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Synthesis and degradation of neurotransmitters Josef Fontana Overview of the lecture • Definition of neurotransmitter and neuromodulator • Metabolism of neurotransmitters and neuromodulators (synthesis, postsynaptic receptor (receptors), the mechanism of removal from the synaptic cleft, the importance for clinical practice and pharmacology) – – – – – – – – – a) Amino acids excitatory: glutamate, aspartate inhibitory: GABA, glycine b) Monoamines Catecholamines: NA, dopamine Serotonin (melatonin) c) Acetylcholine d) Peptides e) Other: purines, gases, endogenous cannabinoids Definition of neurotransmitter and neuromodulator Neurotransmiter neuromodulátor • Neurotransmitter: • a componud secreted into synaptic cleft and bound to postsynaptic receptors • removal from synaptic cleft by spercific biochemical mechanism • Neuromodulator: • a compound secreted by neurons into environment and spread by diffusion (or CSF) • modulates behavior of other neurons Metabolism of neurotransmitters and neuromodulators a) Amino acids excitatory: glutamate, aspartate Glutamate • Most common excitatory neurotransmitter (40% of all synapses) • Synthesis: – 2-KG from Krebs cycle (GDH or transaminase) – Deamination of glutamine (glutaminase) Glutamate • Postsynaptic receptors: – NMDA (N-methyl-D-aspartate) – belongs to ionotropic receptors, requires the binding of the coagonists (glycine and D-serine) for the efficient opening of the ion channel – AMPA (α-amino-3-hydroxy-5- methyl4-isoxazolepropionate) – Cainate D-serine D-cykloserine Glycine Glutamate NR1 NR2 Ca+ Glutamate - Clinical significance • NMDA antagonists: ketamine (dissociative anesthesia), phencyclidine ("angel dust") • excitotoxity: excesive glutamate release (epilepsy, traumatic brain injury), leads to Na+ and Ca2+ IC accumulation - swelling • controlling synaptic plasticity and memory function Aspartate • Excitatory neurotransmitter, mostly in spinal cord • Synthesis: – derived from OAA (Krebs cycle) – • Postsynaptic receptor: – NMDA – lower affinity than glutamate – • Removal from synaptic cleft: re-uptake Metabolism of neurotransmitters and neuromodulators a) Amino acids inhibitory: GABA, glycine GABA = γ-aminobutyric acid • The most important inhibitory neurotransmitter of the brain • Synthesis: GABA shunt GABA - postsynaptic receptors • GABAA: chloride channel • agonists: benzodiazepines, barbiturates • antagonists: flumazenil • GABAB: metabotropic receptor → G-prot → opening of K+ channels • agonist: baclofen Glycine • Inhibitory neurotransmitter of spinal cord • Synthesis: – from serine – • Postsynaptic receptor: – chloride channel: IPSP – (co-agonist on NMDA receptors) – Antagonist = strychnine -„seizure poison“ Metabolism of neurotransmitters and neuromodulators b) Monoamines Catecholamines: NA, dopamine Catecholamines are made from tyrosine • The conversion of tyrosine to epinephrine requires four sequential steps: • 1) ring hydroxylation • 2) decarboxylation • 3) side chain hydroxylation to form norepinephrine • 4) N-methylation to form epinephrine Catecholamines are made from tyrosine • Tyrosine hydroxylase is rate-limiting step for catecholamine synthesis. • It converts L-tyrosine to Ldihydroxyphenylalanine (L-dopa). • As the rate-limiting enzyme, tyrosine hydroxylase is regulated in a variety of ways. • The most important mechanism involves feedback inhibition by the catecholamines. Catecholamines are made from tyrosine • Dopa decarboxylase is present in all tissues. • This enzyme transforms L-dopa to 3,4dihydroxyphenylethylamine (dopamine). • Compounds that resemble L-dopa, such as αmethyldopa, are competitive inhibitors of this reaction – α-methyldopa is effective in treating some kinds of hypertension. Catecholamines are made from tyrosine • Dopamine-β-hydroxylase catalyzes the conversion of dopamine to norepinephrine. Catecholamines are made from tyrosine • Phenylethanolamine-Nmethyltransferase (PNMT) catalyzes the production of epinephrine. • PNMT catalyzes the N-methylation of norepinephrine to form epinephrine in the adrenal medulla. Catecholamin synthesis Tyrosine hydroxylase H C C COOH2 NH3+ 1. Phenylalanin H C C COOH2 NH3+ HO 2. HO Tyrosin 3,4 DihydrOxyPhenylAlanin (DOPA) DOPA decarboxylase H H2 C C HO HO Adrenalin H H2 C C 5. HO OH NH CH3 HO N-methyltransferase H C C COOH2 NH3+ HO OH NH3+ 4. 3. HO HO Dopamine βhydroxylase Noradrenalin Dopamin H2 C C + CO2 H2 NH3+ Catecholamines are made from tyrosine • Catecholamines cannot cross the blood-brain barrier – in the brain they must be synthesized locally. • In certain central nervous system diseases (eg. Parkinson's disease), there is a local deficiency of dopamine synthesis. • L-Dopa, the precursor of dopamine, readily crosses the blood-brain barrier and so is an important agent in the treatment of Parkinson's disease. Catecholamine breakdown Reuptake followed by IC degradation: COMT = catechol-o-methyl transferase MAO = monoaminooxidase MAO HO H C 77 COO78 OH CH3O COMT Inhibitors of MAO (IMAO) = antidepresive drugs Final metabolite: vanilmandelic acid Noradrenalin • Postsynaptic receptors: • metabotropic: α1, β1 … • there are also presynaptic receptors: α2 – inhibit NA release from neuron • Adrenergic systems: • locus coeruleus, lateral tegmentum • arousal, stress, mood Dopamine • Postsynaptic receptors are metabotropic: • D1: Gs-protein → cAMP → modulation of ion. channels → EPSP • D2: Gi-protein: phosphodiesterase activation → IPSP System Anatomy Function Significance Mesocortical tegmentum→fron t. cortex Motivation, mood, Schizophreny will Mesolimbic tegmentum→ nc. accumbens dtto Schizophreny, addiction Nigrostriatal s.nigra→striatum Motoric system M.Parkinson Tuberoinfundibul ar Inhibits prolactin nc. arcuatus→ eminent. mediana secretion Adverse eff. of antipsychotics Dopaminergic systems Nigrostriatal Mesolimbic Mesocortical Tuberoinfundibular Dopamine – Clinical significance • Antipsychotics: • phenothiazines = D-receptor blockers • AE = parkinsonism, hyperprolactinemia • Cocaine, amphetamines: • dopamine and NA re-uptake blockers • Parkinson disease: loss of dopaminergic neurons in s. nigra. Treatment: L-DOPA Metabolism of neurotransmitters and neuromodulators b) Monoamines Serotonin (melatonin) Serotonin • = 5-hydroxytryptamin • Anatomy: limbic system, reticular formation • Function: – anger/aggression, mood, sleep – appetite/satiety/vomitting – body temperature – sexual behavior Degradation by MAO: 5-hydroxyindolacetate Melatonin • Pineal gland • Biorythms • Hormone/neuromodulator Metabolism of neurotransmitters and neuromodulators c) Acetylcholine Acetylcholine • CNS: pontomesencefalotegmental complex • autonomic NS: preganglionic mediator of both symp. and p-symp., postganglionic mediator of p-symp • peripheral NS: neuromuscular junction • synthesis: AcCoA + choline: CH H3C C O O + 3 C C N CH3 H2 H2 CH 3 • degradation: Acetylcholine eserase Acetylcholine - postsynaptic receptors • Nicotinic = inotropic - Na+ channels • NM (muscular) - on the neuromuscular junction • NN receptor (neuronal type) – postsynaptic membranes in autonomic ganglia and brain Acetylcholin - postsynaptické receptory • Muscarinic = metabotropic • M1 = Gq-prot.: ↓K+ current: CNS (cognitive function), autonomic ganglia • M2 = Gi-prot.: ↑K+ current: CNS, heart • M3 = Gq-prot.: eye, glands • M4 and M5: CNS, eye M1, M3, M5 receptors muscarinic receptor M2, M4 receptors muscarinic receptor Acetylcholine – Clinical significance • Lecithin = phosphatidylcholine (acetylcholine precursor) • Acetylcholine esterase inhibitors: • physostigmine (passes through HEB): arousal from general anesthesia • donepezil, rivastigmine and galantamine (pass through HEB): Alzheimer's disease therapy • neostigmine (does not pass): psympatomimetic, myastenia gravis Irreversible inhibitors of ACHE - organophosphates • products used in agriculture (herbicides, pesticides, BC) • chemical warfare agents: tabun, sarin, soman (good penetration through the skin and mucous membranes) • symptoms of poisoning: nausea, vomiting, headache, weakness, sweating, salivation, bradycardia, muscle spasms, breathing difficulty or arrest Acetylcholine – Clinical significance • M-receptor blockade = atropin (parasympatolytics) • N-receptor blockade = curare (arrow poison) - derivatives = muscle relaxants Metabolism of neurotransmitters and neuromodulators d) Peptides Peptides • Appr. 50 known • Mainly in the hypothalamic-pituitary system • Synthesis: prepropeptid → ER, signal sequence cleavage → propeptid in vesicles → further processing → peptide neurotransmitter (1 or more) • Removal from synaptic cleft: Degradation, but not re-uptake Peptides Peptides: examples • Opioids: endorfines, enkefalins • limbic system, inhibit l. coeruleus • axo-axonal synapse • NP-Y • mediates the influence of leptin on food intake • Neurotensine: • regulates LH and prolactin secretion • Substance P… Metabolism of neurotransmitters and neuromodulators e) Other: purines, gases, endogenous cannabinoids Endocannabinoid system • Retrograde neurotransmission: anandamide – synthesized in the postsynaptic neurone – diffuses to presynaptic neurone – bound to CB1 and CB2 rec. (G-prot.) – influence presynaptic neuron behavior • CB1 – in CNS – regulates cognitive function, food intake • CB2 – periphery - the immune system