Ch. 4 The Action Potential (AP)
c cccc c c c Action potential ʹ conveys info. Over long distances in the CNS. At rest cytosol is negative. The frequency and pattern of action potentials constitute the code used by neurons to transfer info. from one location to another. Ups and Downs At rest neuronal membrane is -65 mV. Action potential ʹ becomes positive briefly. Oscilloscope studies the action potential. And records voltage as it changes over time. First part of AP ʹ c a rapid depolarization of the membrane, continues until vm reaches 40 mV ʹ peak. , where inside of neuron is positively charged with respect to the outsidecc c ʹ rapid repolarization until membrane become more neg. than the resting potential. c c c is the last part of falling phase until gradual restoration of resting potential. All of this lasts 2 ms. The Generation of an AP Chain of events of an AP 1.c Thumbtack enters skin 2.c Membrane of nerve fibers in skin is stretched 3.c Na+ permeable channels open and due to large conc. gradient and (-) cytosol Na+ enters through channels. Na+ depolarizes the membrane, cytosol becomes less negative. This is c If GP achieves critical level, membrane goes through AP. Critical level of depolarization that must be crossed is c Therefore, AP are caused by depolarization of membrane beyond threshold. Interneurons - depolarization is usually caused by Na+ entry through channels that are sensitive to NT released by other neurons. The Generation of Multiple AP If we pass continuous depolarizing current into a neuron through a microelectrode, we will generate many AP in succession. Depends on magnitude of depolarizing current ʹ firing frequency. Although there is a limit to the rate at which a neuron can generate AP. 1000Hz ʹ max, once AP initiated, cannot initiate another ʹ c c . c c ʹ amount of current required to depolarize the neuron to AP threshold is elevated above normal. AP in Theory Ideal neuron: Na-K pump, K channel, Na channel. K conc. 20fold inside cell, Na conc. 10fold outside cell.
If, K channel is opened the net movement of K ions across the membrane is an electrical current, we represent this current with Ik. The number of open K channels is proportional to electrical conductance (gK). Ik = gK (Vm-Ek). Initially begin with: Vm = 0 mV ʹ no ion permeable. K flows out of cell as long as membrane potential differs from Ek potential. The Ins and Outs of an AP Membrane permeable to K therefore Vm=Ek= -80mV. Once Na becomes permeable gNa is high, and a large Na current is generate (INa). This influx of Na depolarizes the neuron Vm = 62 mV, approaches ENa. Falling phase: Na channels close and K channels remain open , K would leak out of cell until membrane potential is equal to Ek. Rising phase: Inward Na current Falling phase: Outward K current The AP in Reality Depolarization of neuron to threshold = increase in gNa. Therefore entry of Na, gNa must have a brief increase, restoring membrane potential which is negative would be increase in gK during falling phase allowing K ions to leave the depolarized neuron faster. Voltage clamp ʹ ͚clamps͛ membrane potential by measuring the currents that flowed across the membrane, shows that the rising phase of the AP was caused by a transient increase in gNa, and influx of Na, and falling phase associated with increase in gK and efflux of K ions. Na gates are activated by depolarization above threshold and inactivated when membrane acquires a positive membrane potential. Those gates are activated once again when membrane potential returns to negative value. The Voltage Gated Na Channel Protein that forms a pore in membrane and is selective only to Na ions, it is opened and closed in response to changes in the electrical potential of membrane. c ! "c c! c c Created from single long peptide, with four distinct domains (1-4), each domain consists of 6 transmembrane alpha helices (S1-S6). Four domains clump together to form pore. Pore is closed at negative resting membrane potential. When membrane depolarized to threshold, membrane twists into configuration that allows Na through. Na ions are stripped of associated water molecules as they pass through the channel. Retained water serves as molecular chaperone for ions, necessary for ion to pass selectivity filter. Ion water complex
selects Na and excludes K. Voltage sensor resides in S4 of molecule, positively charged amino acid residues are regularly spaces along coils of helix. An entire segment is forced to move by changing membrane potential. Depolarization͛s twists S4, conformational change causes gate to open. c c c#c c c Patch clamp ʹ study ionic currents passing though individual ion channels. Changing membrane potential from -80 to -40 mV causes channels to pop open. Na channels open, for 1 ms then inactivate. They cannot be opened again by depolarization until membrane potential returns to neg. value near threshold. Another AP cannot occur until the Na channels are de-inactivated. Generalized epilepsy with febrile seizures - result of single amino acid mutations in the EC region of one Na channel, occur in response to high temperature. Mutations slow the inactivation of the Na channel, prolonging the AP. It is a channelopathy, caused by alteration in structure and function of ion channel. $ c c % c c#c c c Tetrodotoxin (TTX) ʹ clogs Na permeable pre by binding tightly to a specific site on outside of channel. Different toxins disrupt channel function by binding to different sites on the protein. Info about toxin binding and its consequences have helped researchers deduc e the 3D structure of Na channel. Voltage Gated K Channels Falling phase of AP partly explained by inactivation of gNa. Also a transient increase in gK that speeds restoration of neg. membrane potential. K gates open in response to depolarization of membrane. K gates do not open immediately upon depolarization, 1ms for them to open. K gate serves to rectify (reset) membrane potential ʹ delayed rectifier. Function to diminish any further depolarization by giving K ions a path to leave the cell. Channel proteins consist of four separate polypeptide subunits that come together to form a pore between them. Putting the Pieces Together ʹ MP at which enough Na channels open so that relative ionic permeability favors Na over K.
c ʹ Inside of membrane has a neg. electrical potential, there is a large driving force of Na ions. Na ions rush into cell causing neuron to depolarize. c- MP goes to a value close to ENa which is greater the 0 mV. c - Na channels inactivate. K channels open. Driving force on K ions when membrane is depolarized. K ions rush out causing membrane potential to become neg.
c- Open k channels add to resting K membrane permeability. MP goes towards Ek causing hyperpolarization relative to resting MP until K channels close. c c - Na channels inactivate once membrane depolarizes. Another AP cannot be generated, until MP becomes neg. to deinactivated channels. c c ʹ MP stays hyperpolarized until K channels close. More depolarizing current needed to bring MP to threshold. AP Conduction The influx of Na pos. charge depolarizes the segment of membrane immediately before it until it reaches threshold and generates it own AP. Works its way down an axon until it reaches the axon terminal initiating synaptic transmission. Orthodromic conduction ʹ AP conduct only in one direction. Backward conduction ʹ antidormic. Factors Influencing Conduction Velocity The farther the current goes down the axons, the farther ahead of the AP the membrane will be depolarized, and the faster the AP will propagate. Therefore AP conduction velocity increases with increasing axonal diameter. Smaller axons require greater depolarization to reach AP threshold and are more sensitive to being blocked by local anesthetics. Myelin and Saltatory Conduction Fat axons ʹ conduct AP faster. Increasing AP conduction velocity ʹ wrapping the axon with myelin. Myelin sheath is many layers of membrane provided by Schwann cells (glial support cells) and oligodendroglia in CNS. Na channels are concentrated on the nodes of Ranvier. AP skip from node to node ʹ salutatory conduction. AP, Axons, and Dendrites Cell body and dendrites membrane do not generate AP, very few Na channels. Axons only have excitable membrane. Part of neuron where axon originates for soma, axon hillock ʹ spike initiation zone. The depolarization of dendrites and soma caused by synaptic input for other neurons leads to generation of AP, if membrane of axon hillock depolarized beyond threshold.
Sensory neurons ʹ spike initiation zone occurs near sensory nerve endings, depolarization caused by sensory stimulation leads to AP that go up sensory nerves. Axons and dendrites are functionally different, differences is specified at molecular level by type of protein at neuronal membrane. Differences in types and density of membrane ion channels also can account for the characteristic electrical property of different types of neuron. Synaptic transmission depends on specialized proteins on neuronal membrane.
Ch. 5 ʹ Synaptic Transmission Synaptic Transmission ʹ process of info transfer at the synapse. Electrical synapse ʹ Electrical current flowing from one neuron to the next. Chemical synapse ʹ Chemical NT transfer info from one neuron to another at the synapse. Types of Synapses Info flows in one direction from a neuron to its target cell. First neuron ʹ presynaptic, target cell ʹ post synaptic. Electrical Synapse Direct transfer of ionic current from one cell the next. Occur at specialized sites ʹ gap junctions. Membranes of two cells are separated and narrow gap is spanned by clusters of protens called connexins. Six connexins = connexon, 2 connexons = gap junction channel. Channel allows ions to pass directly from cytoplasm of one cell to the other. Big enough o allow major cell ions and many small organic molecules to pass through. Allow ionic current to pass through bidirectionally. Cells connected by gap junctions ʹ electrically coupled. When two neurons are electrically coupled an AP in the presynaptic neurons causes a small amount of ionic current to flow across the gap junction channels into the other neuron. Current causes postsynaptic potential (PSP) in the second neuron. Since it is bidirectional, the second neuron generates an AP and induces a PSP in first neuron.
Synaptic integration ʹ several PSP͛s occurring simultaneously and may strongly excite a neuron. Gap junctions interconnect many non neural cells (glia, epithelial, smooth and cardiac muscle cells, liver cells, glandular cells). Chemical Synapse At chemical synapses, post synaptic and pre synaptic membranes separated by synaptic cleft ʹ filled with matrix of fibrous EC protein, functions to make pre and post adhere to each other. Pre synaptic element is axon terminal containing dozens of small membrane enclosed spheres called synaptic vesicles that store NT ʹ used to communicate with the post synaptic neuron. Also contain secretory granules that contain soluble protein ʹ dense core vesicles. Dense accumulations of protein adjacent to and within membrane on either side of synaptic cleft are membrane differentiations. On presynaptic side, proteins jutting into cytoplasm of terminal along IC face of the membrane sometimes look like a field of tiny pyramids ʹ site of NT release called active zones. Synaptic vesicles are clustered in the cytoplasm adjacent to the active zones. Protein accumulated in and just under the postsynaptic membrane is the postsynaptic density ʹ contain NT receptors which convert inter cellular signal into intra cellular signal in postsynaptic cell. Nature of post synaptic response depends upon the type of protein receptor activated by NT. #!c! c If post synaptic membrane is on dendrite, synapse is ʹ axodendritic If post synaptic membrane is on cell body, synapse is ʹ axosomatic If post synaptic membrane is on axon ʹ axoaxonic Dendrites can also form synapses with one another ʹ dendrodendritic Also classified based on appearance of pre and post synaptic membranes. Synapses in which the membrane differentiation on post synaptic side is thicker than the pre synaptic side, are asymmetrical synapses ʹ Grays type 1 synapses Synapses in which membrane differentiations are of similar thickness are symmetrical synapses ʹ Grays type 2 synapses These structural differences predict functional differences Grays type 1 ʹ excitatory Grays type 2 ʹ inhibitory
c# " c& c Synaptic junctions that exist outside of CNS, such as axons of autonomic nervous system ʹ innervates glands, smooth muscle, heart. Also occur between axons of motor neurons of spinal cord, and skeletal muscle. These synapses are fast and reliable, accounted for by structural specializations ʹ one of the largest synapses in the body. Pre synaptic terminal also contains a large number of active zones. Post synaptic membrane contains ʹ motor end plate, a series of shallow folds. Pre synaptic active zones are precisely aligned with motor end plate, post synaptic membrane of the folds is packed with NT receptors. Therefore this structure ensures that many NT molecules are released onto a large surface of chemically sensitive membrane. Principles of Chemical Synaptic Transmission Requirements of chemical synaptic transmission -c Must be a mechanism for synthesizing NT and packing it into synaptic vesicles -c A mechanism for causing vesicles to spill their contents into synaptic cleft in response to a pre synaptic AP -c Mechanism for producing an electrical or biochemical response to NT in post synaptic neuron -c Mechanism for removing NT from synaptic cleft Neurotransmitters Fall into one of three categories -c Amino acids -c Amines -c Peptides Amino acid and amine NT are small organic molecules containing at least one nitrogen atom, they are stored and released in synaptic vesicles. Peptide NT are large molecules stored and released from secretory granules. These NT are released under different conditions. Fast synaptic transmission at CNS synapses mediates by amino acids: Glutamate (Glu), gammaaminobutyric acid (GABA), and glycine (Gly). Acetylcholine (Ach) mediates fast synaptic transmission at all neuromuscular junctions. Slower forms of synaptic transmission are mediated by NT from all three categories.
NT Synthesis and Storage Diff NT synthesizes in diff ways. Glu and Gly are among 20 A.A building blocks of protein ʹ abundant in cells. GABA and amines made only by neurons that release them, contain enzymes that synthesize the NT from various metabolic precursors. Synthesizing enzymes for A.A and amine NT are transported to axon terminal, where they locally and rapidly direct NT synthesis. Once synthesized in axon terminal cytosol, A.A and amine NT taken up by synaptic vesicles. Transporters ʹ concentrate the NT inside the vesicle, they are special proteins embedded in vesicle membrane. Diff mechanisms used to synthesize and store peptides in secretory granules. Peptides formed when A.A are strung together by ribosome͛s of cell body. One long peptide synthesized in RER is split in Golgi apparatus, one of the smaller peptide fragments is the active NT. Secretory granules containing peptide NT bud off Glogi apparatus and are carried to axon terminal by axoplasmic transport. NT Release The depolarization of the terminal membrane causes voltage gated Ca channels in active zones to open. There is a large inward driving force of Ca. Resulting elevation is the signal that causes NT to be released from synaptic vesicles. Released by exocytosis. Suggested that vesicles are already docked at active zones, interaction between proteins in the synaptic vesicle membrane and the active zone. Elevated Ca, proteins alter their conformation so that lipid bi layers of vesicle and pre synaptic membrane fuse, forming a pore that allows NT to escape. Exocytotic fusion pore continues to expand until membrane of vesicle is fully incorporated into pre synaptic membrane. Vesicle membrane recovered by endocytosis, recycled vesicle is refilled with NT. During prolonged stimulation, vesicles mobilized from a reserve pool that is bound to cytoskeleton of axon terminal. Release of these vesicles and their docking to active zone also triggered by Ca elevation. Secretory granules release peptide NT by exocytosis, in a Ca depended fashion, but not at active zones. Occur at a distance from the sites of Ca entry, peptide NT are usually not released in response to every AP invading the terminal. Release of peptides requires high frequency trains of AP, so Ca throughout terminal can build to a level required to trigger release of active zones. It is a leisurely process.
NT Receptors and Effectors " c' c( c c Consist of 4 or 5 subunits that come together to form a pore between them. Without NT the channel is closed, but when NT binds to EC region of the membrane than there are conformational changes and the pore opens. If it brings the membrane potential toward threshold ʹ excitatory post synaptic potential. Synaptic activation of Ach gated and Glu gated ion channels causes EPSP͛s. If transmitter gated channels are permeable to Cl, it will hyperpolarize the post synaptic cell from resting potential, bringing the membrane potential away from threshold, this is inhibitory post synaptic postential.
If, K channel is opened the net movement of K ions across the membrane is an electrical current, we represent this current with Ik. The number of open K channels is proportional to electrical conductance (gK). Ik = gK (Vm-Ek). Initially begin with: Vm = 0 mV ʹ no ion permeable. K flows out of cell as long as membrane potential differs from Ek potential. The Ins and Outs of an AP Membrane permeable to K therefore Vm=Ek= -80mV. Once Na becomes permeable gNa is high, and a large Na current is generate (INa). This influx of Na depolarizes the neuron Vm = 62 mV, approaches ENa. Falling phase: Na channels close and K channels remain open , K would leak out of cell until membrane potential is equal to Ek. Rising phase: Inward Na current Falling phase: Outward K current The AP in Reality Depolarization of neuron to threshold = increase in gNa. Therefore entry of Na, gNa must have a brief increase, restoring membrane potential which is negative would be increase in gK during falling phase allowing K ions to leave the depolarized neuron faster. Voltage clamp ʹ ͚clamps͛ membrane potential by measuring the currents that flowed across the membrane, shows that the rising phase of the AP was caused by a transient increase in gNa, and influx of Na, and falling phase associated with increase in gK and efflux of K ions. Na gates are activated by depolarization above threshold and inactivated when membrane acquires a positive membrane potential. Those gates are activated once again when membrane potential returns to negative value. The Voltage Gated Na Channel Protein that forms a pore in membrane and is selective only to Na ions, it is opened and closed in response to changes in the electrical potential of membrane. c ! "c c! c c Created from single long peptide, with four distinct domains (1-4), each domain consists of 6 transmembrane alpha helices (S1-S6). Four domains clump together to form pore. Pore is closed at negative resting membrane potential. When membrane depolarized to threshold, membrane twists into configuration that allows Na through. Na ions are stripped of associated water molecules as they pass through the channel. Retained water serves as molecular chaperone for ions, necessary for ion to pass selectivity filter. Ion water complex
selects Na and excludes K. Voltage sensor resides in S4 of molecule, positively charged amino acid residues are regularly spaces along coils of helix. An entire segment is forced to move by changing membrane potential. Depolarization͛s twists S4, conformational change causes gate to open. c c c#c c c Patch clamp ʹ study ionic currents passing though individual ion channels. Changing membrane potential from -80 to -40 mV causes channels to pop open. Na channels open, for 1 ms then inactivate. They cannot be opened again by depolarization until membrane potential returns to neg. value near threshold. Another AP cannot occur until the Na channels are de-inactivated. Generalized epilepsy with febrile seizures - result of single amino acid mutations in the EC region of one Na channel, occur in response to high temperature. Mutations slow the inactivation of the Na channel, prolonging the AP. It is a channelopathy, caused by alteration in structure and function of ion channel. $ c c % c c#c c c Tetrodotoxin (TTX) ʹ clogs Na permeable pre by binding tightly to a specific site on outside of channel. Different toxins disrupt channel function by binding to different sites on the protein. Info about toxin binding and its consequences have helped researchers deduc e the 3D structure of Na channel. Voltage Gated K Channels Falling phase of AP partly explained by inactivation of gNa. Also a transient increase in gK that speeds restoration of neg. membrane potential. K gates open in response to depolarization of membrane. K gates do not open immediately upon depolarization, 1ms for them to open. K gate serves to rectify (reset) membrane potential ʹ delayed rectifier. Function to diminish any further depolarization by giving K ions a path to leave the cell. Channel proteins consist of four separate polypeptide subunits that come together to form a pore between them. Putting the Pieces Together ʹ MP at which enough Na channels open so that relative ionic permeability favors Na over K.
c ʹ Inside of membrane has a neg. electrical potential, there is a large driving force of Na ions. Na ions rush into cell causing neuron to depolarize. c- MP goes to a value close to ENa which is greater the 0 mV. c - Na channels inactivate. K channels open. Driving force on K ions when membrane is depolarized. K ions rush out causing membrane potential to become neg.
c- Open k channels add to resting K membrane permeability. MP goes towards Ek causing hyperpolarization relative to resting MP until K channels close. c c - Na channels inactivate once membrane depolarizes. Another AP cannot be generated, until MP becomes neg. to deinactivated channels. c c ʹ MP stays hyperpolarized until K channels close. More depolarizing current needed to bring MP to threshold. AP Conduction The influx of Na pos. charge depolarizes the segment of membrane immediately before it until it reaches threshold and generates it own AP. Works its way down an axon until it reaches the axon terminal initiating synaptic transmission. Orthodromic conduction ʹ AP conduct only in one direction. Backward conduction ʹ antidormic. Factors Influencing Conduction Velocity The farther the current goes down the axons, the farther ahead of the AP the membrane will be depolarized, and the faster the AP will propagate. Therefore AP conduction velocity increases with increasing axonal diameter. Smaller axons require greater depolarization to reach AP threshold and are more sensitive to being blocked by local anesthetics. Myelin and Saltatory Conduction Fat axons ʹ conduct AP faster. Increasing AP conduction velocity ʹ wrapping the axon with myelin. Myelin sheath is many layers of membrane provided by Schwann cells (glial support cells) and oligodendroglia in CNS. Na channels are concentrated on the nodes of Ranvier. AP skip from node to node ʹ salutatory conduction. AP, Axons, and Dendrites Cell body and dendrites membrane do not generate AP, very few Na channels. Axons only have excitable membrane. Part of neuron where axon originates for soma, axon hillock ʹ spike initiation zone. The depolarization of dendrites and soma caused by synaptic input for other neurons leads to generation of AP, if membrane of axon hillock depolarized beyond threshold.
Sensory neurons ʹ spike initiation zone occurs near sensory nerve endings, depolarization caused by sensory stimulation leads to AP that go up sensory nerves. Axons and dendrites are functionally different, differences is specified at molecular level by type of protein at neuronal membrane. Differences in types and density of membrane ion channels also can account for the characteristic electrical property of different types of neuron. Synaptic transmission depends on specialized proteins on neuronal membrane.
Ch. 5 ʹ Synaptic Transmission Synaptic Transmission ʹ process of info transfer at the synapse. Electrical synapse ʹ Electrical current flowing from one neuron to the next. Chemical synapse ʹ Chemical NT transfer info from one neuron to another at the synapse. Types of Synapses Info flows in one direction from a neuron to its target cell. First neuron ʹ presynaptic, target cell ʹ post synaptic. Electrical Synapse Direct transfer of ionic current from one cell the next. Occur at specialized sites ʹ gap junctions. Membranes of two cells are separated and narrow gap is spanned by clusters of protens called connexins. Six connexins = connexon, 2 connexons = gap junction channel. Channel allows ions to pass directly from cytoplasm of one cell to the other. Big enough o allow major cell ions and many small organic molecules to pass through. Allow ionic current to pass through bidirectionally. Cells connected by gap junctions ʹ electrically coupled. When two neurons are electrically coupled an AP in the presynaptic neurons causes a small amount of ionic current to flow across the gap junction channels into the other neuron. Current causes postsynaptic potential (PSP) in the second neuron. Since it is bidirectional, the second neuron generates an AP and induces a PSP in first neuron.
Synaptic integration ʹ several PSP͛s occurring simultaneously and may strongly excite a neuron. Gap junctions interconnect many non neural cells (glia, epithelial, smooth and cardiac muscle cells, liver cells, glandular cells). Chemical Synapse At chemical synapses, post synaptic and pre synaptic membranes separated by synaptic cleft ʹ filled with matrix of fibrous EC protein, functions to make pre and post adhere to each other. Pre synaptic element is axon terminal containing dozens of small membrane enclosed spheres called synaptic vesicles that store NT ʹ used to communicate with the post synaptic neuron. Also contain secretory granules that contain soluble protein ʹ dense core vesicles. Dense accumulations of protein adjacent to and within membrane on either side of synaptic cleft are membrane differentiations. On presynaptic side, proteins jutting into cytoplasm of terminal along IC face of the membrane sometimes look like a field of tiny pyramids ʹ site of NT release called active zones. Synaptic vesicles are clustered in the cytoplasm adjacent to the active zones. Protein accumulated in and just under the postsynaptic membrane is the postsynaptic density ʹ contain NT receptors which convert inter cellular signal into intra cellular signal in postsynaptic cell. Nature of post synaptic response depends upon the type of protein receptor activated by NT. #!c! c If post synaptic membrane is on dendrite, synapse is ʹ axodendritic If post synaptic membrane is on cell body, synapse is ʹ axosomatic If post synaptic membrane is on axon ʹ axoaxonic Dendrites can also form synapses with one another ʹ dendrodendritic Also classified based on appearance of pre and post synaptic membranes. Synapses in which the membrane differentiation on post synaptic side is thicker than the pre synaptic side, are asymmetrical synapses ʹ Grays type 1 synapses Synapses in which membrane differentiations are of similar thickness are symmetrical synapses ʹ Grays type 2 synapses These structural differences predict functional differences Grays type 1 ʹ excitatory Grays type 2 ʹ inhibitory
c# " c& c Synaptic junctions that exist outside of CNS, such as axons of autonomic nervous system ʹ innervates glands, smooth muscle, heart. Also occur between axons of motor neurons of spinal cord, and skeletal muscle. These synapses are fast and reliable, accounted for by structural specializations ʹ one of the largest synapses in the body. Pre synaptic terminal also contains a large number of active zones. Post synaptic membrane contains ʹ motor end plate, a series of shallow folds. Pre synaptic active zones are precisely aligned with motor end plate, post synaptic membrane of the folds is packed with NT receptors. Therefore this structure ensures that many NT molecules are released onto a large surface of chemically sensitive membrane. Principles of Chemical Synaptic Transmission Requirements of chemical synaptic transmission -c Must be a mechanism for synthesizing NT and packing it into synaptic vesicles -c A mechanism for causing vesicles to spill their contents into synaptic cleft in response to a pre synaptic AP -c Mechanism for producing an electrical or biochemical response to NT in post synaptic neuron -c Mechanism for removing NT from synaptic cleft Neurotransmitters Fall into one of three categories -c Amino acids -c Amines -c Peptides Amino acid and amine NT are small organic molecules containing at least one nitrogen atom, they are stored and released in synaptic vesicles. Peptide NT are large molecules stored and released from secretory granules. These NT are released under different conditions. Fast synaptic transmission at CNS synapses mediates by amino acids: Glutamate (Glu), gammaaminobutyric acid (GABA), and glycine (Gly). Acetylcholine (Ach) mediates fast synaptic transmission at all neuromuscular junctions. Slower forms of synaptic transmission are mediated by NT from all three categories.
NT Synthesis and Storage Diff NT synthesizes in diff ways. Glu and Gly are among 20 A.A building blocks of protein ʹ abundant in cells. GABA and amines made only by neurons that release them, contain enzymes that synthesize the NT from various metabolic precursors. Synthesizing enzymes for A.A and amine NT are transported to axon terminal, where they locally and rapidly direct NT synthesis. Once synthesized in axon terminal cytosol, A.A and amine NT taken up by synaptic vesicles. Transporters ʹ concentrate the NT inside the vesicle, they are special proteins embedded in vesicle membrane. Diff mechanisms used to synthesize and store peptides in secretory granules. Peptides formed when A.A are strung together by ribosome͛s of cell body. One long peptide synthesized in RER is split in Golgi apparatus, one of the smaller peptide fragments is the active NT. Secretory granules containing peptide NT bud off Glogi apparatus and are carried to axon terminal by axoplasmic transport. NT Release The depolarization of the terminal membrane causes voltage gated Ca channels in active zones to open. There is a large inward driving force of Ca. Resulting elevation is the signal that causes NT to be released from synaptic vesicles. Released by exocytosis. Suggested that vesicles are already docked at active zones, interaction between proteins in the synaptic vesicle membrane and the active zone. Elevated Ca, proteins alter their conformation so that lipid bi layers of vesicle and pre synaptic membrane fuse, forming a pore that allows NT to escape. Exocytotic fusion pore continues to expand until membrane of vesicle is fully incorporated into pre synaptic membrane. Vesicle membrane recovered by endocytosis, recycled vesicle is refilled with NT. During prolonged stimulation, vesicles mobilized from a reserve pool that is bound to cytoskeleton of axon terminal. Release of these vesicles and their docking to active zone also triggered by Ca elevation. Secretory granules release peptide NT by exocytosis, in a Ca depended fashion, but not at active zones. Occur at a distance from the sites of Ca entry, peptide NT are usually not released in response to every AP invading the terminal. Release of peptides requires high frequency trains of AP, so Ca throughout terminal can build to a level required to trigger release of active zones. It is a leisurely process.
NT Receptors and Effectors " c' c( c c Consist of 4 or 5 subunits that come together to form a pore between them. Without NT the channel is closed, but when NT binds to EC region of the membrane than there are conformational changes and the pore opens. If it brings the membrane potential toward threshold ʹ excitatory post synaptic potential. Synaptic activation of Ach gated and Glu gated ion channels causes EPSP͛s. If transmitter gated channels are permeable to Cl, it will hyperpolarize the post synaptic cell from resting potential, bringing the membrane potential away from threshold, this is inhibitory post synaptic postential.
