Neuromuscular Physiology

Presented by: Dr. Vishal kr. Kandhway Jawaharlal Nehru Medical College, Sawangi, Wardha

• A neuromuscular junction (NMJ) is the synapse or junction of the axon terminal of a motorneuron with the motor end plate, responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract.

• Morphology:• The neuromuscular junction is specialized on the

nerve side and on the muscle side to transmit and receive chemical messages.

• Each motor neuron runs without interruption from the ventral horn of the spinal cord or medulla to the neuromuscular junction as a large, myelinated axon.

• As it approaches the muscle, it branches repeatedly to contact many muscle cells and gather them into a functional group known as a motor unit .

Neuromuscular Junction (NMJ)

• The nerve is separated from the surface of the muscle by a gap of approximately 20 nm, called the junctional or synaptic cleft.

• The nerve and muscle are held in tight alignment by protein filaments called basal lamina that span the cleft between the nerve and end plate.

• The muscle surface is heavily corrugated, with deep invaginations of the junctional cleft—the primary and secondary clefts.

The Neuromuscular junction consists ofA) Axon Terminal: containsaround 300,000 vesicles whichcontain the neurotransmitteracetylcholine (Ach).B) Synaptic Cleft :20 – 30 nm ( nanometer ) spacebetween the axon terminal & themuscle cell membrane. It

containsthe enzyme cholinesterase whichcan destroy Ach .C) Synaptic Gutter ( Synaptic Trough)It is the muscle cell membranewhich is in contact with the nerve terminal . It has many folds called Subneural Clefts , which greatly increase the surface area , allowing for accomodation of large numbers of Ach receptors . Ach receptors are located here .

• Formation of Neurotransmitter at Motor Nerve Endings:-

• The axon of the motor nerve carries electrical signals from the spinal cord to muscles and has all of the biochemical apparatus needed to transform the electrical signal into a chemical one.

• All the ion channels, enzymes, other proteins, macromolecules, and membrane components needed by the nerve ending to synthesize, store, and release acetylcholine and other trophic factors are made in the cell body and transmitted to the nerve ending by axonal transport.

• Ach formed is stored in cytoplasm until it is transported into vesicles for the release.

• How is Ach released…..

Ach release

Ca entry into the nerve

Opening of Ca channelsP channels L Channels (slow)

Na influx

Depolarisation

Nerve Action Potential

Muscle Contraction

Transmission of AP along sarcolemma to open Tubular Ca Channels

Generation of Action Potential

depolarisation

Opening of Na channels

Ach binds to the post junctional receptors

• 1.Upon the arrival of an action potential at the presynaptic neuron terminal, voltage-dependent calcium channels open and Ca2+ ions flow from the extracellular fluids into the presynaptic neuron's cytosol

• 2.This influx of Ca2+ causes neurotransmitter-containing vesicles to dock and fuse to the presynaptic neuron's cell membrane. Fusion of the vesicular membrane with the presynaptic cell membrane results in the emptying of the vesicle's contents (acetylcholine) into the synaptic cleft, a process known as exocytosis.

• 3.Acetylcholine diffuses into the synaptic cleft and binds to the nicotinic acetylcholine receptors bound to the motor end plate.

• 4.These receptors are ligand-gated ion channels, and when they bind acetylcholine, they open, allowing sodium ions to flow in and potassium ions to flow out of the muscle's cytosol.

• 5.Because of the differences in electrochemical gradients across the plasma membrane, more sodium moves in than potassium out, producing a local depolarization of the motor end plate known as an end-plate potential (EPP).

• 6.This depolarization spreads across the surface of the muscle fiber into transverse tubules, eliciting the release of calcium from the sarcoplasmic reticulum, thus initiating muscle contraction.

• 7.The action of acetylcholine is terminated when the enzyme acetylcholinesterase degrades part of the neurotransmitter (producing choline and an acetate group) and the rest of it diffuses away.

• 8. The choline produced by the action of acetylcholinesterase is recycled — it is transported, through reuptake, back into the presynaptic terminal, where it is used to synthesize new acetylcholine molecules.

Acetylcholine (1)

Ach is synthesized locally in the cytoplasm of the nerve terminal , from active acetate (acetylcoenzyme A) and choline.

Then it is rapidly absorbed into the synaptic vesicles and

stored there. The synaptic vesicles themselves

are made by the Golgi Apparatus in the nerve soma ( cell-body).

Then they are carried by Axoplasmic Transport to the nerve terminal , which contains around 300,000 vesicles .

Each vesicle is then filled with around 10,000 Ach molecules .

Acetylcholine (2)

• When a nerve impulse reaches the nerve terminal ,

• it opens calcium channels calcium diffuses from the

ECF int the axon terminal Ca++ releases Ach from vesicles by a process of EXOCYTOSIS

• One nerve impulse can release 125 Ach vesicles.

• The quantity of Ach released by one nerve impulse is more than enough to produce one End-Plate Potential .

Ach combines with its receptors in the subneural clefts. This opens sodium channels & sodium diffuses into the muscle causing a local,non-propagated potential called the “ End-Plate Potential (EPP)”, whose value is 50 – 75 mV.

This EPP triggers a muscle AP which spreads down inside the muscle to make it cntract .

• Fate of Ach….

• After ACh acts on the receptors , it is hydrolyzed by the enzyme Acetylcholinesterase (cholinesterase ) into Acetate & Choline . The Choline is actively reabsorbed into the nerve terminal to be used again to form ACh. This whole process of Ach release, action & destruction takes about 5-10 ms .

Anaesthetic Implication of Ca channels

• Higher than normal concentrations of cations (e.g., magnesium, cadmium, manganese) can also block entry of calcium through P channels and decrease neuromuscular transmission.

• This is the mechanism for muscle weakness in the mother and fetus when magnesium sulfate is administered to treat preeclampsia.

• P channels are not affected by CCB”s– verapamil, diltiazem, and nifedipine. (These drugs have profound effects on the slower L channels present in CVS.)

• As a result, the L-type calcium channel blockers have no significant effect at therapeutic doses on the normal release of Ach

Post-junctional Acetylcholine Receptors

• 3 types:• 1) a junctional or mature receptor, • 2) an extrajunctional or immature (fetal)

receptor• 3) neuronal α7 receptor (recently described)

• Mature receptor - α, β, δ, and ε

• Fetal (immature/extrajunctional)- α, β, δ, and γ; there are two subunits of α and one of each of the others.

• Neuronal α7 AChR consists of five α7-subunits

Drug Effects on Postjunctional Receptors

• Nondepolarizing Muscle Relaxants• All NDMRs impair or block neurotransmission

by competitively preventing the binding of acetylcholine to its receptor.

• The final outcome (i.e., block or transmission) depends on the relative concentrations of the chemicals and their comparative affinities for the receptor.

• Reversal• Normally, acetylcholinesterase destroys acetylcholine

and removes it from competition for a receptor.• Inhibitor of acetylcholinesterase such as neostigmine

blocks it acetylcholine conc rises.• High concentration shifts the competition between

acetylcholine and NDMR in favor of the former, thereby improving the chance of two acetylcholine molecules binding to a receptor.

• This causes reversal of NDMR effect.

• Actions of Depolarizing Muscle Relaxants• have a biphasic action on muscle—an initial contraction,

followed by relaxation lasting minutes to hours.• Not susceptible to hydrolysis by acetylcholinesterasethe

depolarizing relaxants are not eliminated from the junctional cleft until after they are eliminated from plasma.

• The time required to clear the drug from the body is the principal determinant of how long the drug effect lasts.

• Because relaxant molecules are not cleared from the cleft quicklyreact repeatedly with receptors repeatedly depolarizing the end plate and opening channels.(basis of hyperkalemia)

Anaesthetic Implication of DMR”s

• Ocular muscles express both mature and fetal receptors.

• Accommodation (when synapse area is inexcitable through nerve) does not occur, and these muscles can undergo a sustained contracture in the presence of succinylcholine.

• The tension thus developed forces the eye against the orbit increased IOP by depolarizing relaxants.

Nonclassic and Noncompetitive Actions of Neuromuscular Drugs

• Several drugs can interfere with the receptor, directly or through its lipid environment, and change transmission.

• These drugs react with the neuromuscular receptor to change its function and impair transmission but do not act through the acetylcholine binding site.

• These reactions cause drug-induced changes in the dynamics of the receptor,

and instead of opening and closing sharply, the modified channels are sluggish.

• These effects on channels cause corresponding changes in the flow of ions and distortions of the end-plate potential.

• For example, procaine, ketamine, inhaled anesthetics, or other drugs that dissolve in the membrane lipid may change the opening or closing characteristics of the channel.

• If the channel is prevented from opening, transmission is weakened.

• If, however, the channel is prevented from or slowed in closing, transmission may be enhanced.

• Basis is two clinically important reactions: receptor desensitization and channel blockade.

Desensitization Block

• Some receptors that bind to agonists do not undergo the conformational change to open the channel.

• Receptors in these states are called desensitized (i.e., they are not sensitive to the channel-opening actions of agonists).

Anaesthetic Implication

• The drugs acting by this route can decrease neuromuscular transmission.

• They can cause an apparent increase in the capacity of nondepolarizing agents to block transmission.

Drugs Causing Desensitization of Nicotinic Cholinergic Receptors

• Volatile anesthetics : Halothane ,Sevoflurane ,Isoflurane.• Antibiotics : Polymyxin B.• Barbiturates: Thiopental, Pentobarbital.• Agonists: Acetylcholine, Succinylcholine.• Local anesthetics: Dibucaine ,Lidocaine,Prilocaine.• Phenothiazines:Chlorpromazine,Trifluoperazine,Prochlorperaz

ine.

Channel Block

• Block channels at Ach receptors.• The normal flow of ions through the receptor

is impaired, thereby resulting in prevention of depolarization of the end plate and a weaker or blocked neuromuscular transmission.

• Anaesthetic Implication:• Channel block is believed to play a role in cocaine, quinidine,

piperocaine, tricyclic antidepressant, naltrexone, naloxone induced alterations in neuromuscular function.

Extrajunctional, or fetal form of AChR

• is expressed when there is decreased activity in muscle, as seen in the fetus before innervation or

• after chemically or physically induced immobilization;

• after lower or upper motor neuron injury, burns, or sepsis; or

• after other events that cause increased muscle protein catabolism, including sepsis or generalized inflammation.

Anaesthetic Implication

• Depolarizing or agonist drugs such as succinylcholine and acetylcholine depolarize immature receptors more easily,

• thereby resulting in cation fluxes; doses one tenth to one hundredth of those needed for mature receptors can effect depolarization.

Anaesthetic Implication

• most serious side effect with the use of succinylcholine in the presence of upregulated AChRs in one or more muscles is hyperkalemia.

• (immature) receptor channels stay open for a longer timethe amount of potassium that moves from muscle to blood can be considerable. The resulting hyperkalemia can cause dangerous disturbances in cardiac rhythm, including ventricular fibrillation.

Acquired cholinesterase deficiency

Conditions:

• Liver failure• Renal insufficiency• Burn injury • Pregnancy (high

estrogen levels)

Inhibitory drugs: • Anti cholinesterases• Pancuronium• Metoclopramide• Insecticides• Drugs for Glaucoma,

myasthenia• Chemotherapeutic agents

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