2019. 09. 11. 1 Neurotransmission. Receptors and signal transduction mechanisms. Learning objectives 6. and 7. Dr. Gabriella Kékesi 2019 7. Neurotransmission. • Characterize electric synapses including the description of the molecular structure of gap junction operating in these synapses. Compare transmission between electric and chemical synapses (direction of information, speed and way of transmission). • Describe the consecutive events of chemical neurotransmission (starting with the depolarization of presynaptic membrane ending with the development of the graded electric response of the postsynaptic membrane (postsynaptic potential, PSP). Describe the ion currents involved in the development of the following local potentials: excitatory postsynaptic potential (EPSP), inhibitory postsynaptic potential (IPSP), end plate potential (EPP). • Describe the common features of classical neurotransmitters. • Group the neurotransmitters based on their chemical structure: 1. acetyl- choline, 2. amino acids (glutamate, glycine, GABA), 3. biogenic amines (dopamine, noradrenaline, adrenaline, histamine, serotonin), 4. gases (NO, CO), 5. lipids (endocannabinoids, 6. peptides (endophins, encephalins, dynorphins, substance P, CGRP, VIP), 7. purines. Describe the synthesis, mechanism of action and significance of NO. • Describe the fate of released neurotransmitters: receptor binding, enzymatic degradation, diffusion, reuptake. Normal values: synaptic delay: 1-1.5 ms
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2019. 09. 11.
1
Neurotransmission.Receptors and signal transduction
mechanisms.
Learning objectives 6. and 7.
Dr. Gabriella Kékesi
2019
7. Neurotransmission.
• Characterize electric synapses including the description of the molecular structure of gap junction
operating in these synapses. Compare transmission between electric and chemical synapses
(direction of information, speed and way of transmission).
• Describe the consecutive events of chemical neurotransmission (starting with the depolarization
of presynaptic membrane ending with the development of the graded electric response of the
postsynaptic membrane (postsynaptic potential, PSP). Describe the ion currents involved in the
development of the following local potentials: excitatory postsynaptic potential (EPSP),
inhibitory postsynaptic potential (IPSP), end plate potential (EPP).
• Describe the common features of classical neurotransmitters.
• Group the neurotransmitters based on their chemical structure: 1. acetyl- choline, 2. amino acids
• High-frequency stimulation: peptide ntrms. are also released
• Quantal release (Bernard Katz)
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Figure 14-6 Neurotransmitter is released in fixed increments, or quanta. Each quantum of transmitter produces a unit postsynaptic potential of fixed amplitude. The amplitude of the postsynaptic potential evoked by nerve stimulation is equal to the unit amplitude multiplied by the number of quanta of transmitter released. (Adapted from Boyd and Martin 1956.)
Quantal release
Fate of released transmitters
1. Binding to specific receptors
2. Diffusion from the synaptic cleft
• Into capillaries
• Into Lymphatic vessels
• To extrasynapticreceptors
3. Enzymatic degradation inthe synaptic cleft
4. Reuptake into thepresynaptic axon terminalor into the gilal cells1.
The time course of Ca2+ influx in the presynaptic cell determines the onset of synaptic transmission. An action potential in the presynaptic cell (1) causes voltage-gated Ca2+ channels in the terminal to open and a Ca2+ current (2) to flow into the terminal. The Ca2+ influx triggers release of neurotransmitter. The postsynaptic response to the transmitter begins soon afterward (3) and, if sufficiently large (reaches the threshold), will trigger an action potential in the postsynaptic cell (4). (EPSP = excitatory postsynaptic potential.) (Adapted from Llinás 1982.)
Synaptic integrationsummations of PSPs
Temporal summation: PSPs occur one after another at the same site, thereby combining potential in the postsynaptic terminal
Spatial summation: inputs from several presynaptic neurons acting on different areas combine to form an action potential
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Presynaptic regulation of transmitter release
an axoaxonic synapse causes an action potential arriving at the axon terminal to release more neurotransmitter and thereby cause a larger EPSP
the neurotransmitter from the presynaptic neuron atthe axonic synapse causes the postsynaptic axonterminal to release less neurotransmitter
Retrograde signalisatione.g. endocannabinoids
• Refers to the process by which a retrograde messenger, such as anandamide or nitric oxide, is released by a postsynaptic dendrite or cell body, and travels "backwards" across a chemical synapse to bind to the axon terminal of a presynaptic neuron
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Chemical classification of neurotransmitters
• Classical, small molecule neurotransmitters– Acetylcholine
• Other neurotransmitters– Lipids: prostaglandines, leucotrienes, anandamide
– Steroids (hormones): cortisol, aldosterone, sexual steroids…
Synthesis and metabolism of acetylcholine(Ach)
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Cholinergic synapse
Neuromuscular junction (motor endplate
• The axon of a motorneuron (presynaptic) establishes synaptic contact with a striated muscle (postsynaptic) fiber
• Synaptic cleft: 500 nm
• Neurotransmitter: Acetylcholine (Ach)
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Synthesis and metabolism of catecholamines
Neurotransmission in adrenergic neurons
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Neurotransmission in serotonergic neurons
Synthesis and release of steroids
• Steroids are synthesized and released as needed by enzymes in smooth ER and mitochondria from cholesterol.
• All readily diffuse through cell membranes because of their lipophilic character.
• Steroids cannot be stored in membrane bound vesicles and this is why they are synthesized as needed and released immediately.
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Gaseous mediators
Hem
Synthesis and metabolism of peptides
• 1. A prepropeptide is synthesized and released into the rough ER.
• 2. Proteolytic enzymes in the RER cleave off some amino acids to yield propeptides.
• 3. In the smooth ER propeptides are packaged into transport vesicles.
• 4. The vesicles are transported to Golgi complexes.
• 5. Golgi complexes package the propeptide into secretory vesicles. Either in the GA or secretory vesicles more amino acids are cleaved to yield the final peptide.
• 6. The peptides are released by exocytosis.
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Lipids - eicosanoids
• Lipophilic
• Released on demand
• Release of arachidonic acid from phospholipids in the cell membrane by phospholipase A2
Transport of chemical messengers
• Simple diffusion (autocrines, paracrines, neurotransmitters) or by blood transport (hormones, neurohormones)
• Hydrophilic messengers travel in blood in dissolved form or bound to carrier proteins (catecholamines)
• Hydrophobic messengers (steroides and thyroid hormones) bound to carrier proteins
• Blood-born messengers are:
– Degraded by the liver or
– Secreted by the kidney
• Dissolved messengers have a shorter half-life than messengers bound to carrier proteins.
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Receptors
• Receptor: special protein molecule that binds to specific chemical signals (ligand) from outside the cell resulting some form of cellular/tissue responses
• Direct influence of ion channels (activation or inhibition) OR second messenger release
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Action mechanisms of G protein
1. regulate a slow ligand-gated ion channel by either opening or closing the channel. This is in contrast to the more direct ligand-gated channels that only open in response to messenger binding. G protein-linked ion channels also take longer to open and stay open longer.
2. by activating or inhibiting an amplifier protein through the GTP- subunit. The amplifier protein catalyzes the synthesis of a second messenger. The second messenger activates a protein kinase that catalyzes the phosphorylation of a protein. This leads to the response in the cell.
Second messenger systems induce signalamplification
1. Enables one molecule to activate an enormous number of proteins.
2. Enables the cell to be very sensitive in response to the presence of messenger even at very low concentrations.
3. a cascade in which there are sequential steps that progressively increase in magnitude.
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Metabotropic receptors II.second messengers
• cAMP (cyclic adenosine-monophosphate)
• cGMP (cyclic guanosine-monophosphate)
• IP3 (inositol-triphosphate)
• DAG (diacylglycerol)
• Calcium
• (Arachidonic acid)
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Metabotropic receptors III/1.signaling pathways
• Gs/Gi
– Adenylyl-cyclase enzyme (AC) – cAMP – protein kinase A (PKA)• Pl.: α2 (↓) and β1-3 adrenergic receptors (↑); M2,4 acetylcholine receptor (↓);
– Guanylyl-cyclase enzyme (GC) – cGMP – protein kinase G enzyme(PKG)• Pl.: atrial natriuretic peptide (ANP) receptor; NO