Question

Physiologist discover a new disease affecting neuromuscular transmission at the neuromuscular junction NMJ. They called the condition PLT disease and it causes weakness and increasing fatigue in the skeletal muscles, due to the production of antibodies that target membrane bound receptors of the skeletal muscle cells

Part A

How will the antibodies produced in PLT disease affect neuromuscular transmission? Identify the specific receptors on the skeletal muscle cells that will target these antibodies and the neurotransmitters involved

Part B

The physiologists decide to treat the PLT disease with a class of drug that enhances cholinergic transmission at the neuromuscular junction.

Explain why enhancing the cholinergic transmission at the NMJ is a suitable treatment for PLT disease which causes skeletal muscle weakness.

Response should include detailed explanation of the events involved in cholinergic transmission, the role of cholinesterase in normal NMJ physiology, specific action of anticholinesterases on cholinesterase, and how anticholinesterase will affect skeletal muscle contraction.

Answer 1

Neuromuscular junction: The neuromuscular junction (NMJ) is the synapse that is formed when the motor neuron innervates the muscle fibers in skeletal muscle. In skeletal muscle contraction, a nerve impulse in form of action potential either from CNS or PNS first reaches the presynaptic membrane of the motor neurons. Action potentials are generated by increased flow of sodium ions, which then travel to the axon. Such nerve impulses causes opening of the voltage gated calcium channels at the axon terminal from extracellular space. Intracellular Calcium ions will then increase, which then associates with SNARE proteins on the synaptic vesicles that contain the neurotransmitter acetylcholine. These interaction causes fusion of synaptic vesicles at the axon terminal. The fusion of the synaptic vesicles with the axon terminal membrane causes release of acetylcholine quanta by exocytosis. The ACH released will then travel to the motor endplate from the synaptic cleft in NMJ. The muscle cell contains nicotinic ACh receptors that are ion channel receptors on the plasma membrane (Sarcolemma). When ACh binds to the ACh receptor, ACh gated channels are opened. This causes the motor endplate to become permeable to sodium ion. As a result of this, sodium ions enter the muscle cell and decrease the potential from -90 to -40 mV, a decrease known as endplate potential. The endplate potential is now carried through the T tubules. This results in the release of calcium ions which stimulate further release of calcium ion from the sarcoplasmic reticulum via the ryanodine receptors. Calcium will bind to troponin, which is present bound to tropomyosin and actin. The binding of calcium releases binding sites of myosin and actin. Actin will now bind to myosin and ATP hydrolysis will stimulate cross bridging. As a result, the muscle will undergo contraction.

The signals are terminated when ACh is hydrolyzed by the enzyme acetylcholinesterase (AChE) in the synaptic cleft). This AChE enzyme breaks down ACh into choline and acetic acid. Thus, AChEwill prevent ACh from binding to its receptors on the sarcolemma. There is a feedback regulation by ACh receptors that controls release of ACh. More release of ACh is prevented in synaptic cleft if ACh receptors are saturated. Anticholinesterases are drugs that inhibit the actions of AChE. Thus, AChE will no longer be able to degrade ACh. This leads to increased binding of ACh to its receptors and thus, cause increased muscle contraction.

Part A. Acetylcholine is the neurotransmitter released by the presynaptic motor neuron in the synaptic cleft. Muscle cells express specific acetylcholine receptors known as nicotinic ACh receptors on the sarcolemma. There are five types of such receptors known- M1, M2, M3, M4 and M5. These are ion gated receptors that allow sodium ions to enter the cell. Antibodies are secreted by the PLT diseased individual that binds to nicotinic ACh receptors. This will inhibit ACh from binding to the nicotinic ACh receptors. Hence, calcium channels are not opened and there will be no increase in intracellular calcium levels. As a result, muscle contraction will be inhibited. The ACh released in synaptic cleft will be degraded increasingly by the AChE enzyme, thereby decreasing its levels in synaptic cleft. Thus, antibodies to ACh receptors will inhibit acetylcholine mediated neuromuscular transmission.

Part B: Cholinergic drugs are drugs that act on the acetylcholine signaling to increase cholinergic transmission. Anticholinesterase drugs are cholinergic drugs can bind to AChE and inhibit it. Thus, more ACh is available to bind to the receptors. In case of PLT, the antibodies are binding to the nicotinic receptors. Increase in ACh will cause increased binding to the receptors and overcome the antibody effect. Cholinergic drugs can also bind to the nicotinic ACh receptors, and increase their activity. When cholinergic transmission is increased, then there is increased binding of ACh to the receptors on the muscle cell sarcolemma. As a result, increased calcium will be released from the sarcoplasmic reticulum. Calcium will bind to troponin and unblock myosin binding sites on actin filaments Myosin can then bind to actin after ATP hydrolysis, undergo power stroke and induce cross bridging. This will cause actin and myosin to come closer and induce muscle contraction. Muscle contraction is followed by muscle relaxation. Fatigue in the PLT patient is mostly due to lack of muscle contraction. Increasing muscle contraction will reduce fatigue and muscle weakness and overcome the symptoms of PLT disease. Thus, enhancing cholinergic transmission that increases muscle contraction is an effective treatment for PLT disease.