Neurotransmitters.pdf

Neurotransmitters Dr. Walaa Nabil Lecturer of Medical Biochemistry & Molecular Biology Students’ learning outcomes By the end of this lecture, the students should be able to: 1. Understand the processes of synaptic transmission 2. Classify the different types of neurotransmitter...

Neurotransmitters Dr. Walaa Nabil Lecturer of Medical Biochemistry & Molecular Biology Students’ learning outcomes By the end of this lecture, the students should be able to: 1. Understand the processes of synaptic transmission 2. Classify the different types of neurotransmitter receptors and explain their roles in signal transduction. 3. Identify the major neurotransmitters and discuss their roles in normal physiological processes and in the pathology of neurological and psychiatric disorders. 4. Evaluate the mechanisms of action of key pharmacological agents that target neurotransmitter systems. What are Neurotransmitters ? Neurotransmitters are chemical messengers that carry chemical signals from one neuron to a neighboring target cell across a synaptic cleft. Target cell may be another neuron or some other kind of cell like a muscle or gland cell.  Synaptic signal transmission All synapses function according to a similar principle: Each chemical synapse consists of: 1. Presynaptic membrane (membrane of the signaling cell) 2. Postsynaptic membrane (membrane of the target or receiving cell) 3. Synaptic cleft (a gap between the presynaptic and postsynaptic membranes) Synaptic signal transmission  Neurotransmitter Receptors They are divided into two large groups according to the effect produced by binding of the transmitter: 1. Ionotropic receptors (Ligand-gated ion channels) 2. Metabotropic receptors (G-protein coupled receptors)  Ionotropic Receptors They open as a result of the transmitter binding, allowing ions to flow into the postsynaoptic cell. If the inflowing ions are cations (Na+,Ca2+) depolarization of the postsynaptic membrane an action potential is triggered on the surface of the postsynaptic cell. This is the way in which stimulatory transmitters work By contrast, If the inflowing ions are anions (Cl–) hyperpolarization of the postsynaptic membrane, which makes the production of the postsynaptic action potential more difficult This is the way in which inhibitory transmitters work Metabotropic Receptors  Classification of Neurotransmitters Physiological Classification: 1. Excitatory neurotransmitters: cause depolarization of the postsynaptic cells and generate an action potential; for example, acetylcholine. 2. Inhibitory neurotransmitters: cause hyperpolarization of the target cells,; for example GABA.  Chemical Classification: Acetylcholine Synthesis : Acetylcholine is synthesized in the nerve endings of cholinergic neurons from choline and acetyl-CoA by choline acetyltransferase enzyme Degradation: Once released, ACh must be removed in order to allow repolarization. Acetylcholine is broken down by acetylcholinesterase enzyme. The remainder is taken back up into the nerve cell by transporters. Functions:  It functions in both central and peripheral nervous systems.  Excitatory in all cases except in the heart.  Acetylcholine Receptors Muscarinic receptors Nicotinic receptor  Metabotropic  More widespread in the  Ionotropic brain  They bind nicotine  Also found in the heart,  Found on the autonomic smooth muscle, glands ganglia and at the and peripheral arteries neuromuscular innervated by junctions. parasympathetic nerves.  Specifically inhibited by Atropine.  Clinical applications 1. ACh agonists, and acetylcholinesterase inhibitors: Used to treat glaucoma by increasing the tone of the muscles of accommodation of the eye Also used to stimulate intestinal function after surgery. 2. Organophosphate insecticides: Inhibit Acetylcholinesterase excess Ach Diarrhea, increased secretory activity of salivary and lacrimal glands, bronchoconstriction, bradycardia. This syndrome can be antagonized by atropine. 3. Myasthenia Gravis (MG): An auto-immune disease characterized by presence of antibodies to the nicotinic Ach receptors of the neuromuscular junctions. In severe forms, respiratory muscles are affected, causing respiratory failure and death. Treatment involves acetylcholinesterase inhibitors 4. Botulism: Botulism causes paralysis because it prevents the release of acetylcholine thus leading to paralysis of the effector muscle. 5. Alzheimer’s disease: A neurodegenerative disorder characterized by learning and memory impairments. Associated with a lack of ACh in certain regions of the brain. Acetylcholinesterase inhibitors help to improve symptoms Catecholamines The principal Catecholamines are: Norepinephrine Epinephrine Dopamine Synthesis: From tyrosine amino acid (produced from hydroxylation of phenylalanine in liver then transported to catecholamine- secreting neurons)  Catecholamine Catabolism: 2 steps: 1. Methylation by Catechol O-methyl transferase (COMT) using S- adenosyl methionine as methyl donor. 2. Deamination by Monoaminoxidase (MAO). The principal metabolite of epinephrine and norepinephrine is vanillylmandelic acid (VMA) increases in pheochromocytoma The major metabolite of dopamine is homovanillic acid (HVA). Functions: 1. Norepinephrine and Epinephrine : Produced in the adrenal medulla and neurons in the CNS and PNS (sympathetic nervous system). Binds to both α- and β-adrenergic receptors (GPCRs). They are Excitatory neurotransmitters They are the primary hormones of the fight-or-flight response of the sympathetic nervous system. Norepinephrine increases alertness and arousal. Functions: 2. Dopamine: In the CNS, dopamine plays a major role in feeding, reward (motivation), mood, attention and memory. As a part of the extrapyramidal motor system, dopamine is important for movement coordination by inhibiting unnecessary movements. Dopaminergic receptors are metapotropic.  Clinical applications: 1. Parkinson’s disease: Destruction of the substantia nigra Dopamine depletion leads to uncontrollable muscle tremors. Treatment involves administering L-dopa. Clinical applications: 2. Schizophrenia: High levels of dopamine in the limbic system lead to positive symptoms of schizophrenia, including delusions, hallucinations or thought disorders. Low levels of dopamine in the prefrontal cortex lead to negative symptoms of schizophrenia, including a decrease in social activity, emotional range, and cognitive function. Serotonin  Serotonin is derived from the amino Synthesis: acid tryptophan in two steps: Serotonin (5-HT) receptors: Seven classes (5-HT1 – 5-HT7) All are metabotropic, except 5-HT3 receptor which is ionotropic. Functions: 1. In the Intestine: Most abundantly expressed in enterochromaffin cells of the gut It regulates digestion, absorption, peristalsis, and release of peptide hormones. 2. In the CNS: Serotoninergic neurons are concentrated in the upper brainstem but project up to the cerebral cortex and down to the spinal cord. Serotonin is implicated in regulation of vegetative behaviors such as food craving, satiety, mood, fear, appetite, sleep, pain control, sensory perception, and sexual behavior.  Catabolism Oxidative deamination by monoamine oxidase 5- hydroxyindole acetic acid (5-HIAA) 5-HIAA increases in urine of patients with malignant carcinoid syndrome (Serotonin producing tumor in the argentaffin tissue of the abdominal cavity).  Clinical Applications 1) Insufficient secretion of serotonin can cause: Depression or mood swings Suicidal tendencies Insomnia Agression, irritability Obsessive-compulsive disorder Carbohydrate cravings. Clinical Applications 2) 5-HT3 blocker (Ondansetron): an antiemetic (used with chemotherapy) 3) 5-HT1D agonist (sumatriptan): can treat Migraine. 4) Amine theory of depression Depression is caused by a relative deficiency of amine neurotransmitters at central synapses (mainly norepinephrine and serotonin). Drugs which increase amine concentrations should improve depression symptoms:  Monoamine oxidase (MAO) inhibitors.  Tricyclic antidepressants (TCA).  Selective serotonin reuptake inhibitors (SSRIs). Histamine Synthesis: by decarboxylation of the amino acid histidine. Histamine is released from : 1. Mast cells: when allergens bind to IgE-antibody complexes, mediating allergic and inflammatory symptoms by acting on H1 receptors. 2. Enterochromaffin-like cells of the stomach: stimulates gastric parietal cells to secrete acid. 3. Hypothalamus, involved in regulating the sleep-wake cycle and promoting arousal when activated. Histamine receptors: There are four histamine receptors (H1–H4) All are metabotropic. Clinical Applications 1) H1 inhibitors (Antiallergic drugs) designed to control allergies caused by release from mast cells act on the H1 receptor and tend to be sedative, suggesting that other central functions also probably exist. 2) H2 inhibitors, such as cimetidine and ranitidine act on H2 receptors in the stomach, therefore used to treat peptic ulcers Gamma-Aminobutyric Acid (GABA) Synthesis: It is derived by decarboxylation of glutamate catalyzed by glutamate decarboxylase (GAD). PLP Functions: Inhibitory neurotransmitter in the CNS. It acts throughout the brain as a brake to balance excitatory neurotransmitters. It is essential for motor control (refines movement), and anxiety regulation. GABA Receptors: GABA-A (ionotropic) GABA-B (metabotropic) Clinical Applications 1) The underproduction of GABA (due to GAD or vitamin B6 deficiency) is associated with anxiety or epileptic seizures. 2) Anxiolytic drugs: Benzodiazepines bind to GABA receptors and potentiate the response to endogenous GABA; reduce anxiety also cause muscle relaxation. Barbiturates bind to GABA receptor and stimulate it directly in the absence of GABA. So lack of dependence on endogenous ligand may cause toxic side effects in overdose. 3) Tetanus: Tetanospasmin toxin prevents the release of GABA causing violent spastic paralysis. Glutamate Function: The most important excitatory transmitter in the CNS, transmitter involved in regulation of general excitability of the CNS, learning processes, cognition and memory. Glutamate receptors: Metabotropic Glutamate receptors (mGluRs), Ionotropic receptors like the N-methyl-D-aspartate receptor (NMDAR). Clinical Applications: 1) Some epileptic conditions are caused by the increase of excitatory neurotransmitter glutamate. 2) N-methyl-D-aspartate receptor (NMDAR) is clinically important because it may cause damage to neurons after stroke (excitotoxicity).  Learning resources Harper’s Illustrated Biochemistry. Lehninger principles of biochemistry. Lippincott Illustrated Reviews: Biochemistry. Thomas M. Devlin. Textbook of Biochemistry with Clinical Correlations.