Da 1218 Biochemistry Neurotransmitter L3 PDF

DA 1218 BIOCHEMISTRY Neurotransmitter L3 Pn. Mariati Abdul Rahman Dept. of Clinical Oral Biology Faculty of Dentistry.  DA 1218 BIOCHEMISTRY Neurotransmitter L3 Pn. Mariati Abdul Rahman Dept. of Clinical Oral Biology go Faculty...

DA 1218 BIOCHEMISTRY Neurotransmitter L3 Pn. Mariati Abdul Rahman Dept. of Clinical Oral Biology Faculty of Dentistry.  DA 1218 BIOCHEMISTRY Neurotransmitter L3 Pn. Mariati Abdul Rahman Dept. of Clinical Oral Biology go Faculty of Dentistry. througheneurtransmit eree  CATECHOLAMINES catechol – dihydroxyphenol with 2 adjacent hydroxyl groups. Catecholamine 1 f amingroup – catechol derivatives with amino group as a side chain. ~american:Noradrenaline:british Norepinephrine (NE), epinephrine (E) & dopamine –are all derived from amino acid -I tyrosine. Also known as biogenic amines (containing amino group). ↳ produce by living organism  ①NOREPINEPHRINE D Major transmitter in the sympathetic nervous system (spinal cord to ganglia). I NE is the transmitter for receptor the postganglionic nerves, where as for ganglia is ACh. Stimulation of these nerves is responsible for the flight or fight :body PREPAR response, such as HOLD stimulating the heart rate, sweating, vasoconstriction in the skin & bronchodilation.  Can alter overall alertness & attention The stimulatory effects of amphetamines are caused by their close chemical similarities to catecholamines. Stimulants for narcolepsy/ADHD but taken as recreational drug -ecstacy Inarcolepsy- sleeping disorder * drug have same simiture  There are also NE-containing neurons in the CNS, largely in the brain-stem. NE containing neurons arise from the locus ceruleus in the brain stem & are distributed throughout the cortex.  ② EPINEPHRINES (ADRENALINE) More active than NE on the heart & lungs, causes redirection of blood from skin to skeletal muscle. Has stimulatory effects on glycogen metabolism in the body liver. Istorage ofglucose-ready to tight/ In response to epinephrine, a right↓ sudden extra glucose is delivered to muscle, the heart & lungs to work harder to pump oxygen around the circulation, the body is now prepared to run or defend itself. ~Stay alive who it Not essential for life, removal of adrenal me medulla is possible without serious consequences.  ADRENORECEPTORS Receptors for NE & E. Divided to 2 classes, 0- & 0-receptors. NEpinephrine acts onepinephrine both receptors, NE Whtmis more specific on -receptors. -blockers – atenolol- use for hypertension treatment & chest pain in ischemic heart disease because they antagonize the stimulatory effect of catecholamines on the heart. A hypotension:don't want any to pump faster  4 enzymes are required for the formation of ; tyrosine hydroxylase (free in cytosol in nerve endings) - DOPA Dihydroxy phenylalanine (DOPA) decarboxylase (cytosol) – I removal of Dopamine carboxyl group Dopamine -hydroxylase - (vesicle membrane) – Norepinephrine Phenylethanolamine N-methyltransferase (vesicle membrane) – Epinephrine. ·have enzyme:got the NT, Downloaded from: StudentConsult (on 20 March 2007 07:17 AM) © 2005 Elsevier Noradrenaline (also called norepinephrine) - synthesized in the synaptic resicle sympathetic nerves. ~ - stored in storage vesicles. - When sufficiently stimulated, the vesicles migrate to the end of the nerve and release noradrenaline into the synaptic cleft, the noradrenaline binds to the adrenergic receptors - Next in the chain of events is noradrenaline metabolism, which involves two uptake mechanisms.  majite p Uptake 1: After stimulating the adrenergic receptors, 85-90% of the noradrenaline is taken back up into the sympathetic nerve (uptake 1) and stored in vesicles or metabolized by monoamine oxidase (specifically, MAO-A) in in the mitochondria. The importance of uptake 1 (neuronal uptake) is reflected by the warnings against combining sympathomimetics (ephedrine, phentermine, etc.) with MAO inhibitors -- the risk of overstimulation would be much too high. Uptake 2: Some of the noradrenaline diffuses away from the receptors and is transported by extra-neuronal cells by ⑳uptake 2 and metabolized by catechol- O-methyl-transferase (COMT). 1 COMT plays a much smaller role in catecholamine dynamics than MAO. COMT I exists in both a soluble and a membrane- bound form. The soluble form of COMT is found in organs and it does not have as high of an affinity for catecholamines as Toward the membrane-bound form. substrate  & stay and awake,getsynaptic --stimulaht dhig * Cocaine prevents reuptake of catecholamines into the adrenergic neurons. So catecholamines remain at the receptor site for longer period of times.  of amount this 3 measure norepinephrine Line use 1. Catecholamines are degraded by oxidation of the amino group by monoamine oxidase (MAO). 2. And by methylation by catecholamine-O-methyl transferase (COMT) Pathway for epinephrine, dopamine & Serotonin (5-HT) are analogous (similar). Samenzyme  Metanephrines & vanillylmandelic acid (VMA) can be detected in the0 urine. This can be use as indicator for the function of adrenal medulla. Particularly increased in patients with tumour of the adrenal medulla – known as pheochromocytoma. This tumour causes hypertension from the C'excess vasoconstriction action of catecholamines it produces. neurotransmitter: of causing hypertension  ③ DOPAMINE NT and intermediate in the synthesis of NE. Major NT that interconnects the basal ganglia in the brain & control voluntary movement. Nerves containing dopamine run in well-defined tract. One of the most important tracts, the nigrostriatal system, A connects the substantia nigra in the mid brain with the basal ganglia below the cortex. Damage to this causes Parkinson’s disease, with loss of fine control of movement.  DOPAMINE Damage (dopamine deficient): Parkinson’s disease, characterised by tremor & difficulties in initiating & controlling movement. start moving:hard Dopamine is also found in pathways affecting limbic systems of the brain – involves in ↳emotional responsesC & Imemory.L Defect in dopaminergic systems are implicated in [schizophrenia-mental disorderI(excess dopamine). Many antipsychotic drugs for the treatment of this disease have been found to bind to dopamine receptors. Parkinson's ~memory · patient given any l emotion · How dopamine ↳ inhibit receptor ↳ To helpdopamine stablonger for bind my postsynaptic  DOPAMINE In the periphery, dopamine causes vasodilation; therefore it is used clinically to stimulate blood flow. Catabolism of dopamine produces homovanillic acid (HVA). detect on unne ·  ⑪ GLUTAMATE Most important excitatory transmitter in the CNS. It acts on both ionotrophic & metabotropic receptors. Ionotropic example: The N-methyl-D-aspartate (NMDA) glutamate receptor. Limbic system in the brain is involved in emotions & memory. It consists of various areas surrounding the upper brain stem including hippocampus, the amygdaloid body & cingulate gyrus. Removal of hippocampus prevents laying down of the short term memory.I consterm Intact amygdaloid function is required for the emotion of fear. Formation of memory requires activation of NMDA receptor and consequent influx of calcium.  GLUTAMATE & EXCITOTOXICITY. This receptor is clinically important – may cause damage to neurons after stroke (excitotoxicity).~IHOW important OFLeCePNU Excess extracellular glutamate increased after trauma/stroke, severe convulsions, Huntington’s chorea, AIDS-related dementia & Parkinson’s disease – after cell damage/ damage to GLU reuptake pathway. activates NMDA receptors, NMDA - allows calcium to enter the cells. ~ Programme ↳eat This activatesCproteases which initiate apoptosis. C Soprevent: - Activation of NMDA receptors also increases nitric oxide (toxic). given amg Drugs are developed to inhibit NMDA activation & suppress excitotoxicity, unfortunately many drugs have the side effects causing paranoia & delusions.  GLUTAMATE SYNTHESIS & INACTIVATION 80% of all glutamate sit E released from nerve · endings derives from Iglutamine in the ⑪ hydrolytic reaction of glutaminase. Glutamate is also taken up into glial cells ~otherincell neuron (astrocytes) & neurons via energy-dependent, Na+ requiring channel- Excitatory amino acid transporter (EATT). Glucose is also the source for glutamate formation Darinson'sdamagine lea in the neuron cells. desanot could ·el  (2) 80% (5) (4) (1) (4) (3) transamination reaction inactivated  GLUTAMATE INACTIVATION Glutamate is then inactivated by conversion into glutamine, catalysed by glutamine synthetase (2). Glutamine is then taken up by the neurons to form glutamate by glutaminase (1). Glutamine also diffuse into CSF where it can act as a storage. & cerebral spino fluid  -AMINO BUTYRIC ACID (GABA) Synthesized from glutamate by glutamate decarboxylase (3). A major inhibitory transmitter in the brain. 2 known receptors, GABAA (ionotrophic) & GABAB(metabotropics). GABAA receptor consists of 5 subunits which arise from several gene families, giving an enormous number of potential receptors with different binding abilities. ↳ large number of variation receptor:protein gene >PNRB *  (2) (5) (4) (1) (4) (3) I transferale of group  GABA decease neural excitability, CACH GABAD increase of Psycoactive drugs to reduce anxiety, insomnia, using agitation seizures & cause muscle relaxation. Benzodiazepins can bind to this receptor and enhance the effect of GABA. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarizing the membrane. SEROTONIN (5-HYDROXYTRYPTAMINE) acid Important NT ~ amino Derived from tryptohan Serotoninergic neurons are concentrated in the raphe nuclei in the upper brain stem, projects up to the cerebral cortex & down the spinal cord. Neurons are more active when subjects are awake than when they are asleep. Serotonin controls – degree of responsiveness of the motor neurons in the spinal cord. Controls feeding, sexual behaviour & temperature control.  - Serotonin has effects on mood, excess serotonin may cause panic attacks, controlled by 5-HT1A-receptor agonist, which will act on the autoreceptors to reduce production of serotonin. Serotonin also has effect on peripheral nervous system & enteric neurons (governs the function of GIT). Powerful vasoconstrictor & increase motility of GIT. Auto receptor - receptor on presynaptic neurons. sensitive on NT where receptor is located.  SEROTONIN BIOSYNTHESIS Tryptophan decarboxylase hydroxylase tetrahydrobiopterin Vit B6 2 to synthesis serotonin  CATABOLISM OF SEROTONIN Serotonin is reabsorbed by serotonergic neuron. 5-hydroxytryptamine Monoamine oxidase (MAO) 5-hydroxyindole-3-acetaldehyde Aldehyde dehydrogenase 5-hydroxyindole 3- acetate (HIAA) HIAA in urine as marker for excessive production or deficiency of serotonin.  SEROTONIN RECEPTORS >12 receptors have been identified. Most are metabotropic 5-HT1A are found on many presynaptic & postsynaptic neurons, acts as autoreceptor to inhibit the release of 5-HT. Autoreceptors - receptors that are sensitive to the neurotransmitter that is released by the neuron on which the receptors are located. -the key component of an ultra-short negative feedback loop whereby the neuron's release of neurotransmitter inhibits its further release of neurotransmitter In general, increasing [5-HT] appears to increase anxiety, to reduce this effect – reduce its concentration. Antidepressant – buspirone – acts as agonist at the receptor& presumably decreases production of 5-HT. An imbalance of serotonin in the brain is thought to contribute to depression, anxiety, poor mood, sexual dysfunction and stress. Prozac prevents reabsortion of serotonin, more will be left floating in the &I synapses. for antidepression  Serotonin also plays a role in perception Hallucinogens (Lysergic acid diethylamide, LSD)- serotonin analog, binds to receptors, blocking Gilleg transmission of perceptual pathways. L Warm milk before bedtimeIwill increase serotonin level. I cannot sleep ·LSD is used to induce riual/auditory hallucinations  HISTAMINE Functions in pain threshold, sexual arousal, pituitary hormone secretion, thirst & blood pressure control. Histidine decarboxylase, B6 This reaction requires vitamin B6 ⑧ serotonin Catabolized to N-methylimidazol acetic acid or Imidazoleacetic acid. Catalysed by diamine oxidase (DAO), Histamine N- methyltransferase (HNMT), MAO & aldehyde dehydrogenase.  GLYCINE Inhibitory NT in the spinal cords Its action is comparable with GABA in the brain causing hyperpolarisation. Glycine is packed in the vesicles, release via exocytosis. Glycine receptor structure is similar to GABAA receptor. Effect: opens up chloride channels.  NITRIC OXIDE GAS Generated by synaptic terminals that innervate smooth muscle in the walls of blood vessels of PNS and at the synapse of several region of the brain. Also known as endothelium derivatives relaxation factor (EDRF). Causes vasodilation hypotension Nitric oxide synthase Arginine Nitric oxide citruline + NADPH + NADP+ O2  NEUROPEPTIDES Synthesis occurs in the neuron bodies as other proteins. Neuropeptide will undergo modification after its synthesis as a result of prohormone action, convertase & carboxypeptidase. Proteolysis product (neuropeptides) are transported to the presynaptic region.  NEUROPEPTIDES ARE INVOLVED IN RESPONSE TO; Substance P pain, regulation of pituitary gland function, control of digestive tract reflexes. Neuropeptide Y Stimulate appetite & food intake OPIODS endorphin Pain control, emotion & behavioral effects are poorly understood. Enkephalins Same as above Dynorphins Same as above  Neuromodulators – compounds that can alter the rate of NT release by presynaptic neurons or change the postsynaptic response to NT. It is difficult to establish the difference between NT & neuromodulators but neuropeptides can also be called neuromodulators. Most neuromodulators will act by binding to receptors on pre-& postsynaptic membrane & activating cytoplasmic enzymes. Eg vasoactive intestinal peptide (VIP). taken up ·some neurotrans miter I degrade ↑