Neurotransmitters Mohammad Nusier Hadeel AL-Momani 1 P a g e Biochemistry #2
Date : 15/2/2016 \ Lecture #2 biochemistry \ Lecture #17 CNS \ Subject : Neurotransmitters Neurotransmitters 1- Excitatory : 2-Inhibitory: 1.Acetylcholine 2. chatecholamines ( Dopamine, E, NE ) 1.Glycine* (acts in spinal cord & brain stem) 2.GABA* (acts in all other parts of brain) 3.Taurine * Major ones The biogenic amines: indolamines 1. Serotonin 2. Histamine The amino acid transmitters: "GGG" 1. Glutamate 2. GABA 3. Glycine Acetylcholine Synthesized in terminals from acetyl CoA (found everywhere) and choline (from blood and recycled ACh, but not synthesized in neurons) Synthesizing enzyme = CAT (choline acetyl transferase) Acetyl CoA + Choline Acetyl Choline (Ach) Inactivated = by ACHesterase; ACh is not taken up into neurons (only degradation ) Used by somatic motor neurons within CNS Two major subtypes of receptors = nicotinic (nachr) and muscarinic (machr), each of which has its own subtypes. 2 P a g e
Nicotinic Receptor type directly gated channels for Na + and K + Places striate muscle (N 1 ) postganglionic neurons (N 2 ); CNS Muscarinic linked to 2 nd messengers visceral smooth, cardiac muscle, glands, postganglionic neurons, CNS Dopamine Is a biogenic amine & specifically a catecholamine, so it shares a pathway with NE & EPI Synthesized from tyrosine (Tyr is from the essential AA Phenyl alanine "Phe") Rate limiting enzyme is tyrosine hydroxylase Carbidopa "drug" blocks conversion of DOPA (dihydroxyphenylalanine) to dopamine by dopa decarboxylase, but cannot cross the BBB >> the difference btw DOPA & Dopamine is the carboxyl group >> if u remove it.. DOPA will become Dopamine. Inactivation of DOPA: either by Reuptake (blocked by cocaine); or Degradation by COMT 1 (extracellular) and by MAO 2 (intracellular) A major Metabolite for DOPA degradation : HVA (homovanillic acid) which shows up in CSF >> look for this metabolite level in the lab to looking for specific disorders!. So far, there are 5 subtypes known, all 2 nd messenger-linked. DA"dopamine" is important in mood disorders, schizophrenia, basal ganglia function. Parkinson's results from loss of DA neurons in basal ganglia. Norepinephrine Shares pathway with other catecholamines (Dopamine) Used in CNS (locus coeruleus and lateral tegmental nuclei of brainstem) and by most post-ganglionic sympathetic neurons 1 catechol-o-methyl transferase.. 2 monoamine oxidase 3 P a g e
Inactivation = reuptake (blocked by cocaine); or degradation by COMT in (extracellular) space and by MAO (intracellular) At least 4 subtypes, all 2 nd messenger-linked. (b1,b2 both increase camp, a2 decreases camp, að1 acts through PLC)>> PLC >> phospholipase C system. Agonists include Ephedrine, Phenylephrine (a), Isoproterenol (b)>> "EPI" Antagonists include phentolamine (a), propranolol (b) >> "PP" A transmitter in a few brain stem neurons an adrenal neurohormone.. ** synthesis of catecholamines:: Epinephrine From the pic above : -focus on the enzymes which are responsible for tyrosine development into Dopamine -Focus on the difference btw DOPA & DA DO U REMMEBER?! -focus on Dopamine β- hydroxylase & its requirement ( ascorbic acid + oxygen ). 4 P a g e
-focus on the difference btw NE & E which is "methyl" group only.. & this converting done by Phenylethanolamine N-methyl transferase enzyme, which convert Adenosyl methionine into Adenosyl homocysteine. ** Catecholamine Metabolites from "degradation ": MAO "intracellular " & COMT "extrcellular " >> intermediates >> mandelic acid "which have diagnostic value for some neurological disorders.. OoooH, how can I memorize this 8arf?? " Joke :P " it's احفظ بصمت **focus on : if MAO did the first step, so the 2 nd step for COMT.. & vise versa. ** all of the following are intermediates for E & NE except :?? HVA : is very important metabolite for Dopamine "also have diagnostic value for some neurological disorders". **focus on : if MAO did the first step, so the 2 nd step for COMT.. & vise versa. ** all of the following are intermediates / metabolites for Dopamine except :?? "**" this sign >> the doctor did't say them.. they are only for Nerds :P the doctor only concentrated on the final result for the metabolism & "MAO, COMT " enzymes. بقية الصفحة للخرابيش! 5 P a g e
Synthesized from tryptophan Serotonin (5HT = 5-hydroxytryptamine) Rate-limiting enzyme = tryptophan hydroxylase Inactivation = reuptake into terminals, degradation by MAO The raphe nuclei of the brain stem are the major source of 5HT raphe nuclei are midline, i.e. unpaired nuclei Many subtypes, many actions Mostly 2 nd messenger-gated ion channels, but at least one direct channel receptor Many anti-depressants are targeted at 5-HT neurons (the popular prozac)>> prolong serotonin action " pleasure hormone action" From pic.>> ** Synthesis of Serotonin by Two processes : 1- Hydroxylation : by hydroxylase >> 5HT 2- Decarboxylation : by decarboxylase >> serotonin ** the source of hydroxyle group in the first step is : Tetrahydrobiopterin.. histamine : A local hormone and a hypothalamic transmitter. At least three receptor subtypes known so far. Synthesized from histidine (amino acid). **The histadine is converted to histamine by Decarboxylase enzyme. 6 P a g e
Glutamate Mediates fast excitatory communication in the CNS (direct channel-linked) Acts through : 1) 3 direct ligand-gated channel receptor types: NMDA, AMPA and kainate (KA) receptors* 2) 2 or more types of metabotropic (G-protein linked) receptors: ACPD and L-AP4* G- protein linked >> phosphorlate certain enzymes which lead to inhibition or activation certain activity in the cells. NOTE"*" : The names reflect their different pharmacological profiles, but physiologically, in the body, they all bind glutamate ; ex : NMDA receptor channels admit Ca ++ which is an important 2 nd messenger GLU (Glutamate ) is an abundant amino acid in the brain "one of the most abundant AA in the brain ", maybe 30% of which is transmitter. Inactivation = reuptake by glial cells, or by conversion to glutamine then it will return to neuron terminal (where it can be reconverted to GLU) --> the difference btw glutamine & glutamate is an amide group only.. Glu is synthesized by 3 methods: 1- Deamination of Glutamine by glutamase "removal of amide group " 2- Amination of alpha ketoglutarate by Glu dehydrogenase ( utilizing free ammonia and then move the amide group to the alpha ketoglutarate ) 3- Transamination of alpha ketoglutarate by transaminase ( utilizing attached amide group from other AA ) **the difference between Amination &transamination is that the Source of amide group. 7 P a g e
Major inhibitory transmitter in the CNS 8 P a g e GABA Altered GABAergic function may play a role in many clinical situations (e.g. basal ganglia disorders, seizure disorders, schizophrenia, sleep disorders) & have a big role in epilepsy. Synthesized from glutamate by GAD (glutamic acid decarboxylase), requires Vit B6 as cofactor so, B6 deficiency can lead to loss of synaptic transmission. P.s : Glutmate "excitatory " GABA "inhibitory ". Inactivation = reuptake by nerve terminals for reuse by glia, where it undergoes conversion to glutamine, then return to neuron terminal (where it can be reconverted to Glu and then to GABA) >> as Glutamate inactivation. At least two major receptor subtypes: 1- GABA A is a direct-gated Cl - channel 2- GABA B is G-protein linked, inhibited by K + permeability, Ca ++ influx (especially as presynaptic inhibition), which will camp. Benzodiazepines (Valium) and, probably, neurosteroids bind to GABA A receptor, increase GABA effect >> they increase the inhibitory effect. Agonists: Muscimol (A), baclofen (B) >> in math science "-ve X +ve = -ve " so the agonist increase the " vitiy" >> the inhibition. Antagonists: Bicuculline (A) >> in math science " ve X ve = +ve " so the antagonists decrease the "-vitiy " >> the inhibition. Glycine The other inhibitory transmitter in the CNS Receptor is direct ligand-gated Cl - channel Used by Renshaw cells (inhibitory interneurons in spinal cord, supplying recurrent inhibition) Antagonist = strychnine >> the inhibition.
GABA is synthesis from decarboxylation of glutamate ; which need Vit6 cofactor. So Vit 6 deficiency leads to loss of synaptic transmission. Receptors A & B play a role in Epilepsy. Glycine- about 1/2 of neurons in spinal cord use glycine receptors similar to GABAa receptors & both of them are rapidly reuptake by glia & neuron after they exert their action. Hyperglycinemia- defect in glycine uptake and removal leads to severe mental retardation. ** Both GABA and glycine are rapidly taken up by glia and neurons. ** GABA & Glysine : Most inhibitory neurons use one or the other & Inhibits the ability to fire action potentials. Similar to glutamate: excitatory NT Functions in fewer pathways Aspartate Made from oxaloacetate by tranamination reaction ; why?bcz the oxaloacetate is α - ketoacid for aspartate! Aspartate can't pass through BBB Nitric Oxide Effects: vasodilatation, neurotransmission (penile erection), killing tumor cells and parasites Made from arginine by NO-synthase NO activates guanylate cyclase: increase cgmp: activates protein kinases Can cross membranes BBB (bcz it's gas). 9 P a g e
This pic illustrate " Synthesis, Release, and Reuptake of GABA and Glycine".. Vesicular transporters regulate the amount and type of neurotransmitters requestered into synaptic vesicles. We have two examples for neurological disorders that related to neurotransmitters : 1-Phenylketonuria (PKU) : Phenylalanine cause mental retardation ; and it's one of the tests that done in neonatal screening.and the treatment is very easy by restrict the Phenylalanine in the diet. This is one of the most common inborn errors of metabolism which affects cerebral activity, affecting approximately 1 out of 20,000 infants. The genetic defect is a lack of phenylalanine hydroxylase and leads to increased concentrations of phenylalanine. The neurochemical mechanisms involve tyrosine and tryptophan pathways. Fortunately, the disorder can be treated in many cases by diet restriction 2- Tay Sachs Disease : This is a lipid-storage disorder transmitted as an autosomal recessive trait. The metabolic defect is a deficiency of the hexosaminidase found in lysosomes involved in ganglioside degradation. Its absence causes lipids and proteins to accumulate in membranous cytoplasmic bodies. There is no established therapy;the treatment is only symptomatic, although recent research has searched for a means of enzyme replacement. % 99 من أطباء امعامل ينصحون مرضامه ابستخدام امساليدات.. امرصاحة أان ثعبت من امكويب بيست لك امتوفيق ع ون (; هذا امتفريغ برعاية )كوجليت \ س ينسوداين \ سيجنل ) معلش إلنه لكهم حاصلني عىل رضا %99 من أطباء السنان ابمعامل :3 Done By your sister : Hadeel Izzat AL-Momani & Checked by : Alanood Albustanji 10 P a g e