NEUROTRANSMITTERS dr. Meizly Andina, M.Biomed

BIOCHEMISTRY DEPARTMENT

www.meizlyandina.blogspot.com

Generation of the Action Potential

Dietmar Schomburg, Gerhard Michal , Biochemical pathways : an atlas of biochemistry and molecular biology 2nd ed. 2012

Role of voltage-gated and ligand-gated ion channels in neural transmission.

Nelson D.L, Cox M.M, Lehninger Principles of Biochemistry Fourth Edition

Neurotransmitters • Transmission of impulses at the chemical synapses is mediated by neurotransmitters. • The most widely distributed transmitter substances in the nervous system are acetylcholine (ACh), glutamate, gammaaminobutyric acid (GABA), and glycine. • Glutamate is the most common excitatory transmitter, GABA is a transmitter of the inhibitory synapses in the brain, and glycine is an inhibitory transmitter in the spinal cord. • The catecholamines norepinephrine (NE) and dopamine (DA) also act as transmitters, and so does serotonin (5-HT). • Many neuropeptides act not only as hormones in the bloodstream but also as transmitters in the synapses (e.g., neurotensin, cholecystokinin, somatostatin).

Location and Effect of the Neurotransmitter

Dietmar Schomburg, Gerhard Michal , Biochemical pathways : an atlas of biochemistry and molecular biology 2nd ed. 2012

Dietmar Schomburg, Gerhard Michal , Biochemical pathways : an atlas of biochemistry and molecular biology 2nd ed. 2012

Agonists and Antagonists for Postsynaptic Receptors

Dietmar Schomburg, Gerhard Michal , Biochemical pathways : an atlas of biochemistry and molecular biology 2nd ed. 2012

Metabolism of aminobutyrate

( -KA, -keto acids; -AA, -amino acids; PLP, pyridoxal phosphate.)

Murray RK, et al, 2009. Harper's Illustrated Biochemistry

Biosynthesis of some neurotransmitters from amino acids (The key step is the same in each case: a PLPdependent decarboxylation, shaded in pink).

Nelson D.L, Cox M.M, Lehninger Principles of Biochemistry Fourth Edition

CLINICAL CORRELATION • •

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Underproductio of Glutamate decarboxylation gives rise to –aminobutyrate (GABA), an inhibitory neurotransmitter, n is associated with epileptic seizures. Glutamate is the amino acid in the highest concentration in the brain and functions as a neurotransmitter in the brain and spinal cord. Memantine is an antiglutamatergic drug used for treatment of Alzheimer disease. Glutamate antagonism is implicated in schizophrenia, in which drugs of abuse, like ketamine and phencyclidine, affect glutamate binding to its receptor Serotonin has multiple physiologic roles, including pain perception, regulation of sleep, appetite, temperature, blood pressure, cognitive functions, and mood (causes a feeling of well-being). Serotonin is an important stimulatory neurotransmitter involved in mood. Selective serotonin reuptake inhibitors (SSRIs) promote serotonin’s actions and are first-line agents in the treatment of depression. Carcinoid tumors overproduce the neurotransmitter serotonin, with the accumulation of the primary metabolite 5-hydroxyindole acetic acid (5-HIAA). When these tumors metastasize to the liver, they cause carcinoid syndrome, which is characterized by diarrhea, flushing, wheezing, and cardiac valve damage. Swanson TA, 2010, Biochemistry, Molecular, Biology, and Genetics Nelson D.L, Cox M.M, Lehninger Principles of Biochemistry Fourth Edition

CLINICAL CORRELATION The catecholamines (dopamine, norepinephrine, and epinephrine) are derived from tyrosine in a series of reactions Synthesis of the catecholamines • Phenylalanine forms tyrosine, which forms dopa. In this case, both of these hydroxylation reactions require BH4 • Decarboxylation of dopa forms the neurotransmitter dopamine. • Hydroxylation of dopamine by an enzyme that requires copper and vitamin C yields the Neurotransmitter norepinephrine. • Methylation of norepinephrine in the adrenal medulla by SAM forms the hormone epinephrine. •

In Parkinson disease, dopamine levels are decreased because of a deficiency in conversion of dopa to dopamine. The common characteristics are tremors, difficulty initiating voluntary movement, a masked face with a staring expression, and a shuffling gait. Infantile forms of the disease have been found to be due to defects in tyrosine hydroxylase. Administration of L-DOPA (levodopa) is the most common treatment.

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Overproduction of dopamine in the brain may be linked to psychological disorders such as schizophrenia.

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The catecholamines are inactivated by monoamine oxidase (MAO), which produces ammonium ion (NH4+) and hydrogen peroxide (H2O2) and converts the catecholamineto an aldehyde, and by catecholamine Omethyltransferase (COMT), which methylatesthe 3-hydroxy group.

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Inhibition of MAO and COMT are both approaches in the treatment of neuropsychiatric disorders such as depression and Parkinson disease. Nelson D.L, Cox M.M, Lehninger Principles of Biochemistry Fourth Edition Swanson TA, 2010, Biochemistry, Molecular, Biology, and Genetics

CLINICAL CORRELATION Histamine is a chemical messenger that mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion, and possibly neurotransmission in parts of the brain. It is secreted by mast cells as a result of allergic reactions or trauma. Histamine has no clinical applications, but agents that interfere with the action of histamine have important therapeutic applications. Acetylcholine is a neurotransmitter, a key substance involved with transmission of nerve impulses in the brain, skeletal muscles, and other areas where nerve impulses occur. An essential step in the proper function of any nerve impulse is its cessation which requires hydrolysis of acetylcholine. Some xenobiotics, such as organophosphate insecticides and carbamates (pesticidal organic derivatives of carbamic acid) inhibit acetylcholinesterase, with the result that acetylcholine accumulates and nerves are overstimulated. Adverse effects may occur in the central nervous system, in the autonomic nervous system, and at neuromuscular junctions (organophosphate  bronchioconstriction, stimulation of muscles in the intestinal tract, resulting in nausea, vomiting, and diarrhea; and muscular twitching and cramps, restlessness, anxiety, and emotional instability, headache and insomnia, depression of the respiratory and circulatory systems, convulsions, and coma may result. In fatal poisonings, death is due to respiratory system paralysis. Patients who recover from the acute toxic effects of organophosphates often suffer continued neurological symptoms. Such toxins are synthesized by Clostridium tetani , common soil bacteria that enter the body largely through puncture wounds, interferes with neurotransmitters, such as acetylcholine, causing tetanus, commonly called lockjaw.

Manahan, Stanley E., 2003. Toxicological chemistry and biochemistry 3rd ed. Harvey RA, 2011. Lippincott’s Illustrated Reviews: Biochemistry

CLINICAL CORRELATION Pyridoxine (B6) • Required for several transaminase and decarboxylation reactions • Most severe symptoms due to the equirement for decarboxylating glutamic acid to the inhibitory neurotransmitter GABA, resulting in seizures. • Deficiency can be associated with isoniazid or penicillamine use. Copper • Component of many oxidases in oxidative metabolism, neurotransmitter synthesis, and collagen synthesis • Deficiency results in muscle weakness, neurologic defects, and abnormal collagen cross-linking.

Swanson TA, 2010, Biochemistry, Molecular, Biology, and Genetics