Neurotransmitter L2 PDF

DA 1218 BIOCHEMISTRY NEUROTRANSMITTER L2 Pn. Mariati Abdul Rahman Dept. of Clinical Oral Biology Faculty of Dentistry.  OBJECTIVES 1. To list out classes of neurotransmitters and their chemical properties. 2. To explain the synthesis and catabolism of neuro...

DA 1218 BIOCHEMISTRY NEUROTRANSMITTER L2 Pn. Mariati Abdul Rahman Dept. of Clinical Oral Biology Faculty of Dentistry.  OBJECTIVES 1. To list out classes of neurotransmitters and their chemical properties. 2. To explain the synthesis and catabolism of neurotransmitters: Acetylcholine, catecholamines, GABA etc. 3. To explain any condition related neurotransmitter deficiency.  INTRODUCTION Neurotransmitters – molecules that acts as chemical signals between nerve cells. Definition of a neurotransmitters 1. Synthesis of the molecules must occur within the neuron, i.e. biosynthetic enzymes, substrates, cofactors etc., are present for de novo synthesis. 2. Storage of the molecule occurs within the nerve ending prior to release e.g. in synaptic vesicles.  NEUROTRANSMITTER 3. Release of the synaptic molecules from the presynaptic ending occurs in response to an appropriate stimulus such as action potential. 4. There is binding and recognition of the neurotransmitter molecule on the post synaptic target cell. 5. Mechanism exist for the inactivation and termination of the biological activity of the neurotransmitter.  NEUROTRANSMITTER CLASSIFICATION Base on effect on postsynaptic membranes, NT are often classified as excitatory or inhibitory NTs. Excitatory NT- cause depolarization & promotes generation of action potentials. Inhibitory NT cause hyperpolarization & suppress generation of action potential.  Any shift from the resting potential towards 0mV – depolarization. Applies to changes from -70 to a smaller negative values (-65,-10mV) & to above 0mV (+10 or +30mV). Repolarization – process of restoring to resting potential after depolarization. Hyperpolarization – increase in the negativity of the resting potential from -70 to -80mV or more.  Signal carried by nerve cell reflects an abrupt change in voltage potential difference across cell membrane. Normal resting potential difference is a few milivolts, inside cell (–ve). Caused by imbalance of ions. Inside cell - [K+] much greater, opposite for [Na+] – maintained by Na+/K+-ATPase pump Common in all cells.  nerve cells contains voltage-dependent sodium channels – opens rapidly during a depolarization change. Huge influx of Na+ into cells, Membrane potential This restores back to the normal becomes +ve. resting balance of ions across This is action potential. membrane. After a short *refractory period, the Almost immediately cell can conduct another action sodium channel closes, K+ potential. channels opens. *Recovery period after an impulse. Normal stimulus won’t cause excitation during repolarization.  EXCITATORY NEUROTRANSMITTER Excitatory NT- cause depolarization & promotes generation of action potentials. Example: Misc Acetylcholine monoamines Norepinephrine, epinephrine, dopamine, serotonin, histamine Amino acids glutamate purines adenosine  INHIBITORY NEUROTRANSMITTERS Inhibitory NT - causes hyperpolarization It changes protein conformation pores which allow negatively charged ion to pass through. Example: Amino acid -amino butyric acid (GABA) Glycine  CLASSIFICATION : CHEMICAL SIMILARITIES Group examples Misc Acetylcholine Amines Norepinephrine, epinephrine, dopamine, serotonin, histamine Amino acids Glutamate, aspartate, GABA, glycine Purines ATP, adenosine Gases Nitric oxide, CO peptides Endorphins, enkephalins, many others.  LOCATION, LOCATION, LOCATION Group location Acetylcholine CNS; brain & spinal cord. PNS: neuromuscular junction, preganglionic synapse of ANS, neuroglandular junction of parasympathetic & sympathetic division of ANS, amacrine cells of retina Norepinephrine CNS;cerebral cortex, hypothalamus, brain stem, cerebellum, spinal cord PNS; most neuromuscular & neurogladular junction of sympathetic division of ANS., epinephrine CNS;thalamus, hypothalamus, midbrain, spinal cord. dopamine CNS: hypothalamus, midbrain, limbic system, cerebral cortex, retina  LOCATION, LOCATION, LOCATION Group location Serotonin CNS: hypothalamus, midbrain, limbic system, cerebral cortex, retina Histamine CNS; hypothalamus Glutamate CNS; cerebral cortex & brain stem Aspartate CNS; cerebral cortex, retina & spinal cord -aminobutyric CNS;Cerebral cortex, cerebellum, interneurons acid (GABA) through brain & spinal cord. Glycine CNS; interneurons in brain stem, spinal cord & retina.  LOCATION, LOCATION, LOCATION ATP, GTP CNS: Spinal cord PNS: Autonomic ganglia adenosine CNS: Cerebral cortex, hippocampus, cerebellum Nitric oxide CNS: Brain, esp at blood vessels PNS: Some sympathetic neuromuscular & neuroglandular junctions. Endorphins, CNS: Thalamus, hypothalamus, brain stem, retina. Enkephalins, CNS: Basal nuclei, hypothalamus, midbrain, pons, medulla oblongata, spinal cord  TYPES OF NEURONS Acetylcholine Cholinergic serotonin serotonergic Adrenaline adrenergic Histamine histaminergic Noradrenaline noradrenergic GABA GABAergic Dopamine dopaminergic Glycine glycinergic  RECEPTORS Several mechanisms for NT to cause propagation of an action potential in a post synaptic neuron. Receptors that directly control the opening of an ion channel – ionotrophic receptors. Metabotrophic receptors – coupled to second messenger systems, which in turn alter the function of the channels which are separated from the receptor.  2.5.2018 Agonist- a substance which initiates a physiological response when combined with a receptor.  IONOTROPHIC RECEPTOR (NICOTINIC ACH RECEPTOR). A. Closed B. Transmembrane protein, 5 non- identical subunit. C. Subunits surrounds a pore that selectively allows certain ions through when it is opened by a ligand (ACh).  When ligand binds, there is a change in 3D structure of the complex which allows the flow of ions through it. The effect on membrane potential depends on the particular ions that are allowed to pass. Nicotinic ACh receptor is comparatively non- specific towards sodium & potassium & causes depolarization, whereas GABAA receptor is a chloride channel causes hyperpolarization.  METABOTROPIC RECEPTORS. All known metabotropic receptors are coupled to G-proteins (second messenger proteins). Act more slower than ionotropic receptors. Have seven transmembrane regions. Typically, coupled either to adenylate cyclase, altering the production of cAMP or to phosphatidyl inositol pathway which alters calcium fluxes. Ion channels that are separate from the receptors are then modified by phosphorylation. E.g. -adrenergic receptor (norepinephrine & epinephrine) causes increase in cAMP, which stimulates a kinase to phosphorylate & activate a calcium channel.  TYPES OF RECEPTORS Acetylcholine *Nicotinic serotonin 5-hydroxy *muscarinic tryptamine Adrenaline 1, 2, 1 Histamine H1, H2 Noradrenalin 1, 2, 1 GABA GABAA GABAB Dopamine D 1, D2 Glycine  (mu), *Originates from nicotine (tobacco leaves) and muscarine (poisonous mushrooms)  (delta), binding to the receptors. -Both acts at diff sites.  (kappa)  ACETYLCHOLINE SYNTHESIS Synthesis, any rate limiting steps? Precursors required? How the NT is stored and released? What are the provisions for termination of the action of the NT?  ACETYLCHOLINE SYNTHESIS Synthesized from choline by choline acetyl transferase. Precursor choline and acetyl CoA. Secreted into the synaptic cleft and broken down by acetylcholinesterase.  ACh BIOSYNTHESIS. 1. Glucose pyruvate (Cytosol) 2. Pyruvate Acetyl CoA citrate (mito) 3. Citrate Acetyl CoA (citrate cleavage enzyme). 4. Acetyl CoA + choline ACh. 5. ACh taken up into vesicles, accumulates to a final conc. of 880mM.  ACh BIOSYNTHESIS & DEGRADATION. Choline from circulation is derived from ACh is cotransported with Na+ into the cell. Requires energy Rate limiting step for synthesis of ACh. Inactivation by Acetylcholinesterase – producing choline and acetate.  EVENTS AT THE CHOLINERGIC SYNAPSE 1. Action potential arrives & depolarizes the synaptic knob, opening the voltage regulated Ca2+ channels. 2. EC Ca2+ enters the synaptic cleft, triggering exocytosis. 3. ACh is released into the synapse.  EVENTS AT THE CHOLINERGIC SYNAPSE 4. ACh binds to receptors and depolarizes postsynaptic membrane. 5. Chemically regulated sodium channels on postsynaptic surface are activated, producing graded depolarization. 6. ACh release is ceased because calcium ions are removed from the cytoplasm. 7. Depolarization ends as ACh is broken down by AChE producing acetate & choline. 8. Synaptic knob reabsorb choline for resynthesis of ACh.  ACETYLCHOLINE RECEPTOR DISTURBANCE Autoimmune disease – Myasthenia Gravis Characterised by muscle weakness (eyes, face & lips) & fatigue Occurs when body inappropriately produces antibodies against ACh receptors, inhibits proper ACh signal transmission.  MYASTHENIA GRAVIS fatigue of eyelid muscles as the patient keeps looking up After a few minutes of rest, the eyelids have returned to near- normal position The symptoms -muscle fatigability, with worsening of symptoms later in the day after their muscles have been fatigued or after being repetitively exercised. The symptoms range from difficulty in eye motion which results in double vision or droopy eyelids, to diffuse weakness and fatigability in the arms and legs. Other symptoms may include fatigue of throat muscles, resulting in swallowing difficulties and choking, and/or fatigue of the muscles of speech, resulting in slurred and unintelligible speech. Myasthenia gravis does not affect bowel and bladder function or the patient's mental capacity. ACETYLCHOLINE DEFICIENCY ACh decreased in both concentration and function in Alzheimer’s. Drugs that inhibits acetylcholinesterase are used in the treatment of Alzheimer’s disease – rivastigmine – reversibly inhibit the enzyme, therefore increasing ACh levels.  On the other hand, when acetylcholinesterase is inhibited by organophosphate insecticides or by nerve gas*, there is excess of ACh. symptoms: increased sweating, salivation, bronchial secretions along with miosis (constriction of the pupil. Severe: Flaccid (lifeless) paralysis, respiratory failure etc. Atropine – anti-cholinergic drug. Competitive binding - muscarinic receptor antagonistic- to antagonize toxic syndrome caused by excess ACh. *Sarin gas – inhibits the enzyme, causing ACh build up at the synapse, & continues to act at the coming nerve impulse. Death within 1 minute at low concentration. (1995 Domestic terrorism in Tokyo Subway 12 deaths)