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Neuromuscular Physiology
Prof. Vajira WeerasingheDepartment of Physiology
Faculty of MedicineUniversity of Peradeniya
• Nerve conduction
• NMJ
• Muscle contraction
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
Membrane potential
• A potential difference exists across all cell membranes– This is referred to as “Resting Membrane Potential” (RMP)– Inside is negative with respect to the outside
What are excitable tissues?
• They are capable of generating electrochemical impulses and transmitting them along the membrane
• Excitability of a tissue depends on its membrane potential– Excitable tissues have more negative RMP
( - 70 to - 90 mV)– Non-excitable tissues have less negative RMP
( - 40 mV)
excitable Non-excitable
Red cellGIT
neuron
muscle
Resting Membrane Potential
• This depends on following factors– Ionic distribution across the membrane– Membrane permeability – Other factors
• Na+/K+ pump
Factors contributing to RMP
• One of the main factors is K+ efflux (Nernst Potential: -94mV)
• Contribution of Na influx is little (Nernst 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: -90 mV inside
Ionic channels
• Leaky channels (K-Na leak channel)– More permeable to K– Allows free flow of ions
K+
Na+
Na/K pump
• Active transport system for Na-K exchange using energy
• It is an electrogenic pump since 3 Na influx coupled with 2 K efflux
• Net effect of causing negative charge inside the membrane
3 Na+
2 K+
ATP ADP
Action Potential (A.P.)
• When an impulse is generated– Inside becomes positive – Causes depolarisation– Nerve impulses are transmitted as AP
Dep
olar
isat
ion R
epolarisation-90
+35
RMP
Hyperpolarisation
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
Physiological basis of AP
• Since Na has come in and K has gone out
• Membrane has become negative
• But ionic distribution has become unequal
• Na/K pump restores Na and K conc slowly– By pumping 3 Na ions outward and 2 K ions inward
• 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
-90 Threshold level +35Na+ Na+
outside
inside
Na+m gate
h gate
– 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
-90 At +35
K+ K+
n gate
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
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
Propagation of AP
• Then the previous area become repolarised
• This process continue to work
• Resulting in propagation of AP
AP propagation along myelinated nerves
• Na channels are conc around nodes
• Therefore depolarisation mainly occurs at nodes
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
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
NMJ function
• Pre-synaptic membrane• Ca channels• Acetycholine release
• Postsynaptic membrane• Acetylcholine receptors• Ligand-gated channels
• Synaptic cleft• cholinesterase
Synapse
• A gap between two neurons
• More commonly chemical
• Rarely they could be electrical (with gap junctions)
Although an axon conducts bothways, conduction through synapse is oneway
presynaptic neuron to postsynaptic neuron
A neurone receives more than 10000 synapses. Postsynaptic activity is an integrated function
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)
Presynaptic terminal (terminal knob, boutons, end-feet or synaptic knobs) Presynaptic membrane contain voltage-gated Ca
channels The quantity of neurotransmitter released is
proportional to the number of Ca entering the terminal Ca 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
Ca2+ Ca2+
• Postsynaptic membrane contain receptors for the neurotransmitter released
• eg: Acetylcholine receptor
AchNa+
•This receptor is Ach-gated Na+ channel•When Ach binds to this, Na+ channel opens up•Na+ influx occurs
• Na+ influx causes depolarisation of the membrane– End Plate Potential (EPP)
• This is a graded potential• Once this reaches the threshold level• AP is generated at the postsynaptic membrane
Ach release
• An average human end plate contains 15-40 million Ach receptors• Each nerve impulse release 60 Ach vesicles• Each vesicle contains about 10,000 molecules of Ach
• Ach is released in quanta (small packets)• Even at rest small quanta are released • Which creates a minute depolarising spike called Miniature End
Plate Potential (MEPP) • When an impulse arrives at the NMJ quanta released are
increased in several times causing EPP
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
Axoplasmic transport
• The process by which mitochondria, synaptic vesicles and other cytoplasmic constituents travel to and from the cell body
• axon contains 100 times the volume of the cell body
• proteins for neurotransmitters and membrane repair are constantly transported anterogradely – to maintain normal axonal function
• If the axon is deprived of proteins because it is severed or crushed– the segment that is distal to the injury cannot support itself
and will degenerate
NMJ blocking
• Useful in general anaesthesia to facilitate inserting tubes
• Muscle paralysis is useful in performing surgery
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
Neuromuscular blocking agents• Non-depolarising type (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– Prolonged action (30 min)– Ach can compete & the effect overcomes by an excess Ach– Anticholinesterases can reverse the action– eg.
• Curare• Tubocurarine• Gallamine• Atracurium
Neuromuscular blocking agents• Depolarising type (non-competitive)
– Act like Ach, but resistant to AchE action– Bind to motor end plate and once depolarises – Persistent depolarisation leads to a block
• Due to inactivation of Na channels– Two phases
• Phase I – depolarisation phase – fasciculations • Phase II – paralysis phase
– Ach cannot compete– Quick action (30 sec), short duration (10 min)– Anticholinesterases cannot reverse the action– eg.
• suxamethonium• Ach in large doses• nicotine
Neuromuscular blocking agents• 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
NMJ disorders
• Myasthenia gravis – Antibodies to Ach receptors– Post synaptic disorder
• Lambert Eaton Syndrome (myasthenic syndrome)– Presynaptic disorder (antibodies against Ca channels)
• Botulism– Presynaptic disorder– Binds to the presynatic region and prevent release of Ach
NMJ disorders
• Snake venom (Presynaptic or postsynaptic disorder)– Krait (bungarotoxin)
• Postsynaptic disorder
– Cobra• Postsynaptic disorder
– Russell’s viper• Presynaptic disorder
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)
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)
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
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
Muscle contraction
• T tubules
• Voltage-gated Ca channels
• Actin-myosin cross bridges
• Muscle contraction
• ATP release
• Reversal of the process
Muscle contraction
• Depolarisation of the muscle membrane spreads through the muscle
• Causes muscle contraction
Muscle contraction
• Excitation - contraction coupling
– Excitation : electrical event– Contraction : mechanical event
Ca++Ca++
• AP spreads through t tubule into the muscle tissue
• Close to the sarcoplasmic reticulum, AP activates a receptor (votage-gated Ca++ channel)
• Ca flows to the myoplasm in the vicinity of actin & myosin
• 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
TroponinActin
Myosin
Tropomyosin
ATP
Ca2+TroponinActin
Myosin
Tropomyosin
Ca2+Myosin binding sites
Ca2+Ca2+
Detachment Sliding
Binding
• 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
slow & fast fibres
• Slow twitch fibre (type I fibre)
• Fast twitch fibre (type II fibre)
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
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