lecture on nmj

1. Neuromuscular
Physiology
Prof. Vajira Weerasinghe
Senior Professor of Physiology
Faculty of Medicine
University of Peradeniya

2. Nerve conduction
• Electrochemical basis
• concentration gradient, membrane permeability
ionic channels
• Resting membrane potential (RMP)
• K+ efflux, Na/K pump
• Leaky channels
• Action potential (AP)
• depolarisation, repolarisation
• Voltage-gated channels
• Propagation of AP
• Local current flow

3. Excitable tissues
• Excitable tissues have more
negative RMP
( - 70 mV to - 90 mV)
excitable Non-excitable
Red cell
GIT
neuron
muscle
• Non-excitable tissues
have less negative RMP
-53 mV epithelial cells
-8.4 mV RBC
-20 to -30 mV fibroblasts
-58 mV adipocytes

4. Factors contributing to RMP
• One of the main factors is K+ efflux
• (Nernst Equilibrium Potential: -94mV)
• Contribution of Na influx is little
• (Nernst Equilibrium Potential: +61mV)
• Na/K pump causes more negativity inside the
membrane
•
Negatively charged protein remaining inside due to
impermeability contributes to the negativity
• Net result: -70 mV inside

5. Ionic channels
• Leaky channels (leak channels)
– Allow free flow of ions
– K+ channels (large number)
– Na+ channels (fewer in number)
– Therefore membrane is more permeable to K+

6. Na/K pump
• Active transport system for Na-K exchange using
energy
• It is an electrogenic pump since 3 Na efflux coupled
with 2 K influx
• Net effect of causing negative charge inside the
membrane
3 Na+
2 K+
ATP ADP

7. -70
+35
RMP
Hyperpolarisation

8. Physiological basis of AP
• When the threshold level is reached
– Voltage-gated Na channels open up
– Since Na conc outside is more than the inside
– Na influx will occur
– Positive ion coming inside increases the positivity of the membrane potential and
causes depolarisation
– When it reaches +35, Na channels closes
– Then Voltage-gated K channels open up
– K efflux occurs
– Positive ion leaving the inside causes more negativity inside the membrane
– Repolarisation occurs
• Na/K pump restores Na and K conc slowly
– By pumping 3 Na ions outward and 2 K ions inward

9. • At rest: the activation gate is closed
• At threshold level: activation gate opens
– Na influx will occur
– Na permeability increases to 500 fold
• when reaching +35, inactivation gate closes
– Na influx stops
• Inactivation gate will not reopen until resting membrane potential is reached
outside
inside
outside
inside
-70 Threshold level +35
Na+ Na+
outside
inside
Na+
m gate
h gate

10. – At rest: K channel is closed
– At +35
• K channel open up slowly
• This slow activation causes K efflux
– After reaching the resting still slow K channels may
remain open: causing further hyperpolarisation
outside
inside
outside
inside
-70 At +35
K+ K+
n gate

11. Refractory Period
• Absolute refractory
period
– During this period nerve
membrane cannot be
excited again
– Because of the closure
of inactivation gate
-70
+30
outside
inside

12. Refractory Period
• Relative refractory
period
– During this period nerve
membrane can be
excited by supra
threshold stimuli
– At the end of
repolarisation phase
inactivation gate opens
and activation gate
closes
– This can be opened by
greater stimuli strength
-70
+30
outside
inside

13. Propagation of AP
• When one area is depolarised
• A potential difference exists between that site
and the adjacent membrane
• A local current flow is initiated
• Local circuit is completed by extra cellular fluid

14. Propagation of AP
• This local current flow will cause opening of
voltage-gated Na channel in the adjacent
membrane
• Na influx will occur
• Membrane is deloparised

15. Propagation of AP
• Then the previous area become repolarised
• This process continue to work
• Resulting in propagation of AP

16. Propagation of AP

17. Propagation of AP

18. Propagation of AP

19. Propagation of AP

20. AP propagation along myelinated
nerves
• Na channels are conc around nodes
• Therefore depolarisation mainly occurs at
nodes

21. AP propagation along myelinated
nerves
• Local current will flow one node to another
• Thus propagation of A.P. is faster. Conduction
through myelinated fibres also faster.
• Known as Saltatory Conduction

25. Membrane stabilisers
• Membrane stabilisers (these decrease excitability)
• Increased serum Ca++
– Hypocalcaemia causes membrane instability and spontaneous activation
of nerve membrane
– Reduced Ca level facilitates Na entry
– Spontaneous activation
• Decreased serum K+
• Local anaesthetics
• Acidosis
• Hypoxia
• Membrane destabilisers (these increase excitability)
• Decreased serum Ca++
• Increased serum K+
• Alkalosis
• Caffeine
• strychnine

26. NMJ function
• Pre-synaptic membrane
• Ca channels
• Acetycholine release
• Postsynaptic membrane
• Acetylcholine receptors
• Ligand-gated channels
• Synaptic cleft
• cholinesterase

27. Synapse
• Synapse is a gap between two neurons
• More commonly chemical
• Rarely they could be electrical (with gap junctions)
– which are pores (as shown in the electron micrograph)
constructed of connexin proteins

28. Typical synapse
• Presynaptic membrane
• Synaptic Cleft
• Postsynaptic membrane

29. Basic structure
• Presynaptic membrane
– Contains neurotransmitter
vesicles
• Synaptic cleft
• Postsynaptic membrane
– Contains receptors for the
neurotransmitter

30. Different types of synapses

31. Types of synapses
• Axo-dendritic synapse
• Most common
• Axon terminal branch (presynaptic
element) synapses on a dendrite
• Axo-somatic synapse
• Axon terminal branch synapses on
a soma (cell body)
• Axo-axonic synapse
• Axon terminal branch synapses on
another axon terminal branch (for
presynaptic inhibition)
• Dendro-dendritic synapse
• Dendrite synapsing on another
dendrite (localised effect)

32. Synaptic ultrastructure
• The presynaptic enlargement
(bouton, varicosity, or end
plate) contains synaptic vesicles
(20 nm diameter)
• Pre- and postsynaptic plasma
membranes are separated by a
synaptic cleft (20 nm wide)
• The cleft contains glycoprotein
linking material and is
surrounded by glial cell
processes
Synaptic
proteins

33. Presynaptic events
• Presynaptic membrane contains voltage gated
calcium channels
• Membrane depolarisation opens up Ca2+ channels
• Ca2+ influx will occur
• Neurotransmitter molecules are released in
proportion to the amount of Ca2+ influx, in turn
proportional to the amount of presynaptic
membrane depolarization

34. Details of presynaptic events
• in the resting state, the presynaptic membrane has resting membrane potential
• when an action potential arrives at the end of the axon
• the adjacent presynaptic membrane is depolarised
• voltage-gated Ca2+ channels open and allow Ca2+ influx (driven by [Ca2+] gradient)
• elevated [Ca2+] activates synaptic proteins
(SNARE proteins: Synaptobrevin, Syntaxin, SNAP 25) and triggers vesicle
mobilization and docking with the plasma membrane
• vesicles fuse with presynaptic plasma membrane and release neurotransmitter
molecules (about 5,000 per vesicle) by exocytosis
• neurotransmitter molecules diffuse across the cleft & bind with postsynaptic
receptor proteins
• neurotransmitter molecules are eliminated from synaptic clefts via pinocytotic
uptake by presynaptic or glial processes and/or via enzymatic degradation at the
postsynaptic membrane
• molecules are recycled
• subsequently, presynaptic plasma membrane repolarises

36. Neurotransmitter receptors
• Once released, the neurotransmitter molecules diffuse across
the synaptic cleft
• When they “arrive” at the postsynaptic membrane, they bind to
neurotransmitter receptors
• Two main classes of receptors:
– Ionotropic receptors
– Metabotropic receptors

37. IONOTROPIC RECEPTORS
• Neurotransmitter molecule binds to the receptor
• Cause a ligand-gated ion channel to open
• Become permeable to either sodium, potassium or chloride
• Accordingly depolarisation (excitation) or hyperpolarisation (inhibition)
• Quick action, short lasting

38. • Neurotransmitter attaches to G-protein-coupled receptors (GPCR) which has slower, longer-lasting and
diverse postsynaptic effects
• They can have effects that change an entire cell’s metabolism
• Activates enzymes that trigger internal metabolic change inside the cell
• Activate cAMP
• Activate cellular genes: forms more receptor proteins
• Activate protein kinase: decrease the number of proteins
• Sometimes open up ion channels also
Metabotropic Receptors

39. • Excitation
– 1. Na+ influx cause accumulation of positive charges
causing excitation (eg. Nicotinic Ach receptor)
– 2. Ca2+ influx
– 3. various internal changes to excite cell, increase
in excitatory receptors, decrease in inhibitory
receptors.

40. • Inhibition
– 1. K+ efflux (GABA B receptor)
– 2. Cl- influx (GABA A receptor)
– 3. activation of receptor enzymes to inhibit
metabolic functions or to increase inhibitory
receptors or decrease excitatory receptors

41. • Excitatory effects of neurotransmitters
– EPSP: excitatory post synaptic potential
• Inhibitory effects of neurotransmitters
– IPSP: inhibitory post synaptic potential

42. Postsynaptic activity
• Synaptic integration
– On average, each neuron in the brain receives about 10,000
synaptic connections from other neurons
– Many (but probably not all) of these connections may be
active at any given time
– Each neuron produces only one output
– One single input is usually not sufficient to trigger this output
– The neuron must integrate a large number of synaptic inputs
and “decide” whether to produce an output or not
– Constant interplay of excitatory and inhibitory activity on the
postsynaptic neuron produces a fluctuating membrane
potential that is the algebraic sum of the hyperpolarizing and
depolarizing activities
– Soma of the neuron thus acts as an integrator

44. Other synaptic activities
• Postsynaptic inhibition
– eg. GABA activates GABA A receptors on the postsynaptic
membrane and opens up Cl- channels and causes
hyperpolarisation and inhibition
• Presynaptic inhibition
– eg. GABA activates GABA B receptors on the presynaptic
membrane and through G proten activation opens up K+
channels and causes hyperpolarisation and inhibition
• Autoreceptors
– eg. Ach released from the presynaptic membrane activates
autoreceptors for Ach on the presynaptic membrane and
causes feedback inhibition
• Renshaw cell inhibition
– Spinal motor neuron activates a collalteral neuron which
secrete glycine or GABA and which inhibit activity of the
spinal motor neuron
• Retrograde signalling
– Neurotransmitter secreted from the postsynaptic
membrane act on the receptor on the presynaptic
membrane and through G protein activation causes
inhibition eg. endocannabinoids

45. Forms of Drug Action at the Synapse
• Ways to agonize
– Stimulate release
– Receptor binding
– Inhibition of reuptake
– Inhibition of deactivation
– Promote synthesis
• Ways antagonize
– Block release
– Receptor blocker
– Prevent synthesis
8.
Autoreceptors

46. Dendritic spine
• Small button like extensions like “door knobs”
found on the dendritic processes that contain
post-synaptic densities
• Axo-dendritic synapses terminates in these
• Dendritic spines are known to change shape, to
the extent of appearing and disappearing entirely
& is the basis of memory
• A mechanism underlying memory loss in
Alzheimer's disease involves a loss of dendritic
spines in hippocampal pyramidal cells
• Ca2+ channels, NMDA receptors are present in
these
• Long-term potentiation (LTP) at Hebbian synapses
in hippocampal region CA1 occurs involving NMDA
receptors in these sites

47. NEUROMUSCULAR JUNCTION
Presynaptic terminal (terminal knob,
boutons, end-feet or synaptic knobs)
 Terminal has synaptic vesicles and mitochondria
 Mitochondria (ATP) are present inside the presynaptic
terminal
Vesicles containing neurotransmitter (Ach)

48. Presynaptic terminal (terminal knob,
boutons, end-feet or synaptic knobs)
 Presynaptic membrane contain voltage-gated Ca2+ channels
 The quantity of neurotransmitter released is proportional to
the number of Ca2+ entering the terminal
 Ca2+ ions binds to the protein molecules on the inner surface
of the synaptic membrane called release sites
 Neurotransmitter binds to these sites and exocytosis occur

49. Ca2+ Ca2+

50. Synthesis of Ach
• Synthesised from choline and acetyl-coenzyme A (acetyl-coA) in the
terminal axoplasm of motor neurons
• Acetyl-coA is synthesised from pyruvate in the mitochondria in the axon
terminals
• Approximately 50% of the choline is extracted from extracellular fluid by a
sodium dependent active transport system
• Other 50% is from acetylcholine breakdown at the neuromuscular junction.
• Majority of the choline originates from the diet with hepatic synthesis only
accounting for a small proportion

51. • Postsynaptic membrane contain nicotinic
acetylcholine receptor
Ach
Na+
• This receptor contains several
sub units (2 alpha, beta, delta &
epsilon)
• Ach binds to alpha subunit
• Na+ channel opens up
• Na+ influx occurs
• End Plate Potential (EPP)
•This is a graded potential
•Once this reaches the threshold
level
•AP is generated at the
postsynaptic membrane
•This is an example of an ionotropic
receptor

52. IONOTROPIC RECEPTORS
• Neurotransmitter molecule (Ach) binds to the receptor (Ach receptor)
• Cause a ligand-gated ion channel (Na+) to open
• Become permeable to either sodium
• Accordingly depolarisation (excitation)
• Quick action, short lasting

53. Ach vesicle docking
• With the help of Ca entering the presynaptic terminal
• Docking of Ach vesicles occur
• Docking:
– Vesicles move toward & interact with membrane of
presynaptic terminal
• There are many proteins necessary for this purpose
• These are called SNARE proteins
• eg. Syntaxin, synaptobrevin etc

54. Muscle contraction
• Depolarisation of the muscle membrane
spreads through the muscle
• Causes muscle contraction
• Excitation - contraction coupling
– Excitation : electrical event
– Contraction : mechanical event

55. Ryanodine receptor (RyR)
• This is a receptor located in the sarcoplasmic
reticulum which provide calcium necessary for
muscle contraction
• Ryanodine receptor releases Ca2+ from
sarcoplasmic reticulum
• Ca2+ flows to the myoplasm in the vicinity of actin &
myosin
• These receptors are essential for excitation-
contraction coupling
• Ryanodine receptors are also known to be present
in the cardiac muscle and brain (hippocampus)
• Dysfunctional RyR-mediated Ca2+ handling has
been implicated in the pathogenesis of heart failure,
cardiac arrhythmias, skeletal myopathies, diabetes,
and neurodegenerative diseases.
• Cognitive dysfunction may be related to RyR
induced calcium release In Alzheimer’s and PTSD

56. • Ca++ binds to troponin
• Troponin shifts tropomyosin
• Myosin binding sites in actin filament
uncovered
• Myosin head binds with actin
• Cross bridges form
• Filaments slide with ATP being broken down
• Muscle shortens
• New ATP occupies myosin head
• Myosin head detaches
• Filaments slide back
• Cycling continues as long as Ca is available
Troponin
Actin
Myosin
Tropomyosin
ATP

57. • Relaxation
– This occurs when Ca++ is removed from myoplasm
by Ca++ pump located in the sarcoplasmic
reticulum
– When Ca++ conc is decreased
– Troponin returns to original state
– Trpomyosin covers myosin binding sites
– Cross-bridge cycling stops

58. Slow twitch fibre (type I fibre)
– Slow cross-bridge cycling
– slow rate of shortening (eg. soleus muscle in calf)
– high resistance to fatigue
– high myoglobin content
– high capillary density
– many mitochondria
– low glycolytic enzyme content
– They are red muscle fibres
– eg. Marathon runners

59. Fast twitch fibre (type II fibre)
– rapid cross-bridge cycling,
– rapid rate of shortening (eg. extra-
ocular muscles)
– low resistance to fatigue
– low myoglobin content
– low capillary density
– few mitochondria
– high glycolytic enzyme content
– fast twitch fibers use anaerobic
metabolism to create fuel, they are
much better at generating short bursts
of strength or speed than slow
muscles
– eg. sprinter

60. NMJ blocking
• Useful in general anaesthesia to facilitate inserting tubes
• Muscle paralysis is useful in performing surgery
• Commonly used to paralyze patients requiring intubation
whether in an emergency as a life-saving intervention or for a
scheduled surgery and procedure
• To assist with mechanical ventilation in patients who have
reduced lung compliance
• Indications for intubation during an emergency
– failure to maintain or protect the airway
– failure to adequately ventilate or oxygenate
– anticipation of a decline in clinical status

61. Earliest known NMJ blocker - Curare
• Curare has long been used in South America as
an extremely potent arrow poison
• Darts were tipped with curare and then
accurately fired through blowguns made of
bamboo
• Death for birds would take one to two minutes,
small mammals up to ten minutes, and large
mammals up to 20 minutes
• NMJ blocker used in patients is tubocurarine
• Atracurium is now used

62. Non-depolarising blocking agents
– eg.
• Curare
• Atracurium
• Rocuronium
• Vencuronium
– Competitive
– Act by competing with Ach for the Ach receptors
– Binds to Ach receptors and blocks
– Prevent Ach from attaching to its receptors
– No depolarisation
– Late onset, prolonged action
– 70–80% of receptors should be occupied to produce an effect
– To produce complete block, at least 92% of receptors must be occupied
– Ach can compete & the effect overcomes by an excess Ach
– Anticholinesterases can reverse the action

63. Depolarising blocking agents
– eg. Succinylcholine
– non-competitive, chemically act like Ach
– Bind to motor end plate and once depolarises
– Persistent depolarisation leads to a block
• Due to inactivation of Na channels
– Ach cannot compete with depolarising blockers
– There are two phases in the depolarising block
– Phase I block and Phase II block
– Phase I block (depolarisation block)
• After a depolarizing agent binds to the motor end plate receptor, the
agent remains bound and thus the end plate cannot repolarize
• During this depolarizing phase the transient muscle fasciculation
occur
• Absence of fade to tetanic stimulation
• Prolonged exposure to succinylcholine leads to desensitisation block.
– This occurs when ACh receptors are insensitive to the channel-opening effects of
agonists, including ACh itself.

64. Depolarising blocking agents
– Phase II block
• This occurs after repeated boluses or a prolonged infusion of
succinylcholine
• After adequate depolarization has occurred, phase II sets in and the
muscles are no longer receptive to acetylcholine released by the
motor neurons
• After the initial depolarization, the membrane potential gradually
returns towards the resting state, even though the neuromuscular
junction is still exposed to the drug. Neurotransmission remains
blocked throughout.
• It is at this point that the depolarizing agent has fully
achieved paralysis
• Fade after tetanic stimulation
– Succinylcholine has quick action start within 1 min and last for 12 min
– Hydrolysed by plasma cholinesterase (also called pseudocholinesterase)
produced in the liver
– Prolonged blockade is seen in liver disease or pregnancy
– Inhibition of plasma cholinesterase occurs with OP compounds
– Side effect: hyperkalaemia
– Bind to nicotinic and muscarinic Ach, causes bradycardia
– Contraindicated in burns

65. Na+
Acetylcholine
Depolarization
Na+
- - - -
+ + + +
- - - -
+ + + +
+ + + +
+ + + +
- - - - - - - -

66. Na+
Acetylcholine
Tubocurarine
Na+
+ + + +
- - - -
- - - -
+ + + +
Competitive neuromuscular blocking drugs

67. Na+
Depolarized
Na+
PHASE I
Membrane depolarizes
resulting in an initial
discharge which
produces transient
fasciculations followed
by flaccid paralysis
- - - -
+ + + +
+ + + +
- - - - - - - -
+ + + + + + + +
- - - -
- - - -
Depolarizing Neuromuscular blocking drugs

68. Repolarized
PHASE II
Membrane repolarizes
but the receptor is
desensitized to effect
of acetylcholine
+ + + +
- - - -
+ + + +
- - - -
- - - -
+ + + +
- - - -
+ + + +
Depolarizing Neuromuscular blocking drugs

69. Anticholinesterases
• AchE inhibitors
– Inhibit AchE so that Ach accumulates and causes
depolarising block
• Reversible
– Competitive inhibitors of AChE
– Block can be overcome by curare
• physostigmine, neostigmine, edrophonium
• Irreversible
– Binds to AChE irreversibly
• , insecticides, nerve gases

70. Reversal of NMJ blockers
• Recovery from the effects of non-depolarising relaxants can
occur spontaneously by elimination of the agent either
unchanged or after metabolism
• However, this process may be slow, of variable time and cannot
be reliably predicted
• Pharmacological antagonism or reversal of NMJ block is
therefore indicated in clinical practice
• Anticholinesterases (eg. Neostigimine) reverse the action of
non-depolarising blockers
• Another drug (eg. sugammadex) which bind to non-depolarising
blocker and reverses its action is used
• There is no antagonist for succinylcholine but its action is short
lasting

71. NMJ disorders
• Myasthenia gravis (MG)
– Antibodies to Ach receptors
– Post synaptic disorder
• Lambert Eaton myasthenic syndrome (LEMS)
– Presynaptic disorder (antibodies against Ca channels)
• Neuromyotonia (Isaac’s syndrome)
– Down-regulation of K+ channels, hyperexcitability due to prolonged
depolarisation
• Botulism
– Presynaptic disorder
– Binds to the presynatic region, cleaves SNARE proteins and prevent
release of Ach
• Tetanus
– Presynaptic disorder
– Blockade of neurotransmitter release (GABA & glycine) of spinal
inhibitory neurons causes hyper-excitable tetanic muscle contractions

72. Botulinum toxin
• Most potent neurotoxin known
• Produced by bacterium Clostridium botulinum
• Causes severe diarrhoeal disease called botulism
• Action:
– enters into the presynaptic terminal
– cleaves proteins (syntaxin, synaptobrevin) necessary for Ach vesicle
release with Ca2+
• Chemical extract is useful for reducing muscle spasms, muscle
spasticity and even removing wrinkles (in plastic surgery)

74. Organophosphates
• Phosphates used as insecticides
• Action
– AchE inhibitors
– Therefore there is an excess Ach
accumulation
– Depolarising type of postsynaptic
block
• Used as a suicidal poison
• Causes muscle paralysis and death
• Nerve gas (sarin)

75. Snake venom
• Common Krait (bungarus
caeruleus)
– Produces neurotoxin known as
bungarotoxin
– Very potent
• Causes muscle paralysis and death
if not treated
• Cobra
– venom contain neurotoxin

76. Myasthenia gravis
• Serious neuromuscular disease
• Antibodies form against acetylcholine nicotinic
postsynaptic receptors at the NMJ
• Characteristic pattern of progressively reduced
muscle strength with repeated use of the muscle and
recovery of muscle strength following a period of rest
• Present with ptosis, fatiguability, speech difficulty,
respiratory difficulty
• Treated with cholinesterase inhibitors

77. Type Neurotransmitter
Amines Serotonin (5HT), Dopamine, Norepinephrine, Acetylcholine, Histamine
Amino acids Gamma-aminobutyric acid (GABA), Glycine, Glutamate, Aspartate
Opioids Beta-endorphin, Enkephalins, Dynorphin, Nociceptin, Kyotorphin
Neurokinins Substance P, Neurokinin A, B
Endocannabinoids Endocannabinoids (Anandamide, 2AG)
Mixed types Nitric oxide and Carbon monoxide (CO)
ATP, ADP
CART (cocaine and amphetamine regulated transcript)
Neuropeptide Y
Orexin
Other Angiotensin, Calcitonin, Glucagon, Insulin, Leptin, Atrial natriuretic factor,
Estrogens, Androgens, Progestins, Thyroid hormones, Cortisol. Hypothalamic
releasing hormones, Corticotrophin-releasing hormone (CRH), Gonadotropin
releasing hormone (GnRH), Luteinizing hormone releasing hormone (LHRH),
Somatostatin, Thyrotropin releasing hormone (TRH), Growth hormone releasing
hormone (GHRH), Pituitary peptides, Corticotrophin (ACTH), Growth
hormone (GH), Lipotropin (opioid), Alpha-melanocyte-stimulating hormone(alpha-
MSH), Oxytocin, Vasopressin, Thyroid stimulating hormone (TSH), Prolactin,
Gut hormones Cholecystokinin (CCK), Gastrin, Motilin, Pacreatic polypeptide, Secr
etin, Vasoactive intestinalpeptide (VIP), Bombesin, Bradykinin, Carnosine
(antioxidant), Calcitonin G related peptide CGRP (useful in migraine), Delta sleep
inducing peptide (DSIP), Galanin (neuropeptide), Melanocyte concentrating
hormone (MCH)

78. Acetylcholine (Ach)
• earliest neurotransmitter discovered
• secreted at the following sites
– neuromuscular junction (skeletal muscle contraction excitatory)
– heart (inhibitory)
– autonomic ganglia (both sympathetic and parasympathetic)
– adrenal medulla
– parasympathetic postganglionic nerve endings
– central pathways in the brain (neocortex, hippocampus) and basal forebrain
(cognition, memory, arousal, attention)
– brainstem (REM sleep)
– large pyramidal cells of the motor cortex
– basal ganglia (striatum)
• receptors
– nicotinic (NN: autonomic ganglia, NM: NMJ) – ionotropic receptors Na+ influx
– muscarinic (parasympathetc terminal)
• sub types: M1, M2, M3, M4, M5
• metabotropic receptors with G protein and second messenger cAMP and K+
channel opening

79. Acetylcholine (Ach)
Clinical aspects
• NMJ blockers (postsynaptic blocker): competitive blocker (atracurium) &
depolarising blocker (succinylcholine)
• atropine – parasympathetic blocker, anticholinergic, antimuscarinic actions
• botulinum toxin (food poisoning) – Ach release is blocked presynaptically,
Botox is useful in hemifacial spasms, writer’s cramps, torticollis, dystonia,
plastic surgery
• organophosphate (insecticide poisoning) – anticholinesterase action causing
increased Ach level and depolarising blocking action causing cholinergic
effects, treated with atropine
• Antibodies against Ach receptors in myasthenia gravis – treated with
anticholinesterases (neostigmine, pyridostigmine)
• loss of Ach neurons in Alzheimer’s patients: treated with donepezil and
rivastigmine (anticholinesterases, increases Ach level)
• pilocarpine – muscarinic (M3) cholinergic eye drops are used in glaucoma to
reduce intra-ocular pressure, causes miosis (pupillary constriction) whereas
atropine causes mydriasis (pupillary dilatation)
• anticholinergics are useful in Parkinson disease (to treat tremor)
• anticholinergics causing bronchodilatation useful in COPD

80. Neuromuscular junction in smooth muscle
• There is intrinsic innervation in smooth muscles eg. In GI tract, extrinsic
innervation from autonomic nervous system
• There is no specialized connection between the nerve fiber and the smooth
muscle cell
• The nerve fibers essentially passes "close" to the smooth muscle cells and
releases the neurotransmitter
• The neurotransmitter can bind to any one of the nearby smooth muscle cells
• many different neurotransmitters can be released from the many different
nerves that innervate smooth muscle cells
• They could be excitatory or inhibitory
• eg. Ach, norepinephrine, nitric oxide, prostacyclin, endothelin
• There is nothing equivalent to the motor endplate in smooth muscle,
therefore receptors for the neurotransmitters are located throughout the
smooth muscle membrane
• Smooth muscle can be made to contract by hormones and paracrine agents

81. Channelopathies
• In excitable cells
– periodic paralysis (K+ channel, Na+ channel)
– myasthenia (nicotinic Ach receptor with a ligand Na+
channel)
– myotonia (K+ channel)
– malignant hypothermia (Ryanodine Receptor, a Ca2+
channel),
– long QT syndrome (Na+ and K+ channel)
• In nonexcitable cells
– cystic fibrosis (Cl- channel)
– Bartter’s syndrome (K+ channel)

82. Clinical Scenarios
• A patient presented with right sided weakness
of face, arm and leg
• Questions
• Domains tested
– Knowledge
– Communication

83. Clinical Scenarios
• eg.
A patient presented with right sided weakness
of face, arm and leg
• Questions
• Domains tested
– Knowledge
– Communication