8 nerve cell


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8 nerve cell

  1. 1. Nerve cellsNeurotransmission across synapsesBiochemistry IILecture 6 2011 (E.T.)
  2. 2. Nervous tissue•  2,4% of adults body weight, of which 83% is the brain• Large consumption of energy• Consumption of 20% O2 from the total amount• Content of specific complex lipids• Rapid turnover of proteins• Types of cells: CNS - neurons, astrocytes, oligodendrocytes, ependymal cells, microglia PNS – neurons, Schwann cells, satelite cells 2
  3. 3. Types of the cells neuron oligodendrocyte astrocytemicroglia capilary 3
  4. 4. Endotel lining of vessels in brain Blood-brain barier Free transport of substrates from blood is restricted The all hydrophilic substrates must have transportion systems Only water and small lipophilic molecules are freely permeable Kapilary beds in peripheral tissues Kapilary beds in CNS Glc Continuous basement membrane astrocytesinterstitial fluid – free diffusion through intercellular space – numerous tight junctions limit free diffusion – pinocytosis (transcytosis) – lack of pinocytosis – glucose transporters – the basement membrane is highly consistent 4 – transporters GLUT have low efficiency
  5. 5. Endotelial cells in brain• Protect the brain• Many drug-metabolizing enzyme systems• Active P-glycoprotein pumps• Specific transport systems for most of compounds• Only small lipophilic molekules readily cross blood-brain barrier by passive difusion• Basement membrane surrounds cappilaries 5
  6. 6. Glucose transporters in brain• Endothelial membranes – GLUT 1• Glial cells: GLUT1• Neurons membranes – GLUT 3• Rate of glucose transport is limited by KM for GLUT 1Transport of glucose through capillary walls is much less efficient(blood-brain barrier).When the glucose level drops below 3 mmol/l transport is not sufficient,hypoglycemic symptoms develop 6
  7. 7. Transport of other molecules through blood – brain barrier• Monocarboxylic acids (lactate, acetate, pyruvate, ketone bodies) – specific transporters• Esential AA (phenylalanine, leucine, tyrosine, isoleucine, valine, tryptophan, methionine, histidine ) – rapidly enter CFS via a single amino acid transporters• Non essential AA – transport is markedly restricted, they are synthetized in the brain• Vitamins – specific transporters• Some proteins (e.g.*insulin, transferrin, IGF) cross the blood-brain barrier by receptor mediated endocytosis 7
  8. 8. Lipids in the brain• Fatty acids and other lipids (cholesterol, phospholipids, glycolipids ..) cannot penetrate blood-brain barrier• All these lipids must be synthesized in the brain• Only essential fatty acids (linolenic and linoleic) have specific transporters• Very long fatty acids are synthesized in brain (necessary for myeline formation)• DHA is most abundant (22:6 (n-3))• -oxidation, peroxisomal fatty acids oxidation occur in brain 8
  9. 9. Insulin receptors• insulin receptors are observed in certain parts of themammalian brain (mostly on neurons)• brain is an insulinsensitive tissue and, in association with othernutrient and adiposity signals, such as fatty acids, amino acids,and leptin, probably plays an important role in the regulation ofenergy balance and glucose homeostasis. 9
  10. 10. Energy production in brain• metabolisms of glucose ( 100 g of glucose /d)• utilisation of keton bodies (during starvation nearly 50% )• Citric acid cycle• Aerobic metabolism – consumption of 20% of O2 10
  11. 11. DendritesNeurons with receptors of neurotransmitters. Perikaryon – the metabolic centre of neuron with intensive proteosynthesis, is highly susceptible to low supply of oxygen. Axon – the primary active transport of Na+ and K+ ions across axolemma and voltage operated ion channels enables inception and spreading of action potentials. – axonal transport (both anterograde and retrograde) provides shifts of proteins, mitochondria, and synaptic vesicles between perikaryon and synaptic terminals. - myelin sheat enables the rapid saltatory conduction of nerve impulses. Axon terminals - synapses – neurotransmitters are released from synaptic vesicles 11 into the synaptic cleft by exocytosis.
  12. 12. Axonal transport In the axon, there is a fast axonal transport along microtubules. It works on the principle of a molecular motor, via the motile proteins. Kinesin drifts proteins, synaptic vesicles, and *mitochondria in anterograde transport, dynein in retrograde transport. anterograde transport retrograde transport*Mitochondria are mobile organelles and cells regulate mitochondrial movement in order tomeet the changing energy needs of each cellular region. Ca2+ signaling, which halts both 12anterograde and retrograde mitochondrial motion, serves as one regulatory input.
  13. 13. Myelin sheaths are formed by wrapping Myelin of protruding parts of glial cells round the axons; oligodendrocytes (CNS) Schwann cells (PNS). Numerous plasma membranes are tightly packed so that the original intracellular and extracellular spaces cannot be differentiated easily.Myelin membranes contain about 80 % lipids cytoplasmic sides(30% of cholesterol, 16% of cerebrosides).The main structural proteins are the "outer“ sides - proteolipidic protein, - the basic protein of myelin (encephalitogen), - high molecular-weight protein called Wolframs protein. 13
  14. 14. Myeline damage• Demyelination disease - loss or damage of myelin, both in the CNS and in the PNS• E.g. Multiple sclerosis The cause has yet to be determined; autoimmune proces demyelination of white matter of brain tissue and multifocal inflammation  damaged nerve conduction along the demyelinated area Presence of oligoclonal immunoglobulins in cerebrospinal fluid 14
  15. 15. AstrocytesRoles of astrocytes:• connected by gap junctions - syncitium• support for migration of neurons, matrix that keeps them in place• synthesis and degradation of glycogen• uptake and metabolism of neurotransmiters (e.g. GABA, glutamate)• by phagocytoses take up debris left behind by cells• control the brain extracellular ionic enviroment (Na+/K+- pump, K+-„uptake“, Na+-HCO3 – cotransport, transport of gases.)• secretion of neurotransmiters (NO, VIP /vasoactive intestinal peptide/ PGE2) 15
  16. 16. Metabolism of ammonia in brain• Glutamate released by neurons into the synaptic cleft is taken up by astrocytes and recycled into the form of glutamine• NH3 crosses the H-E barrier• If the concentration of ammonia in blood is high, it is incorporated into Glu a Gln in astrocytes (glutamate dehydrogenase, glutamin synthetase).•  depletion of ATP, due to depletion of 2-oxoglutarate for CAC  accumulation of Gln and Glu in astrocytes.• Accumulation of Glu in astrocytes lieds to fall in transport of Glu from synaptic cleft (and damage of neurons by excitotoxic effects of Glu).• Surplus of Gln results in damage of osmotic regulation in astrocyte, increased intake of water  oedem of brain 16
  17. 17. Metabolism of ammonia in brain Blood- Astroglial cell Neuron Capilary brain barier glutamate NH4+ NH3 NH4+ NH3+ 2-oxoglutarate ATP glutamate GABANH4+ NH3 NH3 NH4+ ATP glutamine glutamate 17
  18. 18. Nerve impulse•Neurons are irritable cells•The lipidic bilayer is practically impermeable to theunevenly distributed Na+ and K+ ions.•The resting membrane potential is –70 mV on the innerside of the plasma membrane.•This potential is maintained by Na+,K+–ATPase. Channels present in the membrane: ligand-gated Na+/K+ channel, – voltage-operated Na+ channel, and – voltage-operated K+ channel. 18
  19. 19. Changes of membrane mV Spike potential during an 35 potential action potential Na+ channels (propagation of nerve opened impuls along the repolarization mebrane) Treshhold potential Resting -70 potential Time (ms)•stimulus triggers the depolarization• if the depolarization reaches the „treshold value“ voltage operating Na+ channels will open,Na+ enters massively the cell, depolarization takes place• this triggers the slow opening K+ channels, Na+ channels will slowly close, potassium fluxesinside the cell, repolarization takes place• Na+/K+ pump restores the concentration gradients disrupted by action potential•Action potential is propagated to the axon terminals 19
  20. 20. Transmiting the nerve impuls across the synaptic cleft•Action potential travels down the axon to the axon terminal•Each axon terminal is swollen, forming a synaptic knob•The synaptic knob is filled with membrane –bounded vesiclescontaining a neurotransmitter•Arrival of an action potential at the synaptic knob opens voltage-gated Ca2+-channels in the plasma membrane•The influx of Ca2+ triggers the exocytosis of some of the vesicles•The nerotransmitter is released into the synaptic cleft•The neurotrabnsmitter bind to receptors on the postsynaptic 20membrane
  21. 21. Synaptic transmissionNeurotransmitters act as chemical signals between nerve cellsor between nerve cells and the target cells. voltage-gated Ca2+ channel depolarization wave Ca2+ receptor synaptic vesicles (synaptosomes) postsynaptic membrane synaptic cleft The response to the neurotransmitter depends on the receptor type: – ionotropic receptors (ion channels) evoke a change in the membrane potential - an electrical signal, – metabotropic receptors are coupled to second messenger pathway, the evoked signal is a chemical one. 21
  22. 22. NeurotransmittersA large number (much more than 30) of neurotransmitters have been described.Many of them are derived from simple compounds, such as amino acids andbiogenic amines, but some peptides are also known to be importantneurotransmitters. The principal transporters:Central nervous systeminhibitory GABA (at least 50 %) glycine (spinal cord) Peripheral neuronsexcitatory glutamate (more than 10 %) – efferent acetylcholine (about10 %) excitatory acetylcholine dopamine noradrenaline (about 1 %, in the striatum 15 %) serotonin histamine – afferent sensory neurons aspartate glutamate noradrenaline (less than 1 %, neuropeptides but in the hypothalamus 5 %) adenosineneuromodulatory endorphins, enkephalins, endozepines, delta-sleep inducing peptide, and possibly endopsychosins. 22
  23. 23. Neurotransmitter receptors Contrary to various types of hormone receptors, only two basal types of neurotransmitter receptors occur:Ionotropic receptors – ligand-gated ion channels (ROC), e.g. excitatory – acetylcholine nicotinic - Na+/K+ channel, – glutamate (CNS, some afferent sensory neurons) - Na+/Ca2+/K+ channel, inhibitory – GABAA receptor (brain) - Cl– channelMetabotropic receptors activating G proteins, e.g. Gs protein – -adrenergic, GABAB receptor, dopamine D1, Gi protein – 2-adrenergic, dopamine D3, acetylcholine muscarinic M2 (opens also K+ channel), Gq protein – acetylcholine muscarinic M1, 1-adrenergic. 23
  24. 24. Acetylcholine receptors nicotinic muscarinicacetylcholine-operatedNa+/K+ channels ; M1-M5 Metabotropic, act throuhg G-proteinsin the peripheral nervoussystem M1 –Gq protein, vegetative ganglia, CNS, b.exocrine glandsin the dendrites of nearly M2 –Gi, in heart, opens K+-chanelsall peripheral efferentneurons (including M3 - Gq protein, in smooth muscleadrenergic neurons) M4 –Gi, v CNS at neuromuscular M5 –Gq, v CNSjunctions ion the cytoplasmicmembrane of skeletalmuscles. Atropin is an acetylcholine antagonist at muscarinic receptors 24 .
  25. 25. Cholinergic synapse acetylcholine receptors depolarization wave Na+ Ca2+choline acetyltransferase(by axonal transport) ACETYLCHOLINE acetyl-CoA ATP membrane-bound acetylcholinesterase reuptake choline acetate Increase in intracellular [Ca2+] activates Ca2+-calmodulin-dependent protein- kinase that phosphorylates synapsin-1; its interaction with the membrane of synaptic vesicles initiates their fusion with the presynaptic membrane and neurotransmitter exocytosis. The membranes of vesicles are recycled. At neuromuscular junctions, the arrival of a nerve impulse releases about 300 vesicles (approx. 40 000 acetylcholine molecules in each), which raises the acetylcholine concentration in the cleft more than 10 000 times. 25
  26. 26. Myastenia gravis• Myastenia gravis is an aquired autoimmune disease caused by production of an antibody directed against the acetylcholine receptor in skeletal muscle• The antibodies bind to the receptor forming receptor- antibody complex• Complex is endocytosed and incorporated into lysosomes Number of receptors is reduced Muscle weakness 26
  27. 27. Acetylcholine esterase• Hydrolysis of acetylcholine to acetate and choline• Serine hydrolase 27
  28. 28. Inhibitors of acetylcholinesterase CH3 CH3 H CH3 N N HN• a) reverzible: carbamates (physostigmine, O O rivastigmine, neostigmine) CH3• b) irreverzible: organophosphates phyzostigmin (diisopropylfluorphosphate, soman, sarin) e Binding of toxic organo phosphates occurs in two phases: reversible ( it may be affected by reactivators) ireversible – formation of covalent bond between organophosphate and an enzyme 28
  29. 29. Reversible phaseIrreversible phase 29
  30. 30. Reactivators of acetylcholinesterase Oximes with pyridine heterocycle CH3 - Cl + N OH N pralidoxime - - Cl Cl obidoxime + +OH N O N OHN N 30
  31. 31. Function of reactivatorsRegeneration of acetylcholin esterase 31
  32. 32. Acetylcholine nicotinic receptor – Na+/K+ channel•asymmetric pentamer of four kinds of membrane-spanning homologous subunits•activated by binding of two molecules of acetylcholine. 2-subunits bind two acetylcholine molecules the closed state Na+ K+ a large inward 2 2 flow of Na+  a smaller outwardsynaptic flow of K+ cleft – –cytoplasm binding sites for local anaesthetics, changes in conformation, the channel psychotropic phenothiazines. etc. undergoes frequent transitions between open and closed states in few milliseconds D-Tubocurarine is an antagonist of acetylcholine that prevents channel opening. Succinylcholine is a myorelaxant that produces muscular end plate depolarization. 32
  33. 33. Acetylcholine (cholinergic) receptorsof the peripheral efferent neurons N N N N N Most postganglionic neurons of the sympathetic path are adrenergic Adrenergic N M1 receptors motor neurons parasympathetic sympathetic (neuromuscular junction) system system 33
  34. 34. Adrenergic synapse Neurotransmitter of most postganglionic sympathetic neurons is noradrenaline. Varicosities of the postganglionic sympathetic depolarization wave axons are analogous to the nerve terminals.DA -hydroxylase synaptic vesicles (axonal transport) Ca2+ presynaptic adrenergic mitochondrial receptors NORADRENALINE monoamine oxidase partial reuptake adrenergic receptors in extracellular COMT membranes of the target cells (catechol O-methyltransferase) 34
  35. 35. Synthesis and storage of catecholamines• Synthesis from tyrosine DOPA dopamin in cytosol• Dopamin is transported into vesicles (ATP dependent transport)• Vesicles are transported to nerve terminals• -hydroxylation to noradrenalin occurs in vesicles 35
  36. 36. Adrenergic receptors of all types are receptors cooperating with G proteins.-Adrenergic receptorsAfter binding an agonist, all types of -receptors activate Gs proteins so that adenylate cyclase is stimulated, cAMP concentration increases, and proteinkinase A is activated. Particular types differ namely in their location and affinity to various catecholamines: 1 are present in the membranes of cardiomyocytes, 2 in the smooth muscles and blood vessels of the bronchial stem, 3 in the adipose tissue.2-Adrenergic receptorsThe effect is quite opposite to that of -receptors, binding of catecholamines results in the interaction with Gi protein, decrease in adenylate cyclase activity and in cAMP concentration.1-Adrenergic receptorsactivate Gq proteins and initiate the phosphatidylinositol cascade by stimulation of phospholipase C resulting in an increase of intracellular Ca2+ concentration and activation of proteinkinase C. 36
  37. 37. Adrenergic receptors 1, 2, and 3 noradrenaline/adrenaline  receptor AMP cyclase Gas bg ATP H2O cAMP phosphodiesterases inactive AMP proteinkinase A phosphorylations active proteinkinase AThe typical effects of -stimulation: 1 – tachycardia, inotropic effect in the myocard, 2 – bronchodilation, vasodilation in the bronchial tree,, 3 – mobilization of fat stores, thermogenesis. 37
  38. 38. Adrenergic receptors 2 a 1Receptors 2 Receptors 1 adenylate cyclase phospholipase C PL C Gi protein Gq protein IP3 and diacylglycerol cAMP decrease increase in [Ca2+] activation of PK C The typical effects of adrenergic 2-stimulation: 1-stimulation: glandular secretion inhibited vasoconstriction bronchoconstriction motility of GIT inhibited 38
  39. 39. Inhibitory GABAA receptor ligand-gated channel (ROC) for chloride anions. The interaction with -aminobutyric acid (GABA) opens the channel. The influx of Cl– is the cause of hyperpolarization of the postsynaptic membrane and thus its depolarization (formation of an action potential) disabled. Cl– 1 2 2 1 2 – – – – – – –The receptor is a heteropentamer.Besides the binding site for GABA, it has at least eleven allosteric modulatorysites for compounds that enhance the response to endogenous GABA – reductionof anxiety and muscular relaxation: anaesthetics, ethanol, and many useful drugs,e.g. benzodiazepines, meprobamate, barbiturates. Some ligands compete for thediazepam site or act as antagonists (inverse agonists) so that they cause discomfortand anxiety, e.g. endogenous peptides called endozepines. 39
  40. 40. Inhibitory synapseGABA (-aminobutyric acid) is the major inhibitory neurotransmitter in CNS.Gabaergic synapses represent about 60 % of all synapses within the brain. Ca2+ depolarization wave GABA / benzodiazepine GABA receptors mitochondrial synthesis of GABA from glutamate partial reuptake uptake of GABA into glial cells (transporters GAT 1,2,3,4) and breakdown to succinate In the spinal cord and the brain stem, glycine has the similar function as GABA in the brain. The inhibitory actions of glycine are potently blocked by the alkaloid strychnine, a 40 convulsant poison in man and animals.
  41. 41. Receptors for the major neurotransmitters Ion channels Receptors cooperating with G-proteins (ROC) Gs (cAMP increase) Gi (cAMP decrease) Gq (IP3/DG formation)Na+/K+ – acetylcholine – acetylcholine acetylcholine nicotinic muscarinic M2,4 muscarinic M1,3,5 – adrenergic β1, β2, β3 adrenergic α2 adrenergic α1Na+/Ca2+/K+ glutamate mGluR glutamate mGluR – glutamate ionophors – group II and III group I – dopamine D1,5 dopamin D3,4 dopamine D2 – serotonin 5-HT3 serotonin 5-HT4,6 serotonin 5-HT1 serotonin 5-HT2 – histamine H2 histamine H3,4 histamine H1 – – – tachykinin NK-1 for substance PCl– – GABAA GABAB (metabotropic) – – glycine 41