Editing Chemical synapse (section)

== Signaling in chemical synapses ==

===Overview===
Here is a summary of the sequence of events that take place in synaptic transmission from a presynaptic neuron to a postsynaptic cell.  Each step is explained in more detail below.  Note that with the exception of the final step, the entire process may run only a few hundred microseconds, in the fastest synapses.<ref name=":0">{{Cite book |title=Neuroscience: exploring the brain |url=https://archive.org/details/neuroscienceexpl00bear_099 |url-access=limited |author1=Bear, Mark F |author2=Connors, Barry W |author3=Paradiso, Michael A |publisher=Lippincott Williams & Wilkins |year=2007 |location=Philadelphia, PA|pages=[https://archive.org/details/neuroscienceexpl00bear_099/page/n146 113]–118}}</ref>

[[File:Synapse.theora.ogv|right|200px]]
# The process begins with a wave of electrochemical excitation called an [[action potential]] traveling along the membrane of the presynaptic cell, until it reaches the synapse.
# The electrical [[depolarization]] of the membrane at the synapse causes channels to open that are permeable to calcium ions.
# Calcium ions flow through the presynaptic membrane, rapidly increasing the calcium concentration in the interior.
# The high calcium concentration activates a set of calcium-sensitive proteins attached to [[Synaptic vesicle|vesicles]] that contain a [[neurotransmitter]] chemical.
# These proteins change shape, causing the membranes of some "docked" vesicles to fuse with the membrane of the presynaptic cell, thereby opening the vesicles and dumping their neurotransmitter contents into the synaptic cleft, the narrow space between the membranes of the pre- and postsynaptic cells.
# The neurotransmitter diffuses within the cleft.  Some of it escapes, but some of it binds to [[chemical receptor]] molecules located on the membrane of the postsynaptic cell.
# The binding of neurotransmitter causes the receptor molecule to be ''activated'' in some way.  Several types of activation are possible, as described in more detail below.  In any case, this is the key step by which the synaptic process affects the behavior of the postsynaptic cell.
# Due to [[Johnson–Nyquist noise|thermal vibration]], the motion of atoms, vibrating about their equilibrium positions in a crystalline solid, neurotransmitter molecules eventually break loose from the receptors and drift away.
# The neurotransmitter is either reabsorbed by the presynaptic cell, and then repackaged for future release, or else it is broken down metabolically.

===Neurotransmitter release===
[[File:Neuro Muscular Junction.png|thumb|Release of neurotransmitter occurs at the end of axonal branches.]]
The release of a neurotransmitter is triggered by the arrival of a nerve impulse (or [[action potential]]) and occurs through an unusually rapid process of cellular secretion ([[exocytosis]]). Within the presynaptic nerve terminal, [[vesicle (biology)|vesicle]]s containing neurotransmitter are localized near the synaptic membrane. The arriving action potential produces an influx of [[second messenger|calcium ions]] through [[Voltage-dependent calcium channel|voltage-dependent, calcium-selective ion channels]] at the down stroke of the action potential (tail current).<ref name="Llinás81">
{{cite journal |vauthors=Llinás R, Steinberg IZ, Walton K |title=Relationship between presynaptic calcium current and postsynaptic potential in squid giant synapse |journal=Biophysical Journal |volume=33 |issue=3 |pages=323–351 |year=1981 |pmid=6261850 |doi=10.1016/S0006-3495(81)84899-0 |pmc=1327434 |bibcode=1981BpJ....33..323L }}</ref> Calcium ions then bind to [[synaptotagmin]] proteins found within the membranes of the synaptic vesicles, allowing the vesicles to fuse with the presynaptic membrane.<ref>{{Cite journal|last=Chapman|first=Edwin R.|date=2002|title=Synaptotagmin: A Ca2+ sensor that triggers exocytosis?|journal=Nature Reviews Molecular Cell Biology|language=En|volume=3|issue=7|pages=498–508|doi=10.1038/nrm855|pmid=12094216|s2cid=12384262|issn=1471-0080}}</ref> The fusion of a vesicle is a [[stochastic]] process, leading to frequent failure of synaptic transmission at the very small synapses that are typical for the [[central nervous system]]. Large chemical synapses (e.g. the [[neuromuscular junction]]), on the other hand, have a synaptic release probability, in effect, of 1. [[Vesicle fusion]] is driven by the action of a set of proteins in the presynaptic terminal known as [[SNARE (protein)|SNAREs]]. As a whole, the protein complex or structure that mediates the docking and fusion of presynaptic vesicles is called the active zone.<ref>Craig C. Garner and Kang Shen. Structure and Function of Vertebrate and Invertebrate Active Zones. Structure and Functional Organization of the Synapse. Ed: Johannes Hell and Michael Ehlers. Springer, 2008.</ref> The membrane added by the fusion process is later retrieved by [[endocytosis]] and [[Endocytic cycle|recycled]] for the formation of fresh neurotransmitter-filled vesicles.

An exception to the general trend of neurotransmitter release by vesicular fusion is found in the type II receptor cells of  mammalian [[taste bud]]s. Here the neurotransmitter [[Adenosine triphosphate|ATP]] is released directly from the cytoplasm into the synaptic cleft via voltage gated channels.<ref name="RomanovLasher2018">{{cite journal|last1=Romanov|first1=Roman A.|last2=Lasher|first2=Robert S.|last3=High|first3=Brigit|last4=Savidge|first4=Logan E.|last5=Lawson|first5=Adam|last6=Rogachevskaja|first6=Olga A.|last7=Zhao|first7=Haitian|last8=Rogachevsky|first8=Vadim V.|last9=Bystrova|first9=Marina F.|last10=Churbanov|first10=Gleb D.|last11=Adameyko|first11=Igor|last12=Harkany|first12=Tibor|last13=Yang|first13=Ruibiao|last14=Kidd|first14=Grahame J.|last15=Marambaud|first15=Philippe|last16=Kinnamon|first16=John C.|last17=Kolesnikov|first17=Stanislav S.|last18=Finger|first18=Thomas E.|title=Chemical synapses without synaptic vesicles: Purinergic neurotransmission through a CALHM1 channel-mitochondrial signaling complex|journal=Science Signaling|volume=11|issue=529|year=2018|pages=eaao1815|issn=1945-0877|doi=10.1126/scisignal.aao1815|pmid=29739879|pmc=5966022}}</ref>

===Receptor binding===
Receptors on the opposite side of the synaptic gap bind neurotransmitter molecules. Receptors can respond in either of two general ways. First, the receptors may directly open [[ligand-gated ion channel]]s in the postsynaptic cell membrane, causing ions to enter or exit the cell and changing the local [[transmembrane potential]].<ref name=":0" /> The resulting change in [[voltage]] is called a [[postsynaptic potential]]. In general, the result is ''excitatory'' in the case of [[Depolarization|depolarizing]] currents, and ''inhibitory'' in the case of [[Hyperpolarization (biology)|hyperpolarizing]] currents. Whether a synapse is excitatory or inhibitory depends on what type(s) of ion channel conduct the postsynaptic current(s), which in turn is a function of the type of receptors and neurotransmitter employed at the synapse. The second way a receptor can affect membrane potential is by modulating the production of [[second messenger system|chemical messengers]] inside the postsynaptic neuron. These second messengers can then amplify the inhibitory or excitatory response to neurotransmitters.<ref name=":0" />

===Termination===
After a neurotransmitter molecule binds to a receptor molecule, it must be removed to allow for the postsynaptic membrane to continue to relay subsequent [[Excitatory postsynaptic potential|EPSP]]s and/or [[IPSP]]s. This removal can happen through one or more processes:
* The neurotransmitter may diffuse away due to thermally-induced oscillations of both it and the receptor, making it available to be broken down metabolically outside the neuron or to be reabsorbed.<ref name="Sherwood">Sherwood L., stikawy (2007).  Human Physiology 6e: From Cells to Systems</ref>
* Enzymes within the subsynaptic membrane may inactivate/metabolize the neurotransmitter.
* [[Reuptake]] pumps may actively pump the neurotransmitter back into the presynaptic [[axon terminal]] for reprocessing and re-release following a later action potential.<ref name="Sherwood"/>