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  1. 1. M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar
  2. 2.  Definition : - The chemical substance helpful for signal transmission in central nervous system &peripheral nervous system (via) the chemical synapses is neurotransmitters.  Synaptic transmission is the predominant means by which neurons communicate with each other.
  3. 3.  The criteria for Chemical neurotransmitter  1) found in presynaptic axon terminal.  2) enzymes necessary for synthesis are present in presynaptic neuron .  3) stimulation under physiological conditions results in release.  4) mechanism exist for rapid termination of action.  5) direct application to postsynaptic terminal mimics the activation of nerve stimulus.
  4. 4.  6) drugs that modify metabolism of the neurotransmitter should have predictable physiological effects invivo assuming that the drug is transported to the site where neurotransmitter acts.  Not all neuron to neuron transmission is by neurotransmitters , gap junctions provides direct neuron to neuron electrical conduction.
  5. 5.  Neurotransmitter is stored in synaptic vesicle released in response to nerve impulse & controled by calcium influx.  Release of neurotransmitter is quantal event , that is a nerve impulse reaching presynaptic terminal result in release of transmitter from a fixed number of synaptic vesicle.  Neurotransmitter action is terminated by metabolic degradation , reuptake , or diffusion into other cell types.
  6. 6.  Class :- 1 acetylcholine  Class : -2 The biogenic amines norepinephrine , epinephrine dopamine , serotonin .  Class : - 3 amino acids gamma amino butyric acid (GABA) , glycine , glutamate , aspartate.  Class : - 4 nitric acid (NO) carbonmonoxide ( co )
  7. 7.  In addition to classical neurotransmitters many neuropetides are identified as definite or probable neurotransmitters, eg : - substance p , neurotensin , enkephalin , β – endorphin , histamine, vasoactive intestinal polypeptide, cholecystokinin , neuropeptide Y & somatostatin.
  8. 8.  Neurotransmitters modulate the function of post synaptic cells by binding to specific receptors of 2 types  1) ionotropic receptors ( direct ion channels that open after binding of neurotransmitters. ) 2) metabotropic receptors ( interact with G proteins stimulating production of second messengers & activating protein kinases , which modulate the cellular events. )
  9. 9.  G proteins couple several receptors to intra cellular signaling system , linking neuronal excitability to energy metabolism & second messenger systems.  G protein binding receptors include adenosine , Ach ( muscarnic ), norepinephrine , dopamine , serotonin
  10. 10.  Kinetics of ionotropic receptors are fast , (< 1 ms ) , because neurotransmitters directly alter the electrical property of the postsynaptic cell.  Kinetics of metabotropic receptors functions over longer time periods. This contributes to the potential for selective & finely modulated signaling by neurotransmitters
  11. 11.  The membrane of neuronal cell maintains an asymmetry of inside outside voltage , & is electrically excitable.  Neuronal membranes are polarized to a potential of - 90 mV by the activity of Na+_k+ ATPase transport system.
  12. 12.  Factors that control the neuroexcitability 1)voltage gated ion channels 2) neurotransmitter activated ion channels. 3)neuromodulators 4)second messenger system.  The control of neuronal activity within normal limits is by the modulation of excitatory & inhibotory events simultaneously.
  13. 13.  Ligand gated channels are responsible for communication between cells.  Voltage gated sodium channels are involved in propagation of action potential , rapid activation is at -60mV due to opening of fast transient channels. Voltage gated potassium channels contribute to repolarization ,this regulate repeated firing of action potential by prolonging after spike repolarization.
  14. 14.  Voltage dependent calcium channels trigger neurotransmitter release , at rapid activation is around -70mV.  Autoantibodies to ca++ channels in motor nerve terminal leads to decreased release of Ach from nerve terminal , this is seen in eaton lambert myasthenic syndrome.  Voltage gated channels determine how inhibitory & excitatory influences are integrated .
  15. 15. Acetyl choline  Acetyl choline is the neurotransmitter used by all motor axons that arise from spinal cord, that is at neuromuscular junction.  Junction consist of a single nerve terminal separated from post synaptic region by synaptic cleft.  Motor end plate is the specialized portion of the muscle membrane involved in the junction.
  16. 16.  Junctional folds are prominent they contain high density of Ach receptors.  Synthesis of Ach takes place in cytosol of nerve terminal . choline acetyl transferase acetyl coA+ choline Ach + coA  Ach is incorporated into membrane bound particle called synaptic vesicles.  Assembly of synaptic vesicle with cell membrane resembles assembly of transport vesicle involving SNAREs.
  17. 17.  Release of Ach into synaptic cleft occurs by exocytosis , which involves fusion of vesicle with presynaptic membrane.  Nerve ending is depolarized by transmission of nerve impulse this opens the voltage gated Ca++ channels , permitting influx of Ca++ from synaptic cleft to nerve terminal , this Ca++ plays a role in exocytosis of Ach vesicle.
  18. 18.  Approximately 200 vesicles are released into synaptic space.  Each vesicle contains 10000 molecules of Ach.  Ach binds Ach receptor , receptor undergoes conformational change opening the channel in the receptor that allows entry of Na+, k+ resulting in depolarization of muscle membrane.
  19. 19.  Properties of Ach receptor of NMJ : nicotinic receptor (nicotine is an agonist for the receptor) a membrane glycoprotein containing 5 subunits. ( 2αβγδ subunits). only α subunit binds Ach with high affinity. 2 molecules of Ach binds receptor to open the ion channel which permits Na+ , K+ the receptor is thus transmitter gated ion channel. autoantibodies to receptors are implicated in causation of myasthenia gravis
  20. 20.  Snake venom α bungarotoxin binds tightly to the α subunit & can used to label the receptor . Formation of autoantibodies to Ach receptors in NMJ damage to receptors by autoantibodies reduction in number of receptors Episodic weekness of muscles supplied by cranial nerves
  21. 21.  When the channel closes Ach dissociates & it is hydrolyzed by acetyl choline esterase. acetyl choline esterase Ach + H2O Acetate +choline  Choline is recycled into nerve terminal by active transport , it can be used for synthesis of Ach.
  22. 22.  The classical neurotransmitter of autonomic ganglia whether sympathetic or parasympathic is acetyl choline.  2 classes of receptors are present in autonomic nervous system.  1) nicotinic eceptors ,  2) muscarnic recptors.  Nicotinic receptors in autonomic ganglia are different from those on skeletal muscle.
  23. 23.  Nicotinc & muscarnic receptors mediate excitatory postsynaptic potentials (EPSP) , but these potential have different time course.  Stimulation of presynaptic neuron elicits a fast EPSP followed by a slow EPSP.  Fast EPSP results from activation of nicotinic receptors which cause of ion channels to open.
  24. 24.  Slow EPSP is mediated by activation of muscarnic receptors that inhibit the M current , a current that is produced by K+ conductance.  Besides acetyl choline sympathetic preganglion neurons may release enkephalin , substance p , LHRH , neurotensin or somatostatin.
  25. 25.  Neurotransmitter in parasympathetic postganglionic neurons is acetyl choline.  Actions are mediated by 3 types of muscarnic receptors.  1) M1 receptor (neural ) produces slow excitation of ganglia.  2) M2 receptor (cardiac) activation slows the heart.  3) M3 receptor (glandular) , causing secretion, contraction of visceral smooth muscle , vascular relaxation.
  26. 26.  Muscarnic Ach receptors act by way of inosine triphosphate system & they may also inhibit adenyl cyclase & thus decreasing cAMP synthesis.  Muscarnic recptors also open or close ion channels particularly K+ or Ca++ this action occurs through G proteins.  Muscarnic receptors relax smooth muscle by an effect on endothelial cells which produces nitric oxide (NO) .
  27. 27.  Nitric oxide ( NO ) relaxes smooth muscles by stimulating guanylate cyclase & there by increasing levels of cGMP which in turn activates cGMP dependent protein kinases.  The number of muscarnic receptors are regulated & exposure to muscarnic agonist decreases the number of receptors by internalization of rceptor.
  28. 28.  The betz cells of motor cortex uses acetyl choline as their neurotransmitter.  Acetyl choline probably acts as an imporatant neurotransmitter in basal ganglia which is involved in control of movements.  Deficits in cholinergic path way in the brain implicated in some form of Alzheimer's disease.
  29. 29.  GABA major fast inhibitory neurotransmitter in the fore brain. 30% synapses of C.N.S contain GABA.  Glutamic acid dehydrogenase synthesizes GABA from glutamate in nerve terminal .  3 types of receptors GABA a GABA b GABA c
  30. 30.  GABA a & GABA c are ionotropic receptors & are post synaptic linked to chloride channel.  GABA b receptors are metabotropic may be pre or post synaptic & are coupled to ca+ or k+ ion channels via GTP proteins.  Presynaptic GABA b receptors serve autoreceptors to inhibit release from nerve terminal.
  31. 31.  Binding of GABA leads to an opening of chloride channels & resultant hyperpolarization.  Glycine is inhibitory neurotransmitter in brain stem & spinal cord.  Post synaptic receptor for glycine is ligand gated chloride channel that allows influx of Cl- to hyperpolarize the postsynaptic neuron
  32. 32.  Glutamate & aspartate are excitatory neurotransmitters.  Glutamate is responsible for 75% of excitatory neurotransmission in brain.  Synthesis of glutamate & aspartate within central neuron & glial cells is from carbohydrates involved in TCA cycle.
  33. 33.  Mitochondrial enzyme aspartate transaminase interconverts glutamate & aspartate.  Glia contains glutamine synthase which converts glutamate to glutamine.  Glutamine is subsequently transferred to neuron where it is deaminated to glutamate by glutaminase.
  34. 34.  Glial inactivation & specific uptake systems for glutamate reduces interstitial glutamate levels to terminate neurotransmitter action & prevent excitotoxic damage.  Monosodium glutamate produces migrainous head ache.  Excessive glutamate can result in neurotoxicity , celldeath & neurodegeration seen alzheimer’s disease.
  35. 35.  The receptors are subdivided into 5 classes.  1 )NMDA (N – methyl –D –aspartate )  2 )AMPA (α amino 3 hydroxy 5 methyl 4 isoxazole propionic acid )  3 )The kainate recptor ( isolated from sea weed)  4 )L –AP 4 ( synthetic agonist )  5 )Metabotropic receptors.  First four receptors are cation channels .
  36. 36.  Metebotropic receptors are linked to intracellular production of diacylglycerol,& inositol triphosphate by phosphoinositide path way.  NMDA is receptor is complex contains 5 distinct sites for binding 1 ) site for transmitter binding glutamate 2 ) a regulatory site that binds glycine. 3 ) a voltage dependent Mg++ binding site 4 ) a site that binds phencyclidine 5 ) a site that binds Zn++.
  37. 37.  NMDA receptor opens when glutamate binds & allows influx of Ca++ & Na++ into the cell.  Mg++ , zn++ , poly amines , & steroids can also modulate NMDA.  one of the most important controls on the ionic conductance through the NMDA receptor is voltage sensitive blocking by Mg++
  38. 38.  Activation of AMPA receptor channels may depolarize the neuron sufficiently to remove the voltage dependent Mg++ block & activate NMDA channels.  AMPA & NMDA are co activated & are present on the same part of the neuron.
  39. 39.  A separate site that modulates the gating of NMDA channel binds polyamines such as spermine & spermidine which are synthesized by neurons.different concentration dependent effects have observed.  Endogenous Zn reduces NMDA activated current.  Zinc is present in high concentrations in the hippocampus & released with some neurotransmitter in nervous system.
  40. 40.  Hydrogen ions also modulate the ion conductance which is maximal at slightly alkaline pH , & reduces with increasing acidity.  During hypoxic ischemic injury , progressive acidification resulting from glycolytic metabolism , may turn off the NMDA receptor channel.
  41. 41.  AMPA receptor is coupled to both Na++ , & K ++ channels. it’s activation opens the above channels, depolarizes the neuronal cell rapidly, it is responsible for the majority of rapid excitatory neurotransmission.  Kainate receptor is also coupled to Na++ , k++ channels.  Kainate receptor has slower rate of depolarizing capacity than AMPA receptor.
  42. 42.  Excitatory aminoacids are also able to interact with metabotropic recptors that activate the second messenger system, these receptors are found both pre & post synaptically.  Activation result in presynaptic inhibition & post synaptic excitation.
  43. 43.  The spectrum of neurological disorders mediated by excitotoxicity include epilepsy, stroke , neurodegerative disorders ( parkinson’s disease , amyotropic lateral sclerosis , AIDS dementia )  Most strokes are caused by thromboembolic events causing diminished perfusion resulting in reduction of supply of oxygen & glucose.
  44. 44.  3 subsequent stages are there in the development of brain damage caused by ischemia.  1)induction ,  2)amplification ,  3)expression.  Induction : ischemia causes depolarization of the neuronal membrane leading to release of glutamate.
  45. 45.  Glutamate overexcites the NMDA receptors in adjacent neuron , leading to abnormally large influxes of Ca++ & Na+ and resultant cell injury or death .  In addition glutamate stimulate AMPA – kainate receptor ( leading to additional influx of Na+ ) & also metabotropic receptors , causing the release of ITP & diacylgycerol.
  46. 46.  Amplification : further build up of intra cellular calcium occurs by following mechanism , 1) increased intracellular Na+ activates Na+ - Ca++ transporters.] 2)voltage gated Ca++ channels are activated by depolarozation. 3) ITP release Ca++ into cytosol from within endoplasmic reticulum.
  47. 47.  Expression : high levels of intra cellular Ca++ activates Ca++ dependent nucleases , proteases , & phospholipases. Degradation of phospholipids formation of platelet activating factor (PAF) & release of arachidonic acid eicosanoids (vasoconstriction) damage by oxygen free radicals This is called glutamate cascade.
  48. 48.  Huntington disease characterized by selective neuronal death in corpus striatum & glial proliferation .  Apoptosis , protein aggregation , & excitotoxins may all contribute cell death in huntington disease.  Excitotoxicity is by glutamate cascade.
  49. 49.  The dopaminergic neurons are found in nigrostrital , mesolimbic , mesocortical tuberohypophysial systems.  Dopamine synthesis occurs from tyrosine , tyrosine hydroxylase is rate limiting enzyme in formation.
  50. 50.  Entry of dopamine into synaptic vesicle is is driven by pH gradient established by a protein in vesicular membrane that pumps protons into vesicle at the expense of ATP  Release of dopamine involves exocytosis.  Dopamine has 5 post synaptic recptors D 1 receptor family(D1 & D5) D 2 receptor family(D2, D3, D4)  D4 receptor exhibits 5 polymorphic variants.
  51. 51.  The effect of dopamine is to increase direct path way by D 1 recptor, & supress indirect path way by D 2 receptor.  D 1 receptor activation augments adenylate cyclase ( linked to stimulatory G protein).  D 2 receptor activation decreases the activity of adenylate cyclase ( linked to inhibitory G protein ).
  52. 52.  ATP dependent reuptake of dopamine achieved by a high affinity transporter in presynatic membrane , this is incorporated into vesicles & reused again.  Degradation of dopamine occurs within synaptic cleft or following reuptake ,within presynatic terminal.  Mono amino oxidase B present in the outer membrane of mitochondria & also in synaptic cleft.
  53. 53.  MAO –B & MAO – A are distinguished from each other by preference for different substrates & by their different susceptibility to various inhibitors.  Both the above enzymes acts on dopamine to produce 3 – hydroxyphenyl acetaldehyde (DOPAC).  DOPAC converted to homovanillic acid by the action of catechol o methyl transferase.
  54. 54.  parkinson disease is due to loss of dopaminergic activity & excessive cholinergic activity in basal ganglia.  Signs of parkinson disease reflects a deficiency of dopamine in the substantia nigra , corpus striatum ( caudate nucleus & putamen )
  55. 55.  Basal ganglia are important for motor control they include putamen caudate nucleus globus pallidum substantia nigra subthalamic nucleus .  All circuits in basal ganglia are inhibitory utilizing GABA except glutamatergic subthalamic input to globus pallidum internum(GPi) which is excitatory.
  56. 56.  Cell damage in parkinson disease reflect a process of ageing , 13 % of cells of substantia nigra are lost per decade from 25 age onwards . ( parkinson disease rarely occurs befor 40 years )  Mutattions in gene encoding α synuclein , a presynaptic protein involved in neuronal plasticity is associated with parkinson disease.  Lewy bodies are found strongly stained with antibodies of α synuclein .
  57. 57.  Signs of parkinson disease appear when the level of dopamine is droped in nigrosriatal system by 80%.  Exposure to high levels of Manganese ( miners) leads to parkinson disease.  Reserpine inhibit dopamine storage & many neuroleptics block dopamine receptors.
  58. 58.  Schizophrenia is a manifestation of hyperdopaminergia .  Measurement of dopamine metabolite homovanillic acid in CSF is high in schizophrenics.  Level of D2 receptors appears to be increased in the brains of schizophrenics.  Dopamine mimetic drugs ( L dopa) induces schizophrenia
  59. 59.  Low dopamine activity in prefrontal cortex of the brain of schizophrenics correlate well with the negative symptoms .  Low dopamine activity in prefrontal cortex releases the inhibitory action on subcortical dopamine neurons resulting in elevated dopaminergic activity.
  60. 60.  Adrenergic neurotransmission is by norepinephrine & epinephrine.  The adrenergic neurons of locus ceruleus , pons , & medulla project to every area of brain & spinal cord.  Sympathetic postganglionic neurons typically release norepinephrine.  NE & E serve important role in the regulation of blood volume & blood pressure.
  61. 61.  Norepinephrine is synthesized from tyrosine . dopamine β hydroxylase dopamine norepinephrine cu dopamine β hydroxylase is bound to inner membrane of synaptic vesicle & release norepinephrine in a tetrameric glycoprotein form.
  62. 62.  The overall system of epinephrine synthesis , storage & secretion from adrenal medulla are regulated by neuronal controls & also by glucocorticoid hormones synthesized in & secreted from adrenal cortex in response stress.  Secretion of epinephrine is signaled by neural response to stress , which is transmitted to adrenal medulla by way of a preganglionic acetyl cholinergic neuron.
  63. 63.  A small number of neurons in the medulla contain phenyl ethenolamine –N- methyl tranferase enzyme that converts norepinephrine to epinephrine with SAM as methyl donor.  These neurons project to the thalamus, brainstem , spinal cord.  Concentration of epinephrine secreting terminals in the paraventricular nucleus suggests a role in secreton of oxytocin & vasopressin.
  64. 64.  Dense innervation of dorsal motor nucleus of vagus , & nucleus solitarius suggets role in regulating cardiovascular & respiratory reflexes.  Receptors on target cells may be either α or β adrenergic receptors.  Receptors are further sub divided into α1, α2, β1 , β2 , β3.
  65. 65.  α1 receptor are located postsynaptically but α2 receptors may be either pre or postsynaptic .  Receptors located presynaptically are autoreceptors inhibit release of neurotransmitter.  The effects of α1 receptors are mediated by activation of ITP/ diacyl glycerol second messenger system.  β receptors can be antagonized by action of α1 receptor.
  66. 66.  α2 receptors decease the rate of synthesis of cAMP through an action on inhibitory G protein.  β1&β2 receptors activates stimulatory G protein to increase cellular cAMP levels.  Activation of β receptor result in coactivation of β adrenergic receptor kinase (BARK), this phosphorylates the receptor.  Phophorylation is prominent mechanism of receptor desensitization.
  67. 67.  Number of β receptors is regulated .  β receptor is phosphorylated & desensitized their number also decreased if they become internalized.  β receptors can also be increased by denervation.  The number of α receptor is also regulated.
  68. 68.  β1 adrenergic receptors principally found in heart & cerebral cortex.  β2 receptors principally found in lung & cerebellum.  β1 receptors equally prefer NE & E as agonist.  β2 receptors prefer epinephrine to norepinephrine.
  69. 69.  In synaptic neurons norepinephrine decreases the amplitude of calcium spikes.  Excitatory effects of norepinephrine in various parts of CNS & sympathetic ganglion neuron results from α1 receptor activation. This activity primarily depends on blockade of a resting K+ conductance as a result neuron depolarizes & firing rate increases.
  70. 70.  Inhibitory effects of norepinephrine results from α2 receptor activation , which results in increase of K+ conductance this hyperpolarizes the neuron & decreases it’s firing rates.  NE acting at α2 receptor also block Ca++ current.  Both the above inhibitory mechanisms account for the autoreceptor function of α2 receptors which decreases neurotransmitter release.
  71. 71.  α1 adreno receptor activation results in , 1)vasoconstriction , 2) relaxation of gastrointestinal smooth muscle, 3) salivary secretion , 4)hepatic glcogenolysis.
  72. 72.  α2 adreno receptor activation results in 1) inhibition of transmitter release, (including NE & Ach from autonomic nerves) 2) platelet aggregation 3) contraction of vascular smooth muscle. 4) inhibition of insulin release.
  73. 73.  β1 adreno receptors activation results in 1) increased cardiac rate & force  β2 adreno receptors activation results in 1) bronchodilatation , 2) vasodilation, 3) relaxation of visceral smooth muscle, 4) hepatic glycogenolysis, 5) muscle tremor.  β3 adreno receptor activation results in lipolysis.
  74. 74.  The action of catecholamine neurotransmitters is terminated by reuptake into presynaptic neuron by specific transporters.  Enzymes involved in metabolism are catechol 0 methyl transferase & monoamino oxidase .  End product of norepinephrine & epinephrine metabolism is 3 methoxy 4 hydroxy mandelic acid.
  75. 75. serotonin  More than 95% of body’s serotonin is stored in platelets & GI tract , only 5% is seen in brain.  Serotonin is distributed in brain regions that affect behaviour especially the hypothalamus & limbic system.
  76. 76.  Availability of tryptophan is the main factor regulating synthesis of tryptophan.  Process of synthesis , storage , release , reuptake & degradation are similar to catecholmines.  Urinary 5 HIAA provides a measure of 5 –HT turn over.
  77. 77.  Functions associated with 5-HT path ways 1)hallucination & behavioural changes, 2)sleep, wakefulness & mood , 3) feeding behaviour, 4)control of sensory pathway including nociception, 5) vomiting.  Serotonin receptors are metabotropic.  Melatonin a derived product of 5-HT has role in establishing circadian rhythm.
  78. 78.  Histamine has neurotransmitter role in brain.  Acts on metabotropic receptors.  H1 receptors are excitatory & H2 , H3 receptors are inhibitory.  H1 receptors in cortex & RAS contributes to arousal & wakefulness.  Has role in food & water intake, thermoregulation
  79. 79.  Nitric oxide synthase is present in many CNS neurons.  NO production is increased by mechanisms that raise intracellular Ca++ concentration( eg: transmitter action).  NO affects neuronal functions by increasing cGMP formation ,producing both inhibitory & excitatory effects on neurons.
  80. 80.  ATP functions as neurotransmitter , it acts via ionotropic receptors as fast excitatory transmitter , via metabotropic receptors acts as neuro modulator.  Adenosine exerts inhibitory effects through metabotropic receptors.  Neurons contain CO generating enzyme, heme oxygenase , have role in cerebellum & olfactory neurons which have cGMP sensitive ion channels.