Y1S2 Synapse NMJ Neurotransmitters


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Y1S2 Synapse NMJ Neurotransmitters

  1. 1. Physiology of synapse, neuromuscular junction and neurotransmitters Prof. Vajira Weerasinghe Dept of Physiology Faculty of Medicine University of Peradeniya
  2. 2. What is a synapse? <ul><li>A gap between two neurons </li></ul><ul><li>Mostly chemical </li></ul><ul><li>Rarely electrical </li></ul><ul><ul><li>Mostly present in lower animals </li></ul></ul><ul><ul><li>Gap junctions </li></ul></ul><ul><li>Synapses could be </li></ul><ul><ul><li>Axo-dendritic </li></ul></ul><ul><ul><li>Axo-somatic </li></ul></ul><ul><ul><li>Axo-axonic </li></ul></ul>
  3. 4. Many different types
  4. 5. Basic structure <ul><li>Presynaptic membrane </li></ul><ul><ul><li>Contains neurotransmitter vesicles </li></ul></ul><ul><li>Synaptic cleft </li></ul><ul><li>Postsynaptic membrane </li></ul><ul><ul><li>Contains receptors for the neurotransmitter </li></ul></ul>
  5. 6. Synaptic transmission <ul><li>Action potential passes from the presynaptic neuron to the postsynaptic neuron </li></ul><ul><li>Although an axon conducts both ways, conduction through synapse is one way </li></ul><ul><li>A neuron receives more than 10000 synapses </li></ul><ul><li>Postsynaptic activity is an integrated function </li></ul>
  6. 7. Neurotransmitters <ul><li>Chemicals that facilitate signal transmission across a synapse </li></ul><ul><li>Neurotransmitters are released on the presynaptic side and bind to receptors on the postsynaptic side </li></ul><ul><li>Earliest neurotransmitter discovered was acetylcholine </li></ul><ul><li>There are different chemical types </li></ul><ul><ul><li>Amines </li></ul></ul><ul><ul><ul><li>Norepinephrine, Epinephrine, dopamine, serotonin (5HT), histamine </li></ul></ul></ul><ul><ul><li>Amino acids </li></ul></ul><ul><ul><ul><li>GABA, Glycine, Glutamate, Aspartate </li></ul></ul></ul><ul><ul><li>Peptides </li></ul></ul><ul><ul><ul><li>Beta endorphin, enkephalins, dynorphin </li></ul></ul></ul><ul><ul><li>Others </li></ul></ul><ul><ul><ul><li>Acetylcholine, nitric oxide </li></ul></ul></ul>
  7. 8. Neurotransmitter release <ul><li>“ At rest”, the synapse contains numerous synaptic vesicles filled with neurotransmitter </li></ul><ul><li>Intracellular calcium levels are very low </li></ul><ul><li>Arrival of an action potential causes opening of voltage-gated calcium channels </li></ul><ul><li>Calcium enters the synapse </li></ul><ul><li>Calcium triggers exocytosis and release of neurotransmitter </li></ul><ul><li>Vesicles are recycled by endocytosis </li></ul>
  8. 9. Ca 2+ Ca 2+
  9. 10. Neurotransmitter receptors <ul><li>Once released, the neurotransmitter molecules diffuse across the synaptic cleft </li></ul><ul><li>When they “arrive” at the postsynaptic membrane, they bind to neurotransmitter receptors </li></ul><ul><li>Two main classes of receptors: </li></ul><ul><ul><li>Ligand-gated ion channels </li></ul></ul><ul><ul><ul><li>transmitter molecules bind on the outside, cause the channel to open and become permeable to either sodium, potassium or chloride </li></ul></ul></ul><ul><ul><li>G-protein-coupled receptors </li></ul></ul><ul><ul><ul><li>G-protein-coupled receptors have slower, longer-lasting and diverse postsynaptic effects. They can have effects that change an entire cell’s metabolism </li></ul></ul></ul><ul><ul><ul><li>or an enzyme that activates an internal metabolic change inside the cell </li></ul></ul></ul><ul><ul><ul><li>activate cAMP </li></ul></ul></ul><ul><ul><ul><li>activate cellular genes: forms more receptor proteins </li></ul></ul></ul><ul><ul><ul><li>activate protein kinase: decrease the number of proteins </li></ul></ul></ul>
  10. 11. <ul><li>Excitation </li></ul><ul><ul><li>1. Na + influx cause accumulation of positive charges causing excitation </li></ul></ul><ul><ul><li>2. Decreased K + efflux or Cl - influx </li></ul></ul><ul><ul><li>3. Various internal changes to excite cell, increase in excitatory receptors, decrease in inhibitory receptors. </li></ul></ul>
  11. 12. <ul><li>Inhibition </li></ul><ul><ul><li>1. Efflux of K + </li></ul></ul><ul><ul><li>2. Influx of Cl - </li></ul></ul><ul><ul><li>3. activation of receptor enzymes to inhibit metabolic functions or to increase inhibitory receptors or decrease excitatory receptors </li></ul></ul>
  12. 13. <ul><li>Excitatory effects of neurotransmitters </li></ul><ul><ul><li>EPSP: excitatory post synaptic potential </li></ul></ul><ul><li>Inhibitory effects of neurotransmitters </li></ul><ul><ul><li>IPSP: inhibitory post synaptic potential </li></ul></ul>
  13. 14. Postsynaptic activity <ul><li>Synaptic integration </li></ul><ul><ul><li>On average, each neuron in the brain receives about 10,000 synaptic connections from other neurons </li></ul></ul><ul><ul><li>Many (but probably not all) of these connections may be active at any given time </li></ul></ul><ul><ul><li>Each neuron produces only one output </li></ul></ul><ul><ul><li>One single input is usually not sufficient to trigger this output </li></ul></ul><ul><ul><li>The neuron must integrate a large number of synaptic inputs and “decide” whether to produce an output or not </li></ul></ul>
  14. 15. Neurotransmitters
  15. 16. Acetylcholine (Ach) <ul><ul><li>First neurotransmitter discovered in 1921 </li></ul></ul><ul><ul><li>secreted by motor neurons, autonomic nerves, large pyramidal cells of the motor cortex, basal ganglia (caudate & putamen), hippocampus. </li></ul></ul><ul><ul><li>It is generally excitatory </li></ul></ul><ul><ul><li>receptors </li></ul></ul><ul><ul><ul><li>nicotinic (autonomic ganglia, NMJ) - Na influx </li></ul></ul></ul><ul><ul><ul><li>muscarinic (parasympathetc terminal) </li></ul></ul></ul><ul><ul><ul><ul><ul><li>sub types: M1(brain), M2, M3, M4, M5 </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>second messenger cAMP </li></ul></ul></ul></ul></ul><ul><ul><li>Common Ach blockers: plant poison (curare), botulinum toxin (food poison) </li></ul></ul><ul><ul><li>Loss of Ach neurons in Alzheimer’s patients </li></ul></ul>
  16. 17. Norepinephrine <ul><ul><li>present in the autonomic nerves, brain stem, hypothalamus, locus ceruleus of the pons </li></ul></ul><ul><ul><li>Mostly it causes excitation but sometimes inhibition also happens </li></ul></ul><ul><ul><li>Increases BP and HR </li></ul></ul><ul><ul><li>control the overall activity of the brain and the mood </li></ul></ul><ul><ul><li>receptors </li></ul></ul><ul><ul><ul><li> 1,  2,  1,  2,  3 </li></ul></ul></ul><ul><ul><ul><ul><li>second messenger: cAMP </li></ul></ul></ul></ul>
  17. 18. Dopamine <ul><li>present in the cerebral cortex, hypothalamus </li></ul><ul><li>secreted by neurons in the basal ganglia </li></ul><ul><li>Mainly inhibitory </li></ul><ul><li>Involved in the reward mechanisms in the brain </li></ul><ul><li>Drugs like cocaine, opium, heroin, and alcohol increase the levels of dopamine </li></ul><ul><li>receptors: </li></ul><ul><ul><ul><li>D1, D2, D3, D4, D5 </li></ul></ul></ul><ul><ul><ul><ul><li>second messenger: cAMP </li></ul></ul></ul></ul><ul><li>Increased levels associates with schizophrenia, low levels are associated with Parkinsonism </li></ul>
  18. 19. GABA <ul><li>Present in the basal ganglia </li></ul><ul><li>Also present in the spinal cord, cerebellum & many other areas of the Cortex </li></ul><ul><li>Major inhibitory neurotransmitter of the brain occurring in 30-40% of all synapses </li></ul><ul><li>receptors </li></ul><ul><ul><ul><li>GABA A increase Cl- influx </li></ul></ul></ul><ul><ul><ul><li>GABA B act via G proteins, increase K+ influx </li></ul></ul></ul><ul><li>Low GABA levels are associated with anxiety and epilepsy </li></ul>
  19. 20. Glycine <ul><li>Present in the synapses of the spinal cord, interneurons </li></ul><ul><li>also present in the retina </li></ul><ul><li>Inhibitory (increase Cl influx) </li></ul><ul><li>by its action on NMDA receptors it is excitatory </li></ul>
  20. 21. Glutamate & Aspartate <ul><li>Excitatory amino acids </li></ul><ul><ul><li>glutamate is present in presynaptic terminals in the sensory pathways and other cortical areas </li></ul></ul><ul><ul><li>present in basal ganglia </li></ul></ul><ul><ul><li>Involved in the stretch reflex </li></ul></ul><ul><ul><li>Main excitatory neurotransmitter in brain & spinal cord </li></ul></ul><ul><ul><li>aspartate is present in cortical pyramidal cells & visual cortex </li></ul></ul><ul><ul><li>receptors: metabotropic receptors, kainate, AMPA, NMDA </li></ul></ul><ul><ul><li>NMDA receptors are present in hippocampus, involved in memory & learning </li></ul></ul><ul><ul><li>Increased levels are associated with certain neurological diseases </li></ul></ul>
  21. 22. Serotonin <ul><li>secreted by the nuclei originating in the median raphe of the brain stem and terminate in dorsal horn of the spinal cord and hypothalamus </li></ul><ul><li>Inhibitory </li></ul><ul><li>Control the mood of the person and important in sleep </li></ul><ul><li>also present in GIT, platelets & limbic system </li></ul><ul><li>receptors: 1A, 1B, 1D, 2A, 2C, 3, 4 </li></ul><ul><li>Low levels are associated with depression and other psychiatric disorders. May be involved in migraine </li></ul>
  22. 23. <ul><li>histamine: </li></ul><ul><ul><li>present in pathways from hypothalamus to cortical areas & spinal cord </li></ul></ul><ul><ul><li>receptors: H1, H2, H3 (all present in brain) </li></ul></ul><ul><ul><li>functions related to arousal, sexual behaviour, drinking, pain </li></ul></ul><ul><li>Substance P </li></ul><ul><ul><li>found in primary nerve ending in the spinal cord </li></ul></ul><ul><ul><li>mediator of pain in the spinal cord </li></ul></ul>
  23. 24. NEUROPEPTIDES <ul><li>synthesized by ribosomes in the cell body </li></ul><ul><li>ER and Golgi apparatus enzymatically split the large molecule into smaller precursor or active molecules </li></ul><ul><li>Golgi apparatus makes vesicles </li></ul><ul><li>these vesicles are transported through the axoplasm slowly </li></ul><ul><li>remain in the terminal </li></ul><ul><li>release by a process similar to the other neurotransmitter </li></ul>
  24. 25. NEUROPEPTIDES <ul><li>however vesicle is autolysed and not reused </li></ul><ul><li>quantity of neuropeptides released is smaller than that of other neurotransmitters </li></ul><ul><li>but the neuropeptides are thousand times more potent </li></ul><ul><li>they also cause much more prolonged action </li></ul><ul><li>generally only one type of small molecule neurotransmitter is released by a neuron </li></ul><ul><li>several neuropeptides could be released </li></ul>
  25. 26. NEUROPEPTIDES <ul><li>Removal of neurotransmitter: </li></ul><ul><ul><ul><li>by diffusion into the surrounding fluids </li></ul></ul></ul><ul><ul><ul><li>enzymatic destruction (Ach) </li></ul></ul></ul><ul><ul><ul><li>active transport re-uptake into the presynaptic terminal </li></ul></ul></ul><ul><li>Actions </li></ul><ul><ul><li>prolonged closure of Ca pores </li></ul></ul><ul><ul><li>prolonged changes in cell metabolism </li></ul></ul><ul><ul><li>deactivation of specific genes </li></ul></ul><ul><ul><li>prolonged changes in excitatory or inhibitory receptors </li></ul></ul>
  26. 27. OPIOID PEPTIDES <ul><li> Endorphin </li></ul><ul><ul><li>present in pituitary, earliest discovered opioid peptide </li></ul></ul><ul><li>enkephalins: met-enkephalin, leu-enkephalin </li></ul><ul><ul><li>present at substantia gelatinosa in the spinal cord & brain stem reticular nuclei </li></ul></ul><ul><ul><li>widely distributed </li></ul></ul><ul><li>dynorphin </li></ul><ul><ul><li>recently discovered </li></ul></ul><ul><li>opioid peptides are involved in the descending pain inhibitory pathway </li></ul><ul><li>receptors:  ,  ,  </li></ul>
  27. 28. Other peptides present in the CNS <ul><ul><li>Substance P </li></ul></ul><ul><ul><li>ACTH </li></ul></ul><ul><ul><li>Oxytocin </li></ul></ul><ul><ul><li>Glucagon </li></ul></ul><ul><ul><li>Somatostatin </li></ul></ul><ul><ul><li>VIP </li></ul></ul><ul><ul><li>Prolactin </li></ul></ul><ul><ul><li>LH </li></ul></ul><ul><ul><li>TRH </li></ul></ul><ul><ul><li>Releasing hormones, </li></ul></ul><ul><ul><li>GH </li></ul></ul><ul><ul><li>Gastrin </li></ul></ul><ul><ul><li>CCK </li></ul></ul><ul><ul><li>Neurotensin </li></ul></ul><ul><ul><li>Insulin </li></ul></ul><ul><ul><li>Angiotesin II </li></ul></ul><ul><ul><li>Bradykinin </li></ul></ul><ul><ul><li>Calcitonin gene related peptide (CGRP) </li></ul></ul><ul><ul><li>Neuropeptide Y </li></ul></ul>
  28. 29. <ul><li>nitrous oxide (NO) </li></ul><ul><ul><li>present in brain </li></ul></ul><ul><ul><li>probably involved in memory </li></ul></ul>
  29. 30. Neuromodulators <ul><li>Neurotransmitters transmit an impulse from one neuron to another </li></ul><ul><li>Neuromodulator modulate regions or circuits of the brain </li></ul><ul><li>They affect a group of neurons, causing a modulation of that group </li></ul><ul><li>Neuromodulators alter neuronal activity by amplifying or dampening synaptic activity </li></ul><ul><ul><li>eg. dopamine, serotonin, acetylcholine, histamine, glutamate </li></ul></ul>
  30. 31. Neuromuscular junction
  31. 32. Neuromuscular junction <ul><li>This is a modified synapse </li></ul><ul><li>Consists of </li></ul><ul><ul><li>Presynaptic membrane (nerve terminal) </li></ul></ul><ul><ul><li>Synaptic cleft </li></ul></ul><ul><ul><li>Postsynaptic membrane (motor end plate) </li></ul></ul>
  32. 34. Presynaptic terminal (terminal knob, boutons, end-feet or synaptic knobs) <ul><ul><li>Terminal has synaptic vesicles and mitochondria </li></ul></ul><ul><ul><li>Mitochondria (ATP) are present inside the presynaptic terminal </li></ul></ul>Vesicles containing neurotransmitter (Ach)
  33. 35. Presynaptic terminal (terminal knob, boutons, end-feet or synaptic knobs) <ul><ul><li>Presynaptic membrane contain voltage-gated Ca channels </li></ul></ul><ul><ul><li>The quantity of neurotransmitter released is proportional to the number of Ca entering the terminal </li></ul></ul><ul><ul><li>Ca ions binds to the protein molecules on the inner surface of the synaptic membrane called release sites </li></ul></ul><ul><ul><li>Neurotransmitter binds to these sites and exocytosis occur </li></ul></ul>
  34. 36. Ca 2+ Ca 2+
  35. 37. Postsynaptic membrane (motor end plate) <ul><li>Postsynaptic membrane contain receptors for the neurotransmitter released </li></ul><ul><li>eg: Acetylcholine receptor </li></ul>Ach Na+ <ul><li>This receptor is Ach-gated Na+ channel </li></ul><ul><li>When Ach binds to this, Na+ channel opens up </li></ul><ul><li>Na+ influx occurs </li></ul>
  36. 38. <ul><li>Na+ influx causes depolarisation of the membrane </li></ul><ul><ul><li>End Plate Potential (EPP) </li></ul></ul><ul><ul><ul><li>This is a graded potential </li></ul></ul></ul><ul><ul><ul><li>Once this reaches the threshold level </li></ul></ul></ul><ul><ul><ul><li>AP is generated at the postsynaptic membrane </li></ul></ul></ul>
  37. 39. Ach release <ul><li>An average human end plate contains 15-40 million Ach receptors </li></ul><ul><li>Each nerve impulse release 60 Ach vesicles </li></ul><ul><li>Each vesicle contains about 10,000 molecules of Ach </li></ul><ul><li>Ach is released in quanta (small packets) </li></ul>
  38. 40. End plate potential <ul><li>Even at rest small quanta are released </li></ul><ul><li>Which creates a minute depolarising spike called Miniature End Plate Potential (MEPP) </li></ul><ul><li>When an impulse arrives at the NMJ quanta released are increased in several times causing EPP </li></ul>
  39. 41. Acetylcholinerase (AchE) <ul><li>After the Ach binding is over </li></ul><ul><li>Cholinesterase present in the synaptic cleft will hydrolyse Ach into choline and acetate </li></ul><ul><li>Choline is reuptaken to the presynaptic terminal </li></ul><ul><li>AchE is also found in RBC membranes </li></ul>
  40. 42. Axoplasmic transport <ul><li>A cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the axoplasm </li></ul><ul><li>anterograde transport </li></ul><ul><ul><li>movement toward the synapse is called </li></ul></ul><ul><li>retrograde transport </li></ul><ul><ul><li>Movement toward the cell body </li></ul></ul>
  41. 43. Smooth muscles <ul><li>NMJ not well developed </li></ul><ul><li>Smooth muscle does not depend on motor neurons to be stimulated </li></ul><ul><li>However, motor neurons (of the autonomic system) reach smooth muscle and can stimulate it — or relax it — depending on the neurotransmitter they release (e.g. noradrenaline or nitric oxide, NO)) </li></ul><ul><li>Smooth muscle can also be made to contract </li></ul><ul><ul><li>by other substances released in the vicinity (paracrine stimulation) </li></ul></ul><ul><ul><ul><li>Example: release of histamine causes contraction of the smooth muscle lining our air passages (triggering an attack of asthma) </li></ul></ul></ul><ul><ul><li>by hormones circulating in the blood </li></ul></ul><ul><ul><ul><li>Example: oxytocin reaching the uterus stimulates it to contract to begin childbirth. </li></ul></ul></ul><ul><li>The contraction of smooth muscle tends </li></ul><ul><li>to be slower than that of striated muscle </li></ul><ul><li>It also is often sustained for long periods </li></ul>