Editing Retrograde signaling

{{Short description|In biology, a signal traveling backwards to its source}}
'''Retrograde signaling''' in biology is the process where a signal travels backwards from a target source to its original source. For example, the [[Cell nucleus|nucleus]] of a cell is the original source for creating signaling proteins. During retrograde signaling, instead of signals leaving the nucleus, they are sent to the nucleus.<ref>{{Cite journal|last=Leister|first=Dario|date=2012|title=Retrograde signaling in plants: from simple to complex scenarios|journal=Frontiers in Plant Science|volume=3|pages=135|doi=10.3389/fpls.2012.00135|pmid=22723802|pmc=3377957|issn=1664-462X|doi-access=free}}</ref> In [[cell biology]], this type of signaling typically occurs between the [[Mitochondrion|mitochondria]] or [[chloroplast]] and the nucleus. Signaling molecules from the mitochondria or chloroplast act on the nucleus to affect nuclear gene expression. In this regard, the chloroplast or mitochondria act as a sensor for internal external stimuli which activate a signaling pathway.<ref name="Nott_2006" />
[[File:Synapse Illustration2 tweaked.svg|thumb|The postsynaptic [[dendrite]] (green) and presynaptic neuron (yellow) found in '''retrograde neurotransmission.''']]
In [[neuroscience]], retrograde signaling (or '''retrograde neurotransmission''') refers more specifically to the process by which a retrograde messenger, such as [[anandamide]] or [[nitric oxide]], is released by a postsynaptic [[dendrite]] or [[perikaryon|cell body]], and travels "backwards" across a [[chemical synapse]] to bind to the [[axon terminal]] of a presynaptic [[neuron]].<ref name="Regehr 2009">{{cite journal | vauthors = Regehr WG, Carey MR, Best AR | title = Activity-dependent regulation of synapses by retrograde messengers | journal = Neuron | volume = 63 | issue = 2 | pages = 154–70 | date = July 2009 | pmid = 19640475 | pmc = 3251517 | doi = 10.1016/j.neuron.2009.06.021 }}</ref>

==In cell biology==
Retrograde signals are transmitted from [[plastid]]s to the nucleus in plants and [[Eukaryote|eukaryotic]] algae,<ref name="Lagarias2013">{{cite journal | vauthors = Duanmu D, Casero D, Dent RM, Gallaher S, Yang W, Rockwell NC, Martin SS, Pellegrini M, Niyogi KK, Merchant SS, Grossman AR, Lagarias JC | display-authors = 6 | title = Retrograde bilin signaling enables Chlamydomonas greening and phototrophic survival | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 9 | pages = 3621–6 | date = February 2013 | pmid = 23345435 | pmc = 3587268 | doi = 10.1073/pnas.1222375110 | doi-access = free | bibcode = 2013PNAS..110.3621D }}</ref><ref name="Nott_2006">{{cite journal | vauthors = Nott A, Jung HS, Koussevitzky S, Chory J | title = Plastid-to-nucleus retrograde signaling | journal = Annual Review of Plant Biology | volume = 57 | pages = 739–59 | date = June 2006 | pmid = 16669780 | doi = 10.1146/annurev.arplant.57.032905.105310 }}</ref> and from mitochondria to the nucleus in most eukaryotes.<ref>{{cite journal | vauthors = Liu Z, Butow RA | title = Mitochondrial retrograde signaling | journal = Annual Review of Genetics | volume = 40 | pages = 159–85 | date = December 2006 | pmid = 16771627 | doi = 10.1146/annurev.genet.40.110405.090613 }}</ref> Retrograde signals are generally considered to convey intracellular signals related to stress and environmental sensing.<ref name="pmid16669780">{{cite journal | vauthors = Nott A, Jung HS, Koussevitzky S, Chory J | title = Plastid-to-nucleus retrograde signaling | journal = Annual Review of Plant Biology | volume = 57 | pages = 739–59 | date = 2006 | pmid = 16669780 | doi = 10.1146/annurev.arplant.57.032905.105310 }}</ref> Many of the molecules associated with retrograde signaling act on modifying the [[Transcription (biology)|transcription]] or by directly binding and acting as a [[transcription factor]]. The outcomes of these signaling pathways vary by [[organism]] and by stimuli or stress.<ref name="Lagarias2013" />

== Evolution ==
Retrograde signaling is believed to have arisen after [[endocytosis]] of the mitochondria and chloroplast billions of years ago.<ref>{{cite book | vauthors = Bevan RB, Lang BF | chapter = Mitochondrial genome evolution: the origin of mitochondria and of eukaryotes. | title = Mitochondrial Function and Biogenesis | volume = 8 | date = 2004 | pages = 1–35 | publisher = Springer | location = Berlin, Heidelberg |isbn=978-3-540-21489-2 | doi = 10.1007/b96830 | series = Topics in Current Genetics }}</ref> Originally believed to be photosynthetic bacteria, the mitochondria and chloroplast transferred some of their DNA to the membrane protected nucleus.<ref>{{cite journal | vauthors = da Cunha FM, Torelli NQ, Kowaltowski AJ | title = Mitochondrial Retrograde Signaling: Triggers, Pathways, and Outcomes | journal = Oxidative Medicine and Cellular Longevity | volume = 2015 | pages = 482582 | date = 2015 | pmid = 26583058 | pmc = 4637108 | doi = 10.1155/2015/482582 | doi-access = free }}</ref> Thus, some of the proteins required for the mitochondria or chloroplast are within the nucleus. This transfer of DNA further required a network of communication to properly respond to external and internal signals and produce requisite proteins.<ref>{{cite journal | vauthors = Whelan SP, Zuckerbraun BS | title = Mitochondrial signaling: forwards, backwards, and in between | journal = Oxidative Medicine and Cellular Longevity | volume = 2013 | pages = 351613 | date = 2013 | pmid = 23819011 | pmc = 3681274 | doi = 10.1155/2013/351613 | doi-access = free }}</ref>

=== In yeast ===
The first retrograde signaling pathways discovered in [[yeast]] is the RTG pathway.<ref>{{cite journal | vauthors = Parikh VS, Morgan MM, Scott R, Clements LS, Butow RA | title = The mitochondrial genotype can influence nuclear gene expression in yeast | journal = Science | volume = 235 | issue = 4788 | pages = 576–80 | date = January 1987 | pmid = 3027892 | doi = 10.1126/science.3027892 | bibcode = 1987Sci...235..576P }}</ref><ref name="Liu_2001">{{cite journal | vauthors = Liu Z, Sekito T, Epstein CB, Butow RA | title = RTG-dependent mitochondria to nucleus signaling is negatively regulated by the seven WD-repeat protein Lst8p | journal = The EMBO Journal | volume = 20 | issue = 24 | pages = 7209–19 | date = December 2001 | pmid = 11742997 | pmc = 125777 | doi = 10.1093/emboj/20.24.7209 }}</ref> The RTG pathway plays an important role in maintaining the metabolic homeostasis of yeast.<ref name="Liu_2001" /> Under limited resources the mitochondria must maintain a balance of [[Glutamic acid|glutamate]] for the [[citric acid cycle]].<ref>{{cite journal | vauthors = Jazwinski SM, Kriete A | title = The yeast retrograde response as a model of intracellular signaling of mitochondrial dysfunction | journal = Frontiers in Physiology | volume = 3 | pages = 139 | date = 2012 | pmid = 22629248 | pmc = 3354551 | doi = 10.3389/fphys.2012.00139 | doi-access = free }}</ref> Retrograde signaling from the mitochondria initiates production precursor molecules of glutamate to properly balance supplies within the mitochondria.<ref name="Liu_1999">{{cite journal | vauthors = Liu Z, Butow RA | title = A transcriptional switch in the expression of yeast tricarboxylic acid cycle genes in response to a reduction or loss of respiratory function | journal = Molecular and Cellular Biology | volume = 19 | issue = 10 | pages = 6720–8 | date = October 1999 | pmid = 10490611 | pmc = 84662 | doi = 10.1128/MCB.19.10.6720 }}</ref> Retrograde signaling can also act to arrest growth if problems are encountered. In ''[[Saccharomyces cerevisiae]],'' if the mitochondria fails to develop properly, they will stop growing until the issue is addressed or cell death is induced.<ref name="Liu_1999" /> This mechanism is vital to maintain homeostasis of the cell and ensure proper function of the mitochondria.<ref name="Liu_1999" />

=== In plants ===
One of the most studied retrograde signaling molecules in plants are [[reactive oxygen species]] (ROS).<ref>{{cite journal | vauthors = Maruta T, Noshi M, Tanouchi A, Tamoi M, Yabuta Y, Yoshimura K, Ishikawa T, Shigeoka S | display-authors = 6 | title = H2O2-triggered retrograde signaling from chloroplasts to nucleus plays specific role in response to stress | journal = The Journal of Biological Chemistry | volume = 287 | issue = 15 | pages = 11717–29 | date = April 2012 | pmid = 22334687 | pmc = 3320920 | doi = 10.1074/jbc.m111.292847 | doi-access = free }}</ref> These compounds, previously believed to be damaging to the cell, have since been discovered to act as a signaling molecule.<ref name="Schieber_2014">{{cite journal | vauthors = Schieber M, Chandel NS | title = ROS function in redox signaling and oxidative stress | journal = Current Biology | volume = 24 | issue = 10 | pages = R453-62 | date = May 2014 | pmid = 24845678 | pmc = 4055301 | doi = 10.1016/j.cub.2014.03.034 | bibcode = 2014CBio...24.R453S }}</ref> Reactive oxygen species are created as a by-product of aerobic respiration and act on genes involved in the stress response.<ref name="Schieber_2014" /> Depending on the stress, reactive oxygen species can act on neighboring cells to initiate a local signal.<ref name="Shapiguzov_2012">{{cite journal | vauthors = Shapiguzov A, Vainonen JP, Wrzaczek M, Kangasjärvi J | title = ROS-talk - how the apoplast, the chloroplast, and the nucleus get the message through | journal = Frontiers in Plant Science | volume = 3 | pages = 292 | date = 2012 | pmid = 23293644 | pmc = 3530830 | doi = 10.3389/fpls.2012.00292 | doi-access = free }}</ref> By doing this, surrounding cells are "primed" to react to the stress because genes involved in stress response are initiated prior to encountering the stress.<ref name="Shapiguzov_2012" /> The chloroplast can also act as a sensor for pathogen response and drought. Detection of these stresses in the cell will induce the formation of compounds that can then act on the nucleus to produce pathogen resistance genes or drought tolerance.<ref>{{cite journal | vauthors = Estavillo GM, Chan KX, Phua SY, Pogson BJ | title = Reconsidering the nature and mode of action of metabolite retrograde signals from the chloroplast | journal = Frontiers in Plant Science | volume = 3 | pages = 300 | date = 2013 | pmid = 23316207 | pmc = 3539676 | doi = 10.3389/fpls.2012.00300 | doi-access = free }}</ref> 

==In neuroscience==
[[File:General Feedback Loop.svg|thumb|Feedback loop found in retrograde neurological signaling. ]]
The primary purpose of retrograde neurotransmission is regulation of chemical [[neurotransmission]].<ref name="Regehr 2009" /> For this reason, retrograde neurotransmission allows [[biological neural network|neural circuit]]s to create [[feedback loop]]s. In the sense that retrograde neurotransmission mainly serves to regulate typical, anterograde neurotransmission, rather than to actually distribute any information, it is similar to [[electrical synapse|electrical neurotransmission]].

In contrast to conventional (anterograde) neurotransmitters, retrograde neurotransmitters are synthesized in the postsynaptic neuron, and bind to receptors on the [[axon terminal]] of the presynaptic neuron.<ref>{{Cite journal|last1=Tao|first1=Huizhong W.|last2=Poo|first2=Mu-ming|date=2001-09-25|title=Retrograde signaling at central synapses|journal=Proceedings of the National Academy of Sciences|language=en|volume=98|issue=20|pages=11009–11015|doi=10.1073/pnas.191351698|issn=0027-8424|pmid=11572961|pmc=58675|bibcode=2001PNAS...9811009T|doi-access=free}}</ref> Additionally, retrograde signaling initiates a signaling cascade that focuses on the presynaptic neuron. Once retrograde signaling is initiated, there is an increase in action potentials that begin in the presynaptic neuron, which directly impacts the postsynaptic neuron by increasing the number of its receptors.<ref name=":0">{{Cite web|title=Endocannabinoids Performance through Retrograde Signaling {{!}} Cannabis Sciences|url=https://www.labroots.com/trending/cannabis-sciences/8519/endocannabinoids-performance-retrograde-signaling|access-date=2021-05-05|website=Labroots}}</ref>

[[Endocannabinoid]]s like [[anandamide]] are known to act as retrograde messengers,<ref name="Alger 2002">{{cite journal | vauthors = Alger BE | title = Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids | journal = Progress in Neurobiology | volume = 68 | issue = 4 | pages = 247–86 | date = November 2002 | pmid = 12498988 | doi = 10.1016/S0301-0082(02)00080-1 | s2cid = 22754679 }}</ref><ref name="Wilson 2001">{{cite journal | vauthors = Wilson RI, Nicoll RA | title = Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses | journal = Nature | volume = 410 | issue = 6828 | pages = 588–92 | date = March 2001 | pmid = 11279497 | doi = 10.1038/35069076 | bibcode = 2001Natur.410..588W | s2cid = 52803281 }}</ref><ref>{{cite journal | vauthors = Kreitzer AC, Regehr WG | title = Retrograde signaling by endocannabinoids | journal = Current Opinion in Neurobiology | volume = 12 | issue = 3 | pages = 324–30 | date = June 2002 | pmid = 12049940 | doi = 10.1016/S0959-4388(02)00328-8 | s2cid = 5846728 }}</ref> as is nitric oxide.<ref name="O'Dell 1991">{{cite journal | vauthors = O'Dell TJ, Hawkins RD, Kandel ER, Arancio O | title = Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 24 | pages = 11285–9 | date = December 1991 | pmid = 1684863 | pmc = 53119 | doi = 10.1073/pnas.88.24.11285 | bibcode = 1991PNAS...8811285O | doi-access = free }}</ref><ref name="Malen 1997">{{cite journal | vauthors = Malen PL, Chapman PF | title = Nitric oxide facilitates long-term potentiation, but not long-term depression | journal = The Journal of Neuroscience | volume = 17 | issue = 7 | pages = 2645–51 | date = April 1997 | pmid = 9065524 | pmc = 6573517 | doi = 10.1523/JNEUROSCI.17-07-02645.1997 }}</ref>

Retrograde signaling may also play a role in [[long-term potentiation]] (LTP), a proposed mechanism of learning and memory, although this is controversial.<ref name="Regehr_2009">{{cite journal | vauthors = Regehr WG, Carey MR, Best AR | title = Activity-dependent regulation of synapses by retrograde messengers | journal = Neuron | volume = 63 | issue = 2 | pages = 154–70 | date = July 2009 | pmid = 19640475 | doi = 10.1016/j.neuron.2009.06.021 | pmc = 3251517 }}</ref><ref name="Nicoll_1995">{{cite journal | vauthors = Nicoll RA, Malenka RC | title = Contrasting properties of two forms of long-term potentiation in the hippocampus | journal = Nature | volume = 377 | issue = 6545 | pages = 115–8 | date = September 1995 | pmid = 7675078 | doi = 10.1038/377115a0 | bibcode = 1995Natur.377..115N | s2cid = 4311817 }}</ref><ref>{{cite journal | vauthors = Abraham WC, Jones OD, Glanzman DL | title = Is plasticity of synapses the mechanism of long-term memory storage? | journal = npj Science of Learning | volume = 4 | issue = 1 | pages = 9 | date = December 2019 | pmid = 31285847 | pmc = 6606636 | doi = 10.1038/s41539-019-0048-y | bibcode = 2019npjSL...4....9A }}</ref>

===Formal definition of a retrograde neurotransmitter===
In 2009, Regehr ''et al.'' proposed criteria for defining retrograde neurotransmitters. According to their work, a signaling molecule can be considered a retrograde neurotransmitter if it satisfies all of the following criteria:<ref name="Regehr 2009" />

*The appropriate machinery for synthesizing and releasing the retrograde messenger must be located in the postsynaptic neuron
*Disrupting the synthesis and/or release of the messenger from the postsynaptic neuron must prevent retrograde signaling
*The appropriate targets for the retrograde messenger must be located in the presynaptic bouton
*Disrupting the targets for the retrograde messenger in the presynaptic boutons must eliminate retrograde signaling
*Exposing the presynaptic bouton to the messenger should mimic retrograde signaling provided the presence of the retrograde messenger is sufficient for retrograde signaling to occur
*In cases where the retrograde messenger is not sufficient, pairing the other factors with the retrograde signal should mimic the phenomenon

===Types of retrograde neurotransmitters===
The most prevalent endogenous retrograde neurotransmitters are [[nitric oxide]]<ref name="O'Dell 1991" /><ref name="Malen 1997" /> and various [[cannabinoid|endocannabinoid]]s, which are lipophilic ligands.<ref name=":0" /><ref>{{Cite book|last1=Vaughan|first1=C. W.|last2=Christie|first2=M. J.|date=2005|title=Retrograde signalling by endocannabinoids|series=Handbook of Experimental Pharmacology|volume=168|issue=168|pages=367–383|doi=10.1007/3-540-26573-2_12|issn=0171-2004|pmid=16596781|isbn=3-540-22565-X}}</ref>

The retrograde neurotransmitter, nitric oxide (NO) is a soluble gas that can readily diffuse through various cell membranes.<ref>{{Cite journal|last1=Arancio|first1=Ottavio|last2=Kiebler|first2=Michael|last3=Lee|first3=C. Justin|last4=Lev-Ram|first4=Varda|last5=Tsien|first5=Roger Y.|last6=Kandel|first6=Eric R.|last7=Hawkins|first7=Robert D.|date=1996-12-13|title=Nitric Oxide Acts Directly in the Presynaptic Neuron to Produce Long-Term Potentiationin Cultured Hippocampal Neurons|journal=Cell|language=English|volume=87|issue=6|pages=1025–1035|doi=10.1016/S0092-8674(00)81797-3|pmid=8978607|s2cid=10550701|issn=0092-8674|doi-access=free}}</ref> Nitric oxide synthase is the enzyme responsible for the synthesis of NO in various presynaptic cells.<ref>{{Cite journal|last1=Overeem|first1=Kathie A.|last2=Ota|first2=Kristie T.|last3=Monsey|first3=Melissa S.|last4=Ploski|first4=Jonathan E.|last5=Schafe|first5=Glenn E.|date=2010-02-05|title=A Role for Nitric Oxide-Driven Retrograde Signaling in the Consolidation of a Fear Memory|journal=Frontiers in Behavioral Neuroscience|volume=4|page=2|doi=10.3389/neuro.08.002.2010|issn=1662-5153|pmc=2820379|pmid=20161806|doi-access=free}}</ref> Specifically, NO is known to play a critical role in LTP, which plays an important role in memory storage within the hippocampus.<ref>{{Cite web|title=Long-Term Potentiation - an overview {{!}} ScienceDirect Topics|url=https://www.sciencedirect.com/topics/neuroscience/long-term-potentiation|access-date=2021-05-05|website=www.sciencedirect.com}}</ref> Additionally, literature suggests that NO can act as intracellular messengers in the brain and can also have an effect on the presynaptic glutamatergic and GABAergic synapses.<ref>{{Cite journal|last1=Hardingham|first1=Neil|last2=Dachtler|first2=James|last3=Fox|first3=Kevin|date=2013|title=The role of nitric oxide in pre-synaptic plasticity and homeostasis|journal=Frontiers in Cellular Neuroscience|language=English|volume=7|page=190|doi=10.3389/fncel.2013.00190|pmid=24198758|pmc=3813972|issn=1662-5102|doi-access=free}}</ref>

Utilizing retrograde signaling, endocannabinoids, a type of retrograde neurotransmitter, are activated when they bind to G-protein coupled receptors on the presynaptic terminals of neurons.<ref name=":1">{{Cite journal|date=2002-06-01|title=Retrograde signaling by endocannabinoids|url=https://www.sciencedirect.com/science/article/abs/pii/S0959438802003288|journal=Current Opinion in Neurobiology|language=en|volume=12|issue=3|pages=324–330|doi=10.1016/S0959-4388(02)00328-8|issn=0959-4388|last1=Kreitzer|first1=A.|last2=Regehr|first2=W. G.|pmid=12049940|s2cid=5846728|url-access=subscription}}</ref> The activation of endocannabinoids results in the release of particular neurotransmitters at the excitatory and inhibitory synapses of a neuron, ultimately impacting various forms of plasticity.<ref>{{Cite journal|date=2012-10-04|title=Endocannabinoid Signaling and Synaptic Function|journal=Neuron|language=en|volume=76|issue=1|pages=70–81|doi=10.1016/j.neuron.2012.09.020|issn=0896-6273|doi-access=free|last1=Castillo|first1=Pablo E.|last2=Younts|first2=Thomas J.|last3=Chávez|first3=Andrés E.|last4=Hashimotodani|first4=Yuki|pmid=23040807|pmc=3517813}}</ref><ref name=":0" /><ref name=":1" />

===Retrograde signaling in long-term potentiation===
{{main|Long-term potentiation}}
As it pertains to LTP, retrograde signaling is a hypothesis describing how events underlying LTP may begin in the [[postsynaptic neuron]] but be propagated to the [[presynaptic neuron]], even though normal [[synaptic transmission|communication]] across a [[chemical synapse]] occurs in a presynaptic to postsynaptic direction. It is used most commonly by those who argue that presynaptic neurons contribute significantly to the expression of LTP.<ref>{{cite book |last=Matthies|first=H.|chapter=Long-Term Synaptic Potentiation and Macromolecular Changes in Memory Formation|date=1988 | doi = 10.1007/978-3-642-73202-7_35|title=Synaptic Plasticity in the Hippocampus|pages=119–121|publisher=Springer Berlin Heidelberg|isbn=9783642732041}}</ref>

====Background====
Long-term potentiation is the persistent increase in the strength of a [[chemical synapse]] that lasts from hours to days.<ref name="Warburton_2015">{{cite book | vauthors = Warburton EC | chapter = Long-Term Potentiation and Memory | title = Encyclopedia of Psychopharmacology | date = 2015 | pages = 928–32 | doi = 10.1007/978-3-642-27772-6_345-2 | isbn = 978-3-642-27772-6 }}</ref> It is thought to occur via two temporally separated events, with ''induction'' occurring first, followed by ''expression''.<ref name="Warburton_2015" /> Most LTP investigators agree that induction is entirely postsynaptic, whereas there is disagreement as to whether expression is principally a presynaptic or postsynaptic event.<ref name="Nicoll_1995" /> Some researchers believe that both presynaptic and postsynaptic mechanisms play a role in LTP expression.<ref name="Nicoll_1995" />

Were LTP entirely induced and expressed postsynaptically, there would be no need for the postsynaptic cell to communicate with the presynaptic cell following LTP induction. However, postsynaptic induction combined with ''presynaptic'' expression requires that, following induction, the postsynaptic cell must communicate with the presynaptic cell. Because normal [[synaptic transmission]] occurs in a presynaptic to postsynaptic direction, postsynaptic to presynaptic communication is considered a form of ''retrograde'' transmission.<ref name="Regehr_2009" />

====Mechanism====
The retrograde signaling hypothesis proposes that during the early stages of LTP expression, the postsynaptic cell "sends a message" to the presynaptic cell to notify it that an LTP-inducing stimulus has been received postsynaptically. The general hypothesis of retrograde signaling does not propose a precise mechanism by which this message is sent and received. One mechanism may be that the postsynaptic cell synthesizes and releases a retrograde messenger upon receipt of LTP-inducing stimulation.<ref name="Garthwaite 1991">{{cite journal | vauthors = Garthwaite J | title = Glutamate, nitric oxide and cell-cell signalling in the nervous system | journal = Trends in Neurosciences | volume = 14 | issue = 2 | pages = 60–7 | date = February 1991 | pmid = 1708538 | doi = 10.1016/0166-2236(91)90022-M | s2cid = 22628126 }}</ref><ref name="Lei 2000">{{cite journal | vauthors = Lei S, Jackson MF, Jia Z, Roder J, Bai D, Orser BA, MacDonald JF | title = Cyclic GMP-dependent feedback inhibition of AMPA receptors is independent of PKG | journal = Nature Neuroscience | volume = 3 | issue = 6 | pages = 559–65 | date = June 2000 | pmid = 10816311 | doi = 10.1038/75729 | s2cid = 21783160 }}</ref> Another is that it releases a preformed retrograde messenger upon such activation. Yet another mechanism is that synapse-spanning proteins may be altered by LTP-inducing stimuli in the postsynaptic cell, and that changes in conformation of these proteins propagates this information across the synapse and to the presynaptic cell.<ref name="Malenka 2004">{{cite journal | vauthors = Malenka RC, Bear MF | title = LTP and LTD: an embarrassment of riches | journal = Neuron | volume = 44 | issue = 1 | pages = 5–21 | date = September 2004 | pmid = 15450156 | doi = 10.1016/j.neuron.2004.09.012 | s2cid = 79844 | doi-access = free }}</ref>

====Identity of the messenger====
Of these mechanisms, the retrograde messenger hypothesis has received the most attention. Among proponents of the model, there is disagreement over the identity of the retrograde messenger. A flurry of work in the early 1990s to demonstrate the existence of a retrograde messenger and to determine its identity generated a list of candidates including [[carbon monoxide]],<ref>{{cite journal | vauthors = Alkadhi KA, Al-Hijailan RS, Malik K, Hogan YH | title = Retrograde carbon monoxide is required for induction of long-term potentiation in rat superior cervical ganglion | journal = The Journal of Neuroscience | volume = 21 | issue = 10 | pages = 3515–20 | date = May 2001 | pmid = 11331380 | pmc = 6762490 | doi = 10.1523/JNEUROSCI.21-10-03515.2001 }}</ref> [[platelet-activating factor]],<ref>{{cite journal | vauthors = Kato K, Zorumski CF | title = Platelet-activating factor as a potential retrograde messenger | journal = Journal of Lipid Mediators and Cell Signalling | volume = 14 | issue = 1–3 | pages = 341–8 | date = September 1996 | pmid = 8906580 | doi = 10.1016/0929-7855(96)00543-3 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kato K, Clark GD, Bazan NG, Zorumski CF | title = Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation | journal = Nature | volume = 367 | issue = 6459 | pages = 175–9 | date = January 1994 | pmid = 8114914 | doi = 10.1038/367175a0 | bibcode = 1994Natur.367..175K | s2cid = 4326359 }}</ref> [[arachidonic acid]],<ref name="Carta 2014">{{cite journal | vauthors = Carta M, Lanore F, Rebola N, Szabo Z, Da Silva SV, Lourenço J, Verraes A, Nadler A, Schultz C, Blanchet C, Mulle C | display-authors = 6 | title = Membrane lipids tune synaptic transmission by direct modulation of presynaptic potassium channels | journal = Neuron | volume = 81 | issue = 4 | pages = 787–99 | date = February 2014 | pmid = 24486086 | doi = 10.1016/j.neuron.2013.12.028 | doi-access = free }}</ref> and nitric oxide. Nitric oxide has received a great deal of attention in the past, but has recently been superseded by [[adhesion protein]]s that span the synaptic cleft to join the presynaptic and postsynaptic cells.<ref name="Malenka 2004"/> The [[endocannabinoids]] [[anandamide]] and/or [[2-AG]], acting through [[GPCR|G-protein coupled]] [[cannabinoid receptor]]s, may play an important role in retrograde signaling in LTP.<ref name="Alger 2002" /><ref name="Wilson 2001" />

== References ==
{{reflist}}

[[Category:Cell signaling]]
[[Category:Neurophysiology]]