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1
- Dr. Chandini Rao
- Moderator: Dr. Padmaja Udaykuma
TRANSMITTERS &
RECEPTORS OF THE ANS
Overview
2
 Introduction
 Transmitters of ANS
 Cholinergic transmission & Receptors – Nicotinic
Muscarinic
 Adrenergic transmission & Receptors (α & β)
 Neuromodulation – Pre-synaptic &
Post-synaptic
Introduction -
 Autonomic nervous system (Visceral/Involuntary
nervous sytem)
- Widely distributed
- Regulates autonomic functions (without
conscious
control)
- Nerves, ganglia, and plexuses  heart, blood
vessels, glands, visceral organs & smooth
muscle in
various tissues.
3
4
 Comprises of 3 divisions –
1. Sympathetic nervous system (Thoraco-
lumbar
outflow)
2. Parasympathetic nervous system (Cranio-
sacral
outflow)
3. Enteric nervous system
5
• Basic pattern –
6
Physiology of ANS
• ANS controls –
 Smooth muscle (visceral & vascular),
 Exocrine secretions,
 Rate & force of heart contraction,
 Metabolic processes (e.g. glucose utilisation).
• SNS & PNS have opposing actions in some
situations (e.g. control of heart rate, GI smooth
muscles),
but not in others (e.g. salivary glands, ciliary
muscle).
7
• Sympathetic activity ↑ in stress (‘fight or flight’
response)
Parasympathetic activity – satiation & repose.
• ENS (‘2nd brain’) –
- Intramural (Myenteric) & submucosal plexus
- receives inputs from sympathetic &
parasympathetic
systems
- can act on its own to control motor & secretory
functions of the intestine.
Transmitters of ANS
8
• The principal
transmitters are
 Acetylcholine
(Ach)
 Noradrenaline
(NA)
• Others –
Adrenaline, Dopamine,
Isoprenaline
History -
9
• After 20th C: Lewandowsky and Langley –
similarity between effects of injection of extracts
of
adrenal gland & stimulation of Sympathetic
nerves.
• 1914: Dale
- pharmacological properties of ACh & other
choline
esters (muscarinic & nicotinic actions)
- “Parasympathomimetic”
10
• 1921:
Loewi – Parasympathin
(Vagusstoff or “vagus substance”)
Cannon & Uridil – Sympathin
(“Epinephrine-like substance”)
• 1946:
Von Euler – Norepinephrine-like substance
(bovine splenic nerve)
Non-adrenergic non-cholinergic
transmitters (NANC)
11
• ENS
* Capsaicin
(Substance
P)
Co-transmission
12
• Neurons release > 1 transmitter  specific
receptors both Pre- & Post-synaptic effects
13
Advantages:
1) Long-lasting effect :
1 NT removed/inactivated more slowly than the
other
Eg. Ach & GnRh in sympathetic ganglia
2) Differential release of I or more transmitters
 Varying impulse patterns
Eg. NA & NPY
(NPY release @higher stimulation frequencies)
Cholinergic
transmission14
 Synthesis, storage, and release of ACh :
 Cholinergic synapses -
 Skeletal neuromuscular junctions
 Preganglionic Sympathetic and
Parasympathetic
terminals
 Postganglionic Parasympathetic terminals
 Postganglionic Sympathetic terminals 
sweat glands in skin & in CNS.
15
16
Electrical events in transmission
Ach
↓
Post-synaptic membrane (nicotinic)
↓
Inflow of Na+
↓
Depolarization of post-synaptic membrane
↓
End-plate potential (EPP)/ Fast EPSP
↓
Action potential
↓
Contraction (muscle fibre)
Main mechanisms of Cholinergic
blockade
17
 Inhibition of choline uptake
 Inhibition of ACh release
 Blockade of postsynaptic receptors or ion
channels
 Persistent postsynaptic depolarisation
(Depolarization block)
Depolarization block
18
• Due to persistent activation
of
nAChRs
↓
↓ in electrical excitability of
post-synaptic cell
• Voltage sensitive Na+
channels become
inactivated (i.e. refractory)
Figure:
19
Application of Nicotine on Sympathetic ganglion
↓
Depolarization & AP discharge
↓
↓
Discharge ↓ & transmission blocked
↓
↓
Partial repolarization & return of electrical excitability
But transmission still blocked.
- Secondary, Non-depolarising block
(Eg. Suxamethonium)
d/t receptor desensitization
Cholinergic Receptors
20
• 1914: Dale distinguished 2 types of activity in Ach
- Muscarinic (Amanita muscaria)
& Nicotinic (Nicotine)
• Muscarinic actions – resemble effects of
parasympathetic stimulation
• Nicotinic effects –
- Stimulation of all autonomic ganglia
- Stimulation of voluntary muscles
- Secretion of adrenaline from adrenal medulla
Nicotinic Receptors
21
Structure
• Pentameric structures
• Ligand-gated ion channels.
• 5 subunits – Receptor-channel
complex
- 17 members:
α (10 types),
β (4 types),
γ, δ & ε
(one of each).
22
Agonists & Antagonists
23
Muscarinic Receptors
24
• Typical GPCRs
• 5 distinct subtypes -
25
M5 receptor (CNS)M4receptor
(CNS)
26
Agonists & Antagonists
27
Adrenergic transmission
28
Catecholamines
(catechol moiety – benzene
ring)
NE - principal transmitter of
most sympathetic
postganglionic fibers
DA - mammalian
extrapyramidal system,
metabolic precursor of
epinephrine & NA
Physiology of NA
transmission
29
NA synthesis
Metyrosin
e
Cu
chelating
agents,
Disulfiram
30
Methylphenidat
e
Atomoxetine
Reboxetine
Maprotiline
Tapentedol etc
Termination of action
31
Uptake
• 75% of NA released  reuptake into vesicles
• By NET (NE transporter)
Metabolic degradation
• 2 enzymes – MAO & COMT
• Catecholamines
MAO
Aldehydes
Aldehyde DH
Carboxylic acid
32
• COMT  methylation of 1 of the catechol OH
groups
• Final product: Vanillyl mandelic acid (VMA)
↓
Urine
• In adrenal tumors - ↑ catecholamine secretion
Urinary excretion of VMA is markedly ↑
- diagnostic test
Adrenergic Receptors
33
• 1948: Ahlquist – 2 kinds of adrenergic receptors
α & β
α: noradrenaline > adrenaline >
isoprenaline
β: isoprenaline > adrenaline >
noradrenaline
• α 𝟏 & α 𝟐 β 𝟏, β 𝟐 & β 𝟑
(α 𝟏𝐀, α 𝟏𝐁, α 𝟏𝐃 &
α 𝟐𝐀, α 𝟐𝐁, α 𝟐𝐂 )
Signal transduction
34
35
β 𝟏 -- Heart (positive
Inotropic &
Chronotropic
effects)
β 𝟐 -- Smooth
muscle
relaxation in
organs
β 𝟑 -- Adipose tissue
• α 𝟏 – CVS & lower
urinary tract.
α 𝟐 -- Neuronal.
inhibit
transmitter
release in
brain
& periphery
36
37
Agonists & Antagonists
38
Neuromodulation
39
Mediator acts to ↑ or ↓ the efficacy of synaptic
transmission without participating directly as a
transmitter.
 Pre-synaptic modulation
 Post-synaptic modulation
• Involves slower processes (taking seconds to days)
• Cascades of intracellular messengers
Presynaptic modulation
40
• Presynaptic terminals are themselves sensitive to
transmitters & to other substances produced
locally.
• 2 types –
1. Heterotropic interactions:
1 neurotransmitter affects the release of
another.
2. Homotropic interactions: (Autoinhibitory
feedback)
41
Heart & myenteric plexus –
Mutual presynaptic inhibition b/w Noradrenergic
Cholinergic nerve terminals
Eg. For heterotropic interaction –
42
• Autoinhibitory feedback (homotropic) acts
powerfully
at Noradrenergic nerve terminals
• Cholinergic & noradrenergic nerve terminals also
respond to other substances released as
co-transmitters (ATP & NPY), or
derived from other sources
(NO, prostaglandins, adenosine, dopamine,
5-hydroxytryptamine)
Post-synaptic modulation
43
• Neurons, smooth
muscle cells, cardiac
muscle cells etc
- excitability is altered
• Caused by changes in
Ca2+ &/or K+ channel
function mediated by
a 2nd messenger.
44
References -
45
1) The Pharmacological Basis of Therapeutics –
Goodman & Gilman
2) Basic & Clinical Pharmacology
– Katzung & Trevor
3) Rang & Dale’s Pharmacology

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Transmitters and Receptors of the Autonomic Nervous System

  • 1. 1 - Dr. Chandini Rao - Moderator: Dr. Padmaja Udaykuma TRANSMITTERS & RECEPTORS OF THE ANS
  • 2. Overview 2  Introduction  Transmitters of ANS  Cholinergic transmission & Receptors – Nicotinic Muscarinic  Adrenergic transmission & Receptors (α & β)  Neuromodulation – Pre-synaptic & Post-synaptic
  • 3. Introduction -  Autonomic nervous system (Visceral/Involuntary nervous sytem) - Widely distributed - Regulates autonomic functions (without conscious control) - Nerves, ganglia, and plexuses  heart, blood vessels, glands, visceral organs & smooth muscle in various tissues. 3
  • 4. 4  Comprises of 3 divisions – 1. Sympathetic nervous system (Thoraco- lumbar outflow) 2. Parasympathetic nervous system (Cranio- sacral outflow) 3. Enteric nervous system
  • 6. 6 Physiology of ANS • ANS controls –  Smooth muscle (visceral & vascular),  Exocrine secretions,  Rate & force of heart contraction,  Metabolic processes (e.g. glucose utilisation). • SNS & PNS have opposing actions in some situations (e.g. control of heart rate, GI smooth muscles), but not in others (e.g. salivary glands, ciliary muscle).
  • 7. 7 • Sympathetic activity ↑ in stress (‘fight or flight’ response) Parasympathetic activity – satiation & repose. • ENS (‘2nd brain’) – - Intramural (Myenteric) & submucosal plexus - receives inputs from sympathetic & parasympathetic systems - can act on its own to control motor & secretory functions of the intestine.
  • 8. Transmitters of ANS 8 • The principal transmitters are  Acetylcholine (Ach)  Noradrenaline (NA) • Others – Adrenaline, Dopamine, Isoprenaline
  • 9. History - 9 • After 20th C: Lewandowsky and Langley – similarity between effects of injection of extracts of adrenal gland & stimulation of Sympathetic nerves. • 1914: Dale - pharmacological properties of ACh & other choline esters (muscarinic & nicotinic actions) - “Parasympathomimetic”
  • 10. 10 • 1921: Loewi – Parasympathin (Vagusstoff or “vagus substance”) Cannon & Uridil – Sympathin (“Epinephrine-like substance”) • 1946: Von Euler – Norepinephrine-like substance (bovine splenic nerve)
  • 12. Co-transmission 12 • Neurons release > 1 transmitter  specific receptors both Pre- & Post-synaptic effects
  • 13. 13 Advantages: 1) Long-lasting effect : 1 NT removed/inactivated more slowly than the other Eg. Ach & GnRh in sympathetic ganglia 2) Differential release of I or more transmitters  Varying impulse patterns Eg. NA & NPY (NPY release @higher stimulation frequencies)
  • 14. Cholinergic transmission14  Synthesis, storage, and release of ACh :  Cholinergic synapses -  Skeletal neuromuscular junctions  Preganglionic Sympathetic and Parasympathetic terminals  Postganglionic Parasympathetic terminals  Postganglionic Sympathetic terminals  sweat glands in skin & in CNS.
  • 15. 15
  • 16. 16 Electrical events in transmission Ach ↓ Post-synaptic membrane (nicotinic) ↓ Inflow of Na+ ↓ Depolarization of post-synaptic membrane ↓ End-plate potential (EPP)/ Fast EPSP ↓ Action potential ↓ Contraction (muscle fibre)
  • 17. Main mechanisms of Cholinergic blockade 17  Inhibition of choline uptake  Inhibition of ACh release  Blockade of postsynaptic receptors or ion channels  Persistent postsynaptic depolarisation (Depolarization block)
  • 18. Depolarization block 18 • Due to persistent activation of nAChRs ↓ ↓ in electrical excitability of post-synaptic cell • Voltage sensitive Na+ channels become inactivated (i.e. refractory) Figure:
  • 19. 19 Application of Nicotine on Sympathetic ganglion ↓ Depolarization & AP discharge ↓ ↓ Discharge ↓ & transmission blocked ↓ ↓ Partial repolarization & return of electrical excitability But transmission still blocked. - Secondary, Non-depolarising block (Eg. Suxamethonium) d/t receptor desensitization
  • 20. Cholinergic Receptors 20 • 1914: Dale distinguished 2 types of activity in Ach - Muscarinic (Amanita muscaria) & Nicotinic (Nicotine) • Muscarinic actions – resemble effects of parasympathetic stimulation • Nicotinic effects – - Stimulation of all autonomic ganglia - Stimulation of voluntary muscles - Secretion of adrenaline from adrenal medulla
  • 21. Nicotinic Receptors 21 Structure • Pentameric structures • Ligand-gated ion channels. • 5 subunits – Receptor-channel complex - 17 members: α (10 types), β (4 types), γ, δ & ε (one of each).
  • 22. 22
  • 24. Muscarinic Receptors 24 • Typical GPCRs • 5 distinct subtypes -
  • 26. 26
  • 28. Adrenergic transmission 28 Catecholamines (catechol moiety – benzene ring) NE - principal transmitter of most sympathetic postganglionic fibers DA - mammalian extrapyramidal system, metabolic precursor of epinephrine & NA
  • 29. Physiology of NA transmission 29 NA synthesis Metyrosin e Cu chelating agents, Disulfiram
  • 31. Termination of action 31 Uptake • 75% of NA released  reuptake into vesicles • By NET (NE transporter) Metabolic degradation • 2 enzymes – MAO & COMT • Catecholamines MAO Aldehydes Aldehyde DH Carboxylic acid
  • 32. 32 • COMT  methylation of 1 of the catechol OH groups • Final product: Vanillyl mandelic acid (VMA) ↓ Urine • In adrenal tumors - ↑ catecholamine secretion Urinary excretion of VMA is markedly ↑ - diagnostic test
  • 33. Adrenergic Receptors 33 • 1948: Ahlquist – 2 kinds of adrenergic receptors α & β α: noradrenaline > adrenaline > isoprenaline β: isoprenaline > adrenaline > noradrenaline • α 𝟏 & α 𝟐 β 𝟏, β 𝟐 & β 𝟑 (α 𝟏𝐀, α 𝟏𝐁, α 𝟏𝐃 & α 𝟐𝐀, α 𝟐𝐁, α 𝟐𝐂 )
  • 35. 35 β 𝟏 -- Heart (positive Inotropic & Chronotropic effects) β 𝟐 -- Smooth muscle relaxation in organs β 𝟑 -- Adipose tissue • α 𝟏 – CVS & lower urinary tract. α 𝟐 -- Neuronal. inhibit transmitter release in brain & periphery
  • 36. 36
  • 37. 37
  • 39. Neuromodulation 39 Mediator acts to ↑ or ↓ the efficacy of synaptic transmission without participating directly as a transmitter.  Pre-synaptic modulation  Post-synaptic modulation • Involves slower processes (taking seconds to days) • Cascades of intracellular messengers
  • 40. Presynaptic modulation 40 • Presynaptic terminals are themselves sensitive to transmitters & to other substances produced locally. • 2 types – 1. Heterotropic interactions: 1 neurotransmitter affects the release of another. 2. Homotropic interactions: (Autoinhibitory feedback)
  • 41. 41 Heart & myenteric plexus – Mutual presynaptic inhibition b/w Noradrenergic Cholinergic nerve terminals Eg. For heterotropic interaction –
  • 42. 42 • Autoinhibitory feedback (homotropic) acts powerfully at Noradrenergic nerve terminals • Cholinergic & noradrenergic nerve terminals also respond to other substances released as co-transmitters (ATP & NPY), or derived from other sources (NO, prostaglandins, adenosine, dopamine, 5-hydroxytryptamine)
  • 43. Post-synaptic modulation 43 • Neurons, smooth muscle cells, cardiac muscle cells etc - excitability is altered • Caused by changes in Ca2+ &/or K+ channel function mediated by a 2nd messenger.
  • 44. 44
  • 45. References - 45 1) The Pharmacological Basis of Therapeutics – Goodman & Gilman 2) Basic & Clinical Pharmacology – Katzung & Trevor 3) Rang & Dale’s Pharmacology

Editor's Notes

  1. The autonomic nervous system, also called the visceral, vegetative,orinvoluntary nervous system,is distributed widely throughout the body and regulates autonomic functions that occur without conscious control. In the periphery, it consists of nerves, ganglia, and plexuses that innervate the heart, blood vessels, glands, other visceral organs, and smooth muscle in various tissues.  
  2.  The autonomic nervous system comprises three divisions:  the sympathetic or thoracolumbar outflow and (2) the parasympathetic or craniosacral outflow. (3) enteric nervous system
  3. The basic (two-neuron) pattern of the sympathetic and  parasympathetic systems consists of a preganglionic  neuron with a cell body in the central nervous system  (CNS) and a postganglionic neuron with a cell body in  an autonomic ganglion.
  4. Physiology of ans  The autonomic system controls smooth muscle (visceral  and vascular), exocrine (and some endocrine)  secretions, rate and force of the heart, and certain  metabolic processes (e.g. glucose utilisation). • Sympathetic and parasympathetic systems have  opposing actions in some situations (e.g. control of  heart rate, gastrointestinal smooth muscle), but not in  others (e.g. salivary glands, ciliary muscle). •
  5.  Sympathetic activity increases in stress (‘fight or flight’  response), whereas parasympathetic activity  predominates during satiation and repose.   The enteric nervous system consists of neurons lying in  the intramural plexuses of the gastrointestinal tract.(myenteric plexus) & submucosal plexus. It  receives inputs from sympathetic and parasympathetic  systems, but can act on its own to control the motor  and secretory functions of the intestine.
  6. Transmitters of ans The principal transmitters are acetylcholine (ACh) and  noradrenaline. All preganglionic autonomic fibres leaving the central nervous  system release acetylcholine, which acts mainly on nicotinic receptors All postganglionic parasympathetic fibres release  acetylcholine, which acts on muscarinic receptors. All postganglionic sympathetic fibres (with one  important exception) release noradrenaline, which may  act on either α- or β-adrenoceptors (see Ch. 14). The  exception is the sympathetic innervation of sweat  glands, where transmission is due to acetylcholine  acting on muscarinic receptors. Some postganglionic parasympathetic nerves use nitric oxide (NO) as a neurotransmitter; nerves that release NO are referred to as nitrergic The terms cholinergic and adrenergic were proposed originally by Dale to describe neurons that liberate ACh or norepinephrine, respectively.
  7. History – The earliest concrete proposal of a neurohumoral mechanism was made shortly after the turn of the twentieth century. Lewandowsky and Langley independently noted the similarity between the effects of injection of extracts of the adrenal gland and stimulation of s ympathetic nerves. In 1914, Dale investigated the pharmacological properties of ACh and other choline esters and distinguished its nicotine-like and muscarine-like actions. drug reproduced the responses to stimulation of parasympathetic nerves, he introduced the term parasympathomimetic to characterize its effects
  8. The studies of Loewi, begun in 1921, provided the first direct evidence for the chemical mediation of nerve impulses by the release of specific chemical agents Loewi referred to this chemical substance as Vagusstoff(“vagus substance,” “parasympathin”); subsequently… identify it as ACh. In the same year as Loewi’s discovery, Cannon and Uridil reported that stimulation of the sympathetic hepatic nerves resulted in the release of an epinephrine-like substance that increased blood pressure and heart rate. Cannon called this substance “sympathin.” “sympathin” closely resembled epinephrine, In 1946, von Euler found that the sympathomimetic substance in highly purified extracts of bovine splenic nerve resembled norepinephrine by all criteria used
  9. As mentioned above, acetylcholine or noradrenaline are  not the only autonomic transmitters. It has been known for many years that autonomic effector tissues (eg, gut, airways, bladder) contain nerve fibers that do not show the histochemical characteristics of either cholinergic or adrenergic fibers. (it was noticed that autonomic transmission in many organs  could not be completely blocked by drugs that abolish  responses to these transmitters)  non-adrenergic non-cholinergic (NANC) transmission  was coined Although peptides are the most common transmitter substances found in these nerve endings, other substances, eg, nitric oxide synthase and purines, are also present in many nerve terminals (Table 6–1). Capsaicin, a neurotoxin derived from chili peppers, can cause the release of transmitter (especially substance P) from such neurons and, if given in high doses, destruction of the neuron. The enteric system in the gut wall (Figure 6–2) is the most extensively studied system containing NANC neurons
  10. Cotransmission – It is probably the rule rather than the exception that neurons  release more than one transmitter or modulator (see Kupfermann, 1991; Lundberg, 1996), each of which interacts  with specific receptors and produces effects, often both  pre- and postsynaptically. 
  11. Adv – 1) The  possible  advantages include the following. • One constituent of the cocktail (e.g. a peptide) may be  removed or inactivated more slowly than the other  (e.g. a monoamine),  and produce longer-lasting. This appears to be the case, for example, with  acetylcholine and gonadotrophin-releasing hormone in  sympathetic ganglia. 2) transmitters released may vary  under different conditions. At sympathetic nerve  terminals, for example, where noradrenaline and NPY  are stored in separate vesicles, NPY is preferentially  released at high stimulation frequencies, so that  differential release of one or other mediator may result  from varying impulse patterns. 
  12. The synthesis, storage, and release of ACh follow a similar life cycle in all cholinergic synapses, including those at skeletal neuromuscular junctions, preganglionic sympathetic and parasympathetic terminals, postganglionic parasympathetic varicosities, postganglionic sympathetic varicosities innervating sweat glands in the skin, and in the CNS. Two enzymes, choline acetyltransferase and AChE, are involved in ACh synthesis and degradation, respectively.
  13. Figure 8–4. A cholinergic neuroeffector junction showing features of the synthesis, storage, and release of acetylcholine (ACh) and receptors on which ACh acts. The synthesis of ACh in the varicosity depends on the uptake of choline via a sodium-dependent memb Tr. This uptake can be blocked by grp of research drugs hemicholinium. Choline and the acetyl moiety of acetyl coenzyme A, derived from mitochondria, form ACh, a process catalyzed by the enzyme choline acetyl transferase (ChAT). ACh is transported into the storage vesicle by another Tr – vesicle-assoc Tr (VAT) that can be inhibited by vesamicol. ACh is stored in vesicles along with other potential cotransmitters (Co-T) such as ATP and VIP at certain neuroeffector junctions. Vesicles are concentrated on the inner surface of the nerve terminal facing the synapse through the interaction of so-called SNARE proteins on the vesicle (a subgroup of VAMPs called v-SNAREs, especially synaptobrevin). Release of ACh and the Co-T occurs on depolarization of the varicosity, which allows the entry of Ca2+ through voltage-dependent Ca2+ channels. [Ca2+] Calcium interacts with the VAMP synaptotagmin on the vesicle membrane & promotes fusion of the vesicular membrane with the cell membrane, and exocytosis of the transmitters occurs. This fusion process involves the interaction of specialized proteins associated with the vesicular membrane (VAMPs, vesicle-associated membrane proteins) and the membrane of the varicosity (SNAPs, synaptosome-associated proteins).  one presynaptic nerve  impulse releases 100–500 vesicles. The exocytotic release of ACh can be blocked by botulinum toxin. Once released, ACh can interact with the muscarinic receptors (M), which are GPCRs, or nicotinic receptors (N), which are ligand-gated ion channels, to produce the characteristic response of the effector. ACh also can act on presynaptic mAChRs or nAChRs to modify its own release. The action of ACh is terminated by metabolism to choline and acetate by acetylcholinesterase (AChE), which is associated with synaptic membranes. Most cholinergic synapses are richly supplied with acetylcholinesterase; the half-life of acetylcholine molecules in the synapse is therefore very short (a fraction of a second).
  14. ELECTRICAL EVENTS IN TRANSMISSION AT FAST CHOLINERGIC SYNAPSES Acetylcholine, acting on the postsynaptic membrane of a  nicotinic (neuromuscular or ganglionic) synapse, causes a  large increase in its permeability to cations, particularly to  Na+ and K+, and to a lesser extent Ca2+. The resulting inflow  of  Na+  depolarises  the  postsynaptic  membrane.  This  transmitter-mediated depolarisation is called an endplate potential (epp) in a skeletal muscle fibre, or a fast excitatory postsynaptic potential (fast epsp) at the ganglionic synapse. In  a muscle fibre, amplitude  reaches the threshold for excitation, an action potential is  initiated, which propagates to the rest of the fibre and  evokes a contraction.
  15. Main mechanisms of pharmacological block: inhibition  of choline uptake, inhibition of ACh release, block of  postsynaptic receptors or ion channels, persistent  postsynaptic depolarisation
  16. Depolarization block –  Depolarisation block occurs at cholinergic synapses when the excitatory  nAChRs  are  persistently  activated,  and  it  results  from  a  decrease in the electrical excitability of the postsynaptic cell. This is  shown in Figure 13.4. Application of nicotine to a sympathetic ganglion causes a depolarisation of the cell, which at first initiates action  potential discharge. After a few seconds, this discharge ceases and  transmission is blocked. The loss of electrical excitability at this time  is shown by the fact that antidromic stimuli also fail to produce an  action potential. The main reason for the loss of electrical excitability  during a period of maintained depolarisation is that the voltage-sensitive sodium channels (see Ch. 4) become inactivated (i.e. refractory) and no longer able to open in response to a brief depolarising  stimulus
  17. . A second type of effect is also seen in the experiment shown in Figure  13.4. After nicotine has acted for several minutes, the cell partially  repolarises and its electrical excitability returns but, despite this, transmission remains blocked. This type of secondary, non-depolarising block occurs also at the neuromuscular junction if repeated doses of the  depolarising drug suxamethonium4 (see below) are used. The main  factor responsible for the secondary block (known clinically as phase II block) appears to be receptor desensitisation
  18. Cholinergic Rs Analysing the pharmacological actions of ACh in 1914,  Dale distinguished two types of activity, which he designated as muscarinic and nicotinic because they mimicked,  respectively, the effects of injecting muscarine, the active  principle of the poisonous mushroom Amanita muscaria,  and of injecting nicotine.  Muscarinic actions closely resemble the effects of parasympathetic stimulation, as shown in  Table 12.1. After the muscarinic effects have been blocked  by  atropine,  larger  doses  of  ACh  produce  nicotine-like  effects, which include: • stimulation of all autonomic ganglia • stimulation of voluntary muscle • secretion of adrenaline from the adrenal medulla
  19. 2 major classes of Ach R – N & M Nicotinic Rs (pic) All nAChRs are pentameric structures that function as ligandgated  ion  channels  (see  Ch.  3).  The  five  subunits  that  form  the  receptor–channel complex are similar in structure, and so far 17 different members of the family have been identified and cloned, designated α (10 types), β (4 types), γ, δ and ε (one of each).  nAChR subtypes generally contain both α and β subunits,  The two  binding sites for ACh (both of which need to be occupied to cause  the channel to open) reside at the interface between the extracellular  domain of each of the α subunits and its neighbour.
  20. a  This table shows only the main subtypes expressed in mammalian tissues. Several other subtypes are expressed in selected brain regions,  and also in the peripheral nervous system and in non-neuronal tissues.
  21. Muscarinic Rs Muscarinic receptors (mAChRs) are typical G-protein-coupled receptors. In mammals, five distinct subtypes of muscarinic ACh receptors (mAChRs) have been identified,
  22. The M1, M3, and M5 subtypes couple through the pertussis toxin–insensitive Gq/11 responsible for stimulation of phospholipase C (PLC) activity. The immediate result is hydrolysis of membrane phosphatidylinositol 4,5 diphosphate to form inositol polyphosphates. Inositol trisphosphate (IP3) causes release of intracellular Ca2+ from the endoplasmic reticulum, with activation of Ca2+-dependent phenomena such as contraction of smooth muscle and secretion (Chapter 3). The second product of the PLC reaction, diacylglycerol, activates PKC (in conjunction with Ca2+ and phosphatidylserine). This arm of the pathway plays a role in the phosphorylation of numerous proteins, leading to various physiological responses. Activation of M1, M3, and M5 receptors can also cause the activation of phospholipase A2, leading to the release of arachidonic acid and consequent eicosanoid synthesis, resulting in autocrine/paracrine stimulation of adenylyl cyclase and an increase in cyclic AMP. Thus they are excitatory. Stimulation of M2 and M4 cholinergic receptors leads to interaction with other G proteins, (e.g., Giand Go) with a resulting inhibition of adenylyl cyclase, leading to a decrease in cyclic AMP, activation of inwardly rectifying K+ channels, and inhibition of voltage-gated Ca2+ channels (van Koppen and Kaiser, 2003). The functional consequences of these effects are hyperpolarization and inhibition of excitable membranes. These are most clear in myocardium, where inhibition of adenylyl cyclase and activation of K+ conductances account for the negative inotropic and chronotropic effects of ACh.
  23. * RnD
  24. Under this general heading are norepinephrine (NE), the principal transmitter of most sympathetic postganglionic fibers and of certain tracts in the CNS; dopamine (DA), the predominant transmitter of the mammalian extrapyramidal system and of several mesocortical and mesolimbic neuronal pathways;  the metabolic precursor of noradrenaline  and adrenaline and epinephrine, the major hormone of the adrenal medulla. Collectively, these three amines are called catecholamines. Catecholamines  are  compounds  containing  a  catechol  moiety (a benzene ring with two adjacent hydroxyl groups)  and an amine side chain
  25. Physiology of NA transmission NA synthesis –  The metabolic precursor for noradrenaline is L-tyrosine, an aromatic amino acid that is present in  the body fluids and is taken up by adrenergic neurons. Tyrosine hydroxylase, a cytosolic enzyme that catalyses the  conversion  of  tyrosine  to  dihydroxyphenylalanine  (dopa),  is  found  only  in  catecholamine-containing  cells. The hydroxylation of tyrosine by tyrosine hydroxylase (TH) generally is regarded as the rate-limiting step in the biosynthesis of catecholamines.  Tyrosine hydroxylase is inhibited by the end  product of the biosynthe.tic pathway, noradrenaline…regulation of the rate of synthesis. The tyrosine analogue α-methyltyrosine (metyrosine)  strongly inhibits tyrosine hydroxylase and may be used experimentally  to block noradrenaline synthesis. The next step, conversion of dopa to dopamine, is catalysed by dopa decarboxylase, a cytosolic enzyme that is by  no means confined to catecholamine-synthesising cells. Dopamine-β-hydroxylase  (DBH)  is  also  a  relatively  non-specific enzyme, but is restricted to catecholaminesynthesising cells. It is located in synaptic vesicles, Many  drugs  inhibit  DBH,  including  copper-chelating  agents and disulfiram. A rare genetic disorder,  DBH  deficiency,  causes  failure  of  noradrenaline  synthesis resulting in severe orthostatic hypotension. Phenylethanolamine N-methyl transferase (PNMT) catalyses the N-methylation of noradrenaline to adrenaline. The  main location of this enzyme is in the adrenal medulla
  26. An adrenergic neuroeffector junction showing features of the synthesis, storage, release, and receptors for norepinephrine (NE), the cotransmitters neuropeptide Y (NPY), and ATP. Tyrosine is transported into the varicosity and is converted to DOPA by tyrosine hydroxylase (TH) and DOPA to dopamine (DA) by the action of aromatic L-amino acid decarboxylase (AAADC). Dopamine is taken up into the vesicles of the varicosity by a transporter, VMAT2, that can be blocked by reserpine. Dopamine is converted to NE within the vesicle via the action of dopamine-β-hydroxylase (DβH). NE is stored in vesicles along with other cotransmitters, NPY and ATP. Release of the transmitters occurs upon depolarization of the varicosity, which allows entry of Ca2+ through voltage-dependent Ca2+ channels. Elevated levels of Ca2+ promote the fusion of the vesicular membrane with the membrane of the varicosity, with subsequent exocytosis of transmitters. This fusion process involves the interaction of specialized proteins associated with the vesicular membrane (VAMPs, vesicle-associated membrane proteins) and the membrane of the varicosity (SNAPs, synaptosome-associated proteins). Once in the synapse, NE can interact with α and β adrenergic receptors to produce the characteristic response of the effector. The adrenergic receptors are GPCRs. α and β Receptors also can be located presynaptically where NE can either diminish (α2), or facilitate (β) its own release and that of the cotransmitters. The principal mechanism by which NE is cleared from the synapse is via a cocaine-sensitive neuronal uptake transporter, NET. Once transported into the cytosol, NE can be re-stored in the vesicle or metabolized by monoamine oxidase (MAO). NPY produces its effects by activating NPY receptors, ATP produces its effects by activating P2X receptors or P2Y receptors.
  27. Uptake About 75% of the noradrenaline released by sympathetic  neurons is recaptured and repackaged into vesicles. This  serves to cut short the action of the released noradrenaline.  Neuronal uptake is performed by the  plasma  membrane  noradrenaline  transporter  (generally  known  as  NET,  the  norepinephrine transporter),  which  belongs  to  the  family  of  neurotransmitter  transporter    proteins  (NET,  DAT,  SERT,  etc.)  Metabolic degradation Endogenous and exogenous catecholamines are metabolised mainly by two enzymes: monoamine oxidase (MAO)  and catechol-O-methyl transferase (COMT). MAO  converts    catecholamines to their corresponding aldehydes,3 which,  in the periphery, are rapidly metabolised by aldehyde dehydrogenase  to  the  corresponding  carboxylic  acid.
  28. The second major pathway for catecholamine metabolism involves methylation of one of the catechol hydroxyl  groups by COMT to give a methoxy derivative.   The final  product  formed  by  the  sequential  action  of  MAO  and  COMT  is  3-methoxy-4-hydroxyphenylglycol  (MHPG  but most  of it is converted to vanillylmandelic acid (VMA;) and excreted in the urine in this form.4 In patients with  tumours of chromaffin tissue that secrete these amines (a  rare cause of high blood pressure), the urinary excretion of  VMA is markedly increased, this being used as a diagnostic  test for this condition.
  29. Ahlquist found in 1948  postulated the existence of two kinds of receptor, α and  β, defined in terms of agonist potencies as follows: α: noradrenaline > adrenaline > isoprenaline β: isoprenaline > adrenaline > noradrenaline also  suggested  the  existence of further subdivisions of both α and β receptors.  Subsequently it has emerged that  there are two α-receptor subtypes (α1 and α2), each comprising three further subclasses (α1A, α1B, α1D and α2A, α2B,  α2C) and three β-receptor subtypes (β1, β2 and β3)—altogether  nine distinct subtypes—all of which are typical G-proteincoupled  receptors 
  30. Each of the three main receptor subtypes is associated  with a specific second messenger system (Table 14.1). Thus  α1 receptors are coupled to phospholipase C and produce  their effects mainly by the release of intracellular Ca2+; α2  receptors are negatively coupled to adenylyl cyclase, and  reduce cAMP formation. and all three types of β receptor act by stimulation of adenylyl cyclase
  31. Evidence  from  specific    agonists and antagonists, as well as studies on receptor  knockout mice (Philipp & Hein, 2004), has shown that α1  receptors are particularly important in the cardiovascular  system and lower urinary tract, while α2 receptors are predominantly neuronal, acting to inhibit transmitter release  both in the brain and at autonomic nerve terminals in the  periphery. The distinction between β1 and β2 receptors is an important one, for β1 receptors are found mainly in the heart,  where they are responsible for the positive inotropic and  chronotropic  effects  of  catecholamines  (see  Ch.  21).  β2  receptors, on the other hand, are responsible for causing smooth muscle relaxation in many organs. The latter is  often a useful therapeutic effect, while the former is more  often  harmful; … All 3 B Rs are present in both white & brown adipose tissue
  32. β Receptors regulate numerous functional responses, including heart rate and contractility, smooth muscle relaxation, and multiple metabolic events in numerous tissues including adipose and hepatic cells and skeletal muscle
  33. Compounds such as clonidine are more potent agonists at α 2 than at α 1 receptors; by contrast, phenylephrine and methoxamine selectively activate postsynaptic alpha1 Rs
  34. The  pre-  and  postsynaptic  effects  described  above  are    often described as neuromodulation, because the mediator  acts to increase or decrease the efficacy of synaptic transmission  without  participating  directly  as  a  transmitter.  Neuromodulation1  is  loosely  defined  but,  in  general,  involves slower processes (taking seconds to days) than  neurotransmission  (which  occurs  in  milliseconds),  and  operates  through  cascades  of  intracellular  messengers
  35. The  presynaptic  terminals  that  synthesise  and  release  transmitter in response to electrical activity in the nerve  fibre  are  often  themselves  sensitive  to  transmitter  substances  and  to  other  substances  that  may  be  produced  locally in tissues (for review see Boehm & Kubista, 2002).  Such  presynaptic  effects  most  commonly  act  to  inhibit  transmitter release, 2 types – heterotropic interactions,  where one neurotransmitter affects the release of another.  Eg. In heart & myenteric plexus where Noradrenergic and cholinergic nerve terminals often lie  close together - mutual presynaptic inhibition exists (noradrenaline inhibits acetylcholine release &  and acetylcholine also inhibits noradrenaline  release.) Homotropic interactions also occur, where the transmitter, by  binding to presynaptic autoreceptors, affects the nerve terminals from which it is being released. This type of autoinhibitory feedback  acts  powerfully  at  noradrenergic  nerve  terminals Cholinergic and noradrenergic nerve terminals respond  not only to acetylcholine and noradrenaline, as described  above, but also to other substances that are released as  co-transmitters, such as ATP and neuropeptide Y (NPY),  or derived from other sources, including nitric oxide, prostaglandins,  adenosine,  dopamine,  5-hydroxytryptamine,  GABA,  opioid  peptides, 
  36. Chemical mediators often act on postsynaptic structures,  including neurons, smooth muscle cells, cardiac muscle  cells, etc., in such a way that their excitability or spontaneous firing pattern is altered. In many cases, as with presynaptic modulation, this is caused by changes in calcium  and/or potassium channel function mediated by a second  messenger. Few eg –  The slow excitatory effect produced by various  mediators, including acetylcholine and peptides such  as substance P (see Ch. 19), on many peripheral and  central neurons results mainly from a decrease in K+  permeability.   Neuropeptide Y (NPY), which is released as a  co-transmitter with noradrenaline at many sympathetic  nerve endings and acts on smooth muscle cells to  enhance the vasoconstrictor effect of noradrenaline,  thus greatly facilitating transmission