglion) e Postganglionic neuron (after the ganglion) r
CNS Ga anglion Target

Note: A ganglion is a cluster of ne erve cells located outside the CNS

THE ANATOMY OF THE ANS The sympathetic nervous system ymp u y m In the sympathetic nervous sy y p ystem, y , the ganglia are located alo ongside the vertebrae (paraver rtebral sympathetic chain) chain).
CNS Ganglion Target

THE ANATOMY OF THE ANS The parasympathetic nervous system p ymp u y m In the parasympathetic n nervous system, the ganglia are located adjacent to or within the targ j rget
CNS Gangli ion Target

THE ANATOMY OF THE ANS The sympathetic nervous system

The sympathetic preganglionic neurons leave the CNS via thoracic and lumbar spinal roots l Segments T1 L3

THE ANATOMY OF THE ANS The parasympathetic nervous system p ymp u y m The Th parasympathetic th ti preganglionic neurons leave the CNS v a cranial and sacral NS via cran al spinal roots Oculomotor nerve (III) Facial nerve (VII) Glossopharyngeal nerve (IX) Vagus nerve (X) Sacral segments S2, S3, S4

THE FUNCTION OF THE ANS S

The sympathetic nervous system: Operates under normal conditions to maintain homeostatic tone o Fight or flight response Prepares the body for activity The parasympathetic nervous system: p ymp y m: Operates under normal conditions to maintain homeostatic tone o Rest & digest response Acts to conserve energy In most organs the sympathetic an nd parasympathetic innervation exert opposing effects (except in adrenal medulla, blood vessels, liver, kidney, sweat glands and spleen which only have a sympathetic innervation). e

THE FUNCTION OF THE ANS S

Sympathetic
Dilates pupils Inhibits saliva flow Increases heart rate and constricts blood vessels Dilates bronchi Conversion of glycogen to glucose in liver Inhibits stomach peristalsis & secretion p Stimulates renin secretion g y Reduces gut motility Inhibits bladder contraction Stimulates ejaculation Increases gut motility Contracts bladder Stimulates erection

Parasympathetic
Constricts pupils Stimulates saliva flow Decreases heart rate Constricts bronchi Stimulates t Sti l t stomach h peristalsis & secretion

THE NEUROTRANSMITTERS O THE ANS OF The sympathetic nervous system ymp u y m

Preganglionic neurons are cholinergic and acetylcholine at sympathetic ganglia acts via nicotinic receptors li t i i ti i t Postganglionic neurons are noradrener rgic and noradrenaline at sympathetic targets acts via or adrenoceptors g p

Exception: The sympathetic innerv vation of sweat glands where the postganglionic neuron uses acetylcholine! e!) Exception: The adrenal medulla which only h a preganglionic cholinergic E h d l d ll h h l has l h l neuron
CENTR RAL NERVOUS S SYETEM

THE NEUROTRANSMITTERS O THE ANS OF The parasympathetic nervous system p ymp u y m

Preganglionic neurons are cholinergic and acetylcholine at parasympathetic ganglia acts via nicotinic receptors Postganglionic neurons are also cholinergic and parasympathetic targets acts via muscar rinic receptors acetylcholine at

CNS

CHOLINERGIC AND NORADREN NERGIC TRANSMISSION In the peripheral nervous system

Cholinergic & Noradrener rgic Neurotransmission II (Location / Funct tion / Receptors) Dr. Eil Dowd s

CHOLINERGIC RECEPTORS
1. There are 2 types of ACh receptors: Nicotinic (nicotinic actions of ACh can b be mimicked b nicotine) i i k d by i ti ) Muscarinic (muscarinic actions of Ach can b be mimicked by muscarine (an extract from a poisonous mushroom)) f i h )) 2. ACh is more potent at muscarin nic receptors (i.e. larger doses ar p ( g re required to activate nicotin nic receptors) Nicotinic

Muscarinic

CHOLINERGIC RECEPTORS
1. There are 3 subtypes of nicotinic receptors Muscle Ganglion CNS 2. There are 5 subtypes of muscarinic receptors M1 (neural) M2 (h (heart) t) M3 (glandular/smooth muscle) M4 M5 Muscarinic Nicotinic

NICOTINIC ACETYLCHOLINE RECEPTORS

1. All nicotinic acetylcholine y receptors are ligand-gated ion channel receptors 2. Therefore, they mediate 2 Therefore excitatory effects fast

4. They are pentameric (5 subunits) y p ( ) 5. Each subunit is composed of 4 membrane-spanning domains 6. h 6 The M2 d domains f from each h subunit form the ion channel pore

LOCATION OF NICOTINIC AC CETYLCHOLINE RECEPTORS In the peripheral nervous system p p y m

NICOTINIC ACETYLCHOLINE RECEPTORS Overview of function

1. Function of the muscle type of nicoti inic receptor Located at the synapse between the somatic motor neurons and the n skeletal muscles (the neuromuscula junction) ar Located on the muscle cells Mediates fast cholinergic contract tion of the skeletal muscles 2. Function of the ganglion type of nicot tinic receptor Located at th s L t d t the synapse b t s between th preganglionic and postganglionic n the li i d st li i neurons of the autonomic nervous s system Located on the postganglionic neuron Mediates fast cholinergic neurotransmission between the pre and postganglionic neuron 3. Function of th CNS t 3 F ti f the type of nicotinic receptor f i ti ic t Located at the synapse between ne eurons in the brain Mediates fast cholinergic neurotra ansmission in the brain

MUSCARINIC ACETYLCHOLINE RECEPTORS E

1. 1 All muscarinic ACh receptors are G-protein coupled receptors 2. Therefore, th 2 Th f they mediate di t slow excitatory or inhibitory effects

4. G-protein-coupled 4 G protein coupled receptors affect cell functio indirectly by coupling to a Gon protein 5. The G-protein acts as a go-between li ki 5 Th G t i t b t linking the re eceptor and a target proteins 6. The G p G-protein interacting with the target g g protein causes an increase or decrease in the l levels of second messenger signal within the cell

MUSCARINIC ACETYLCHOLINE RECEPTORS E Overview of signal transduction mechanisms m

1. 1 Signal transduction by the M1, M3 and M5 subtypes d These receptors are coupled to a G-protein called Gq The target for Gq is an enzyme calle phosplolipase C ed Phospholipase C is activated by interaction with the G-protein G protein This causes the release of the 2nd m messengers IP3 & DAG This has excitatory effects on the cell (e.g. see later slide) 2. Signal transduction by the M2 and M4 subtypes These receptors are coupled to a G-protein called Gi The target for Gi is an enzyme calle adenylate cyclase ed Adenylate cyclase is inhibited by int teraction with the G-protein This reduces the amount of the 2nd messenger cAMP in the cell This has inhibitory effects on the c (e.g. see later slide) y cell ( g )

LOCATION OF MUSCARINIC A ACETYLCHOLINE RECEPTORS In the peripheral nervous system p p y

MUSCARINIC ACETYLCHOLI INE RECEPTORS Overview of function remember REST & DIGEST r
1. Function of the M1 (neural) type of ni icotinic receptor Located on CNS & peripheral neuron (& gastric parietal cells) ns Mediates slow excitatory effects 2. Function of the M2 (heart) type of nic cotinic receptor Located on the heart (and presynaptic terminals of CNS/peripheral neurons) Mediates slow inhibitory effects (e.g. slows both the rate and force of cardiac contraction) di t ti ) 3. Function of the M3 (glandular/smooth muscle) type of nicotinic receptor Located on glands and smooth muscl le Mediates slow excitatory effects (e.g. stimulation of glandular secretions and contraction of smooth muscle) 4. Little is known about the M4 and M5 s subtypes of muscarinic receptor

So which cholinergic recep ptor subtype do you think mediates each of these pa arasympathetic effects?
Constricts pupils

.. .. .. .. ..

Stimulates saliva flow Decreases heart rate Constricts bronchi

Stimulates stomach peristalsis & secretion l

Increases gut motility l Contracts bladder

..

..

QUESTION
Bearing in mind the normal physiolog g p y g gical functions of the parasympathetic nervous system In what clinical conditions would y you want to enhance cholinergic transmission f th t i i for therapeutic gain? ti in? In what clinical conditions would y you want to reduce cholinergic transmission for therapeutic gain n?

ADRENERGIC RECEPTORS There are 2 types of adrenerg yp rgic receptors:

-adrenoceptors - 1 & 2 -adrenoceptors - 1, 2 & 3 -adrenoceptors

Distinction is based on agonist potencies s s: -adrenoceptors

- noradrenaline > adrenaline > isoprenaline

-adrenoceptors

-adrenoceptors
- isoprenaline > adrenaline > noradrenaline

ADRENERGIC RECEPTORS

1. 1 All adrenergic receptors are G-protein coupled receptors 2. Therefore, th 2 Th f they mediate di t slow excitatory or inhibitory effects

4. G-protein-coupled 4 G protein coupled receptors affect cell functio indirectly by coupling to a Gon protein 5. The G-protein acts as a go-between li ki 5 Th G t i t b t linking the re eceptor and a target proteins 6. The G p G-protein interacting with the target g g protein causes an increase or decrease in the l levels of second messenger signal within the cell

ADRENERGIC RECEPTORS Overview of signal transduction m mechanisms

1. Signal transduction by the 1 subty ype of adrenergic receptor Like h L k the M1, M3, M5 subtypes of muscarinic ACh receptors, this b f h h subtype is also linked to Gq 2. Signal transduction by the 2 subty ype of adrenergic receptor Like the M2 and M4 subtypes of muscarinic ACh receptors, this subtype is also linked to Gi 3. Signal transduction by the 1, 2 and 3 subtypes of adrenergic receptor These receptors are coupled t a G Th t l d to G-protein called G t i ll d Gs Like Gi, the target for Gs is also a adenylate cyclase Adenylate cyclase is activated by interaction with the G-protein This increases the amount of the 2nd messenger cAMP in the cell This has excitatory OR inhibitory effects on the cell

LOCATION OF ADRENERGIC RE ECEPTORS In the peripheral nervous system p p y

ALPHA ADRENERGIC RECEPTOR RS Overview of function remember FIGHT or FLIGHT r

Subtype 1 Location Vascular smooth muscle Visceral smooth muscle Pupils Liver Physiological effect Vasoconstriction Relaxation Dilatation Dil t ti n Glycogenolysis

Vascular smooth muscle Pupils Pancreatic islets

Vasoconstriction Dilatation Inhibition of insulin release

BETA ADRENERGIC RECEPTORS S Overview of function remember FIGHT or FLIGHT r

Subtype 1 Location Heart Physiological effect Increased cardiac rate and force

Bronchial smooth muscle e Visceral smooth muscle e Liver Skeletal muscle

Bronchial dilation Relaxation Glycogenolysis Tremor

Adipose tissue

Lypolysis

So which adrenergic recep ptor subtype do you think mediates each of these sympathetic effects? ..
Dilates pupils

..

Increases heart rate

.. .. ..

Dilates bronchi Conversion of glycogen to glucose in liver l i li

Inhibits stomach peristalsis & secretion

..

Reduces gut motility

..

Inhibits bladder contraction

QUESTION
Bearing in mind the normal physiologi g p y gical functions of the sympathetic nervous s system In what clinical conditions would yo ou want to enhance noradrenergic transmission f th t i i for therapeutic gain? ti i ? In what clinical conditions would yo ou want to reduce noradrenergic transmission for therapeutic gain?

FUTURE LECTURES
1) Cholinergic & Noradrenergic Transm ) g g mission I (Location/Function/Receptors) ( p )
Further reading Rang et al. : Chapter 9 (Chemical Mediators and the ANS) Chapter 1 (Cholinergic Transmission) 10 Chapter 1 (Noradrenergic Transmission) 11

2) Cholinergic & Noradrenergic Trans smission II 3) Cholinergic drugs I 4) Cholinergic drugs II 5) Noradrenergic drugs g g