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Myasthenia gravis is also called as “Grave muscle weakness”. It is a neuromuscular disorder. The antibodies, circulating in the blood bind to Ach receptors and in this way reduce the number of these receptors. As a result, Ach cannot attach to the receptors and no muscle contraction occurs. The signs and symptoms of Myasthenia gravis are double vision, difficulty in swallowing and speaking, skeletal muscle weakness and fatigue. The treatment involves the inhibition of acetylcholine esterase (AchE). AchE is the enzyme that degrades Ach. AchE inhibitors prolong the action of Ach at the muscle end plate and this way they partially compensate for the reduced number of receptors.
Post synaptic potential is a change in the membrane potential of the postsynaptic terminal. When the opening of Na+/ K+ channels lead to net gain of positive charge across the membrane, then the depolarization of the postsynaptic cells occur and is called EPSP. The neurotransmitters that are involved in EPSP are acetylcholine, norepinephrine, epinephrine, dopamine, glutamate and serotonin.
Whereas when the opening of Cl– channels lead to net gain of negative charge across the membrane, then the hyperpolarization of the postsynaptic cells occur and is called IPSP. The neurotransmitters involved in causing IPSP are γ-amino butyric acid (GABA) & glycine.
Acetylcholine is the first neurotransmitter discovered. It is both excitatory and inhibitory. The synthesis of ACh in the nerve terminals is initiated by the binding of Acetyl CoA (synthesized in mitochondria) and choline (transported into the neuron by Na+ dependent choline co-transporters) in the presence of choline acetyltransferase. Then vesicular Ach transporter takes free Ach and loads those into vesicles. Release of ACh requires the presence of Ca++ ions. In the presence of Ca++ ions vesicles fuse with the neuronal membrane that causes the release of ACh by exocytosis. Acetylcholine then binds to the receptors on the postsynaptic membrane and depolarizes the cell. Acetylcholine is then degraded by acetylcholine esterase which is present in the synaptic cleft. Free choline is then transported back into the presynaptic neuron.
Location- Ach is widely distributed and the sites of synthesis of acetylcholine are NMJ and autonomic nervous system.
Action of acetylcholine- Acetylcholine binds to the nicotinic receptor on the postsynaptic membrane and opens the sodium ion channel. As a result, Na+ ions enter into the postsynaptic cell and increase the neuronal excitability (muscle contraction)
Organophosphorus poison causes the inhibition of acetylcholine esterase and in turn, the accumulation of acetylcholine at NMJ. This causes overstimulation of the muscle and muscular paralysis. Antidote for organophosphorus poison is atropine. It blocks the muscarinic receptors. Acetylcholine can no longer bind to the receptors and prevents the overstimulation of muscles.
Norepinephrine acts as a neurotransmitter and is released from locus ceruleus of midbrain, sympathetic nervous system.
Cocaine blocks the reuptake of the norepinephrine (“Feeling good” NT) which causes the state of extreme happiness and euphoria.
The three neurotransmitters dopamine, norepinephrine and epinephrine are called catecholamine because they share the catechol moiety and they are derived from the same precursor Tyrosine. Tyrosine is a non-essential amino acid produced by our body from phenylalanine. Catecholamine synthesis is initiated by the conversion of Tyrosine to L-dopa by the enzyme tyrosine hydroxylase. Then, L-dopa is converted to dopamine by the enzyme dopa decarboxylase and accompanied by the loss of carbon dioxide. Dopamine β-hydroxylase further catalyzed the conversion of dopamine to norepinephrine in the presence of ascorbic acid. Finally, epinephrine is synthesized from the norepinephrine with the help of an enzyme phenylethanolamine-N- methyltrasferase.
Metabolites of norepinephrine are vanillylmandelic acid (VMA), 3, 4-Dihydroxymandelic acid (DOMA), Normetanephrine and 3- methoxy-4-hydroxyphenyglycol (MOPEG)
Serotonin is also known as 5HT. It is a neurotransmitter derived from tryptophan. It is released by the pontine raphe nuclei and dorsal horn of spinal cord. Serotonin is involved in inhibiting pain and elevating mood. Prozac is the medicine that is used for elevating mood. It acts as an inhibitor for serotonin reuptake.
Glutamate is the most common excitatory neurotransmitter. It is also called as “Stroke neurotransmitter”. After stroke, it is involved in increasing intracellular Na+ and Ca2+ ions.
γ- amino butyric acid (GABA) is an inhibitory neurotransmitter. When the presynaptic GABAergic interneurons are activated, GABA is released. GABA binds to postsynaptic GABA receptors and make them activated. This causes influx of Cl– ions and leads to inhibition of postsynaptic cells by hyperpolarization.
Tetanus toxin inhibits the glycine (inhibitory neurotransmitter present in the spinal cord). This overstimulates the muscles and cause sustained muscle contraction called tetany.
Nitric oxide is the inhibitory neurotransmitter in GIT, blood vessels and CNS. It causes the vasodilation and acts for a short period of time.
Substance P is the neurotransmitter that mediates the pain sensation.
Endorphins are body’s own opiates. Endorphins act as natural pain killers by inhibiting the substance P.
Acidosis and alkalosis both influence the neuronal activity. Acidosis involves change in the pH from 7.4 to 7.0. This leads to reduced neuronal activity and may induce coma.
Alkalosis involves change in the pH change from 7.4 to 8.0 and this increases neuronal excitability. Change in pH in this case may induce seizures.
Hypoxia is the result of loss of oxygen to the cells. It can be caused by interruption of brain blood flow for 3 to 7 sec. This leads to unconsciousness.
The mechanism is initiated by the binding of hormone or a ligand to the receptor (such as β-adrenoreceptor and α2-adrenoreceptor) which activates the G-protein inside the cell. Then G protein stimulates the enzyme called adenylate cyclase to convert ATP to cyclic AMP (cAMP). cAMP in turns binds to and stimulate another enzyme called protein kinase A which adds the phosphate group to the specific proteins and phosphorylating those proteins. Phosphodiesterase degrades the cAMP to the inactive form called 5′-APM.
IP3 is an Inositol triphosphate. It is involved in cell to cell signaling. It is a soluble molecule that can diffuse through the cytoplasm to the ER. IP3 mechanism is as follows: The binding of hormone to a receptor in the cell membrane initiates the signal transduction pathway. This leads to the activation of an enzyme called phospholipase C by G-proteins and Ca2+ ions. Phospholipase C breaks down the membrane lipid PIP2 into two smaller molecules called diacylglycerol (DAG) and IP3. Then IP3 diffuses from cell membrane to cytoplasm and binds to the IP3 receptors that lead to the opening of calcium channels. Ca++ ions are released from the endoplasmic reticulum. DAG remains at the membrane and along with
Ca++ ions activate protein kinase C. Protein kinase C causes specific physiological actions by phosphorylating substrate proteins.
Spatial summation occurs when two excitatory inputs from different presynaptic neurons arrive at a postsynaptic neuron simultaneously and produce enhanced depolarization.
Whereas, temporal summation occurs when two excitatory inputs from the single presynaptic neuron, arrive at a postsynaptic neuron in rapid sequence and as a result the intersection of postsynaptic depolarization occurs at the same time. This leads to enhanced depolarization in stepwise fashion.
When a single action potential reaches the presynaptic terminal, it causes the release of calcium ions from the sarcoplasmic reticulum. This results into the production of a single twitch. However, if a muscle is stimulated repetitively before it gets relaxed, there will be a accumulative increase in intracellular calcium ions which will extend the time for cross-bridge cycling. As a result, muscle will not relax at all.