Retrograde signaling

Retrograde signaling in biology is the process where a signal travels backwards from a target source to its original source. For example, the 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.^[1] In cell biology, this type of signaling typically occurs between the 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.^[2]

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 cell body, and travels "backwards" across a chemical synapse to bind to the axon terminal of a presynaptic neuron.^[3]

In cell biology

Retrograde signals are transmitted from plastids to the nucleus in plants and eukaryotic algae,^[4][2] and from mitochondria to the nucleus in most eukaryotes.^[5] Retrograde signals are generally considered to convey intracellular signals related to stress and environmental sensing.^[6] Many of the molecules associated with retrograde signaling act on modifying the 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.^[4]

Evolution

Retrograde signaling is believed to have arisen after endocytosis of the mitochondria and chloroplast billions of years ago.^[7] Originally believed to be photosynthetic bacteria, the mitochondria and chloroplast transferred some of their DNA to the membrane protected nucleus.^[8] 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.^[9]

In yeast

The first retrograde signaling pathways discovered in yeast is the RTG pathway.^[10][11] The RTG pathway plays an important role in maintaining the metabolic homeostasis of yeast.^[11] Under limited resources the mitochondria must maintain a balance of glutamate for the citric acid cycle.^[12] Retrograde signaling form the mitochondria initiates production precursor molecules of glutamate to properly balance supplies within the mitochondria.^[13] 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.^[13] These mechanism are vital to maintain homeostasis of the cell and ensure proper function of the mitochondria.^[13]

In plants

One of the most studied retrograde signaling molecules in plants are reactive oxygen species (ROS).^[14] These compounds, previously believed to be damaging to the cell, have since been discovered to act as a signaling molecule.^[15] Reactive oxygen species are created as a by-product of aerobic respiration and act on genes involved in the stress response.^[15] Depending on the stress, reactive oxygen species can act on neighboring cells to initiate a local signal.^[16] 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.^[16] 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.^[17] 

In neuroscience

 

Feedback loop found in retrograde neurological signaling.

The primary purpose of retrograde neurotransmission is regulation of chemical neurotransmission.^[3] For this reason, retrograde neurotransmission allows neural circuits to create feedback loops. 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 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.^[18] 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.^[19]

Endocannabinoids like anandamide are known to act as retrograde messengers,^[20][21][22] as is nitric oxide.^[23][24]

Retrograde signaling may also play a role in long-term potentiation (LTP), a proposed mechanism of learning and memory, although this is controversial.^[25][26][27]

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:^[3]

• 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^[23][24] and various endocannabinoids, which are lipophilic ligands.^[19][28]

The retrograde neurotransmitter, nitric oxide (NO) is a soluble gas that can readily diffuse through various cell membranes.^[29] Nitric oxide synthase is the enzyme responsible for the synthesis of NO in various presynaptic cells.^[30] Specifically, NO is known to play a critical role in LTP, which plays an important role in memory storage within the hippocampus.^[31] 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.^[32]

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.^[33] 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.^[34][19][33]

Retrograde signaling in long-term potentiation

Main article: 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 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.^[35]

Background

Long-term potentiation is the persistent increase in the strength of a chemical synapse that lasts from hours to days.^[36] It is thought to occur via two temporally separated events, with induction occurring first, followed by expression.^[36] Most LTP investigators agree that induction is entirely postsynaptic, whereas there is disagreement as to whether expression is principally a presynaptic or postsynaptic event.^[26] Some researchers believe that both presynaptic and postsynaptic mechanisms play a role in LTP expression.^[26]

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.^[25]

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.^[37][38] 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.^[39]

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,^[40] platelet-activating factor,^[41][42] arachidonic acid,^[43] and nitric oxide. Nitric oxide has received a great deal of attention in the past, but has recently been superseded by adhesion proteins that span the synaptic cleft to join the presynaptic and postsynaptic cells.^[39] The endocannabinoids anandamide and/or 2-AG, acting through G-protein coupled cannabinoid receptors, may play an important role in retrograde signaling in LTP.^[20][21]

References

1. Leister, Dario (2012). "Retrograde signaling in plants: from simple to complex scenarios". Frontiers in Plant Science. 3: 135. doi:10.3389/fpls.2012.00135. ISSN 1664-462X. PMC 3377957. PMID 22723802.
2. Nott A, Jung HS, Koussevitzky S, Chory J (June 2006). "Plastid-to-nucleus retrograde signaling". Annual Review of Plant Biology. 57: 739–59. doi:10.1146/annurev.arplant.57.032905.105310. PMID 16669780.
3. Regehr WG, Carey MR, Best AR (July 2009). "Activity-dependent regulation of synapses by retrograde messengers". Neuron. 63 (2): 154–70. doi:10.1016/j.neuron.2009.06.021. PMC 3251517. PMID 19640475.
4. Duanmu D, Casero D, Dent RM, Gallaher S, Yang W, Rockwell NC, et al. (February 2013). "Retrograde bilin signaling enables Chlamydomonas greening and phototrophic survival". Proceedings of the National Academy of Sciences of the United States of America. 110 (9): 3621–6. doi:10.1073/pnas.1222375110. PMC 3587268. PMID 23345435.
5. Liu Z, Butow RA (December 2006). "Mitochondrial retrograde signaling". Annual Review of Genetics. 40: 159–85. doi:10.1146/annurev.genet.40.110405.090613. PMID 16771627.
6. Nott A, Jung HS, Koussevitzky S, Chory J (2006). "Plastid-to-nucleus retrograde signaling". Annual Review of Plant Biology. 57: 739–59. doi:10.1146/annurev.arplant.57.032905.105310. PMID 16669780.
7. Bevan RB, Lang BF (2004). "Mitochondrial genome evolution: the origin of mitochondria and of eukaryotes.". Mitochondrial Function and Biogenesis. Topics in Current Genetics. Vol. 8. Berlin, Heidelberg: Springer. pp. 1–35. doi:10.1007/b96830. ISBN 978-3-540-21489-2.
8. da Cunha FM, Torelli NQ, Kowaltowski AJ (2015). "Mitochondrial Retrograde Signaling: Triggers, Pathways, and Outcomes". Oxidative Medicine and Cellular Longevity. 2015: 482582. doi:10.1155/2015/482582. PMC 4637108. PMID 26583058.
9. Whelan SP, Zuckerbraun BS (2013). "Mitochondrial signaling: forwards, backwards, and in between". Oxidative Medicine and Cellular Longevity. 2013: 351613. doi:10.1155/2013/351613. PMC 3681274. PMID 23819011.
10. Parikh VS, Morgan MM, Scott R, Clements LS, Butow RA (January 1987). "The mitochondrial genotype can influence nuclear gene expression in yeast". Science. 235 (4788): 576–80. Bibcode:1987Sci...235..576P. doi:10.1126/science.3027892. PMID 3027892.
11. Liu Z, Sekito T, Epstein CB, Butow RA (December 2001). "RTG-dependent mitochondria to nucleus signaling is negatively regulated by the seven WD-repeat protein Lst8p". The EMBO Journal. 20 (24): 7209–19. doi:10.1093/emboj/20.24.7209. PMC 125777. PMID 11742997.
12. Jazwinski SM, Kriete A (2012). "The yeast retrograde response as a model of intracellular signaling of mitochondrial dysfunction". Frontiers in Physiology. 3: 139. doi:10.3389/fphys.2012.00139. PMC 3354551. PMID 22629248.
13. Liu Z, Butow RA (October 1999). "A transcriptional switch in the expression of yeast tricarboxylic acid cycle genes in response to a reduction or loss of respiratory function". Molecular and Cellular Biology. 19 (10): 6720–8. doi:10.1128/MCB.19.10.6720. PMC 84662. PMID 10490611.
14. Maruta T, Noshi M, Tanouchi A, Tamoi M, Yabuta Y, Yoshimura K, et al. (April 2012). "H2O2-triggered retrograde signaling from chloroplasts to nucleus plays specific role in response to stress". The Journal of Biological Chemistry. 287 (15): 11717–29. doi:10.1074/jbc.m111.292847. PMC 3320920. PMID 22334687.
15. Schieber M, Chandel NS (May 2014). "ROS function in redox signaling and oxidative stress". Current Biology. 24 (10): R453-62. doi:10.1016/j.cub.2014.03.034. PMC 4055301. PMID 24845678.
16. Shapiguzov A, Vainonen JP, Wrzaczek M, Kangasjärvi J (2012). "ROS-talk - how the apoplast, the chloroplast, and the nucleus get the message through". Frontiers in Plant Science. 3: 292. doi:10.3389/fpls.2012.00292. PMC 3530830. PMID 23293644.
17. Estavillo GM, Chan KX, Phua SY, Pogson BJ (2013). "Reconsidering the nature and mode of action of metabolite retrograde signals from the chloroplast". Frontiers in Plant Science. 3: 300. doi:10.3389/fpls.2012.00300. PMC 3539676. PMID 23316207.
18. Tao, Huizhong W.; Poo, Mu-ming (2001-09-25). "Retrograde signaling at central synapses". Proceedings of the National Academy of Sciences. 98 (20): 11009–11015. Bibcode:2001PNAS...9811009T. doi:10.1073/pnas.191351698. ISSN 0027-8424. PMC 58675. PMID 11572961.
19. "Endocannabinoids Performance through Retrograde Signaling | Cannabis Sciences". Labroots. Retrieved 2021-05-05.
20. Alger BE (November 2002). "Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids". Progress in Neurobiology. 68 (4): 247–86. doi:10.1016/S0301-0082(02)00080-1. PMID 12498988. S2CID 22754679.
21. Wilson RI, Nicoll RA (March 2001). "Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses". Nature. 410 (6828): 588–92. Bibcode:2001Natur.410..588W. doi:10.1038/35069076. PMID 11279497. S2CID 52803281.
22. Kreitzer AC, Regehr WG (June 2002). "Retrograde signaling by endocannabinoids". Current Opinion in Neurobiology. 12 (3): 324–30. doi:10.1016/S0959-4388(02)00328-8. PMID 12049940. S2CID 5846728.
23. O'Dell TJ, Hawkins RD, Kandel ER, Arancio O (December 1991). "Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger". Proceedings of the National Academy of Sciences of the United States of America. 88 (24): 11285–9. Bibcode:1991PNAS...8811285O. doi:10.1073/pnas.88.24.11285. PMC 53119. PMID 1684863.
24. Malen PL, Chapman PF (April 1997). "Nitric oxide facilitates long-term potentiation, but not long-term depression". The Journal of Neuroscience. 17 (7): 2645–51. doi:10.1523/JNEUROSCI.17-07-02645.1997. PMC 6573517. PMID 9065524.
25. Regehr WG, Carey MR, Best AR (July 2009). "Activity-dependent regulation of synapses by retrograde messengers". Neuron. 63 (2): 154–70. doi:10.1016/j.neuron.2009.06.021. PMC 3251517. PMID 19640475.
26. Nicoll RA, Malenka RC (September 1995). "Contrasting properties of two forms of long-term potentiation in the hippocampus". Nature. 377 (6545): 115–8. Bibcode:1995Natur.377..115N. doi:10.1038/377115a0. PMID 7675078. S2CID 4311817.
27. Abraham WC, Jones OD, Glanzman DL (December 2019). "Is plasticity of synapses the mechanism of long-term memory storage?". npj Science of Learning. 4 (1): 9. Bibcode:2019npjSL...4....9A. doi:10.1038/s41539-019-0048-y. PMC 6606636. PMID 31285847.
28. Vaughan, C. W.; Christie, M. J. (2005). Retrograde signalling by endocannabinoids. Handbook of Experimental Pharmacology. Vol. 168. pp. 367–383. doi:10.1007/3-540-26573-2_12. ISBN 3-540-22565-X. ISSN 0171-2004. PMID 16596781.
29. Arancio, Ottavio; Kiebler, Michael; Lee, C. Justin; Lev-Ram, Varda; Tsien, Roger Y.; Kandel, Eric R.; Hawkins, Robert D. (1996-12-13). "Nitric Oxide Acts Directly in the Presynaptic Neuron to Produce Long-Term Potentiationin Cultured Hippocampal Neurons". Cell. 87 (6): 1025–1035. doi:10.1016/S0092-8674(00)81797-3. ISSN 0092-8674. PMID 8978607. S2CID 10550701.
30. Overeem, Kathie A.; Ota, Kristie T.; Monsey, Melissa S.; Ploski, Jonathan E.; Schafe, Glenn E. (2010-02-05). "A Role for Nitric Oxide-Driven Retrograde Signaling in the Consolidation of a Fear Memory". Frontiers in Behavioral Neuroscience. 4: 2. doi:10.3389/neuro.08.002.2010. ISSN 1662-5153. PMC 2820379. PMID 20161806.
31. "Long-Term Potentiation - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2021-05-05.
32. Hardingham, Neil; Dachtler, James; Fox, Kevin (2013). "The role of nitric oxide in pre-synaptic plasticity and homeostasis". Frontiers in Cellular Neuroscience. 7: 190. doi:10.3389/fncel.2013.00190. ISSN 1662-5102. PMC 3813972. PMID 24198758.
33. Kreitzer, A.; Regehr, W. G. (2002-06-01). "Retrograde signaling by endocannabinoids". Current Opinion in Neurobiology. 12 (3): 324–330. doi:10.1016/S0959-4388(02)00328-8. ISSN 0959-4388. PMID 12049940. S2CID 5846728.
34. Castillo, Pablo E.; Younts, Thomas J.; Chávez, Andrés E.; Hashimotodani, Yuki (2012-10-04). "Endocannabinoid Signaling and Synaptic Function". Neuron. 76 (1): 70–81. doi:10.1016/j.neuron.2012.09.020. ISSN 0896-6273. PMC 3517813. PMID 23040807.
35. Matthies, H. (1988). "Long-Term Synaptic Potentiation and Macromolecular Changes in Memory Formation". Synaptic Plasticity in the Hippocampus. Springer Berlin Heidelberg. pp. 119–121. doi:10.1007/978-3-642-73202-7_35. ISBN 9783642732041.
36. Warburton EC (2015). "Long-Term Potentiation and Memory". Encyclopedia of Psychopharmacology. pp. 928–32. doi:10.1007/978-3-642-27772-6_345-2. ISBN 978-3-642-27772-6.
37. Garthwaite J (February 1991). "Glutamate, nitric oxide and cell-cell signalling in the nervous system". Trends in Neurosciences. 14 (2): 60–7. doi:10.1016/0166-2236(91)90022-M. PMID 1708538. S2CID 22628126.
38. Lei S, Jackson MF, Jia Z, Roder J, Bai D, Orser BA, MacDonald JF (June 2000). "Cyclic GMP-dependent feedback inhibition of AMPA receptors is independent of PKG". Nature Neuroscience. 3 (6): 559–65. doi:10.1038/75729. PMID 10816311. S2CID 21783160.
39. Malenka RC, Bear MF (September 2004). "LTP and LTD: an embarrassment of riches". Neuron. 44 (1): 5–21. doi:10.1016/j.neuron.2004.09.012. PMID 15450156. S2CID 79844.
40. Alkadhi KA, Al-Hijailan RS, Malik K, Hogan YH (May 2001). "Retrograde carbon monoxide is required for induction of long-term potentiation in rat superior cervical ganglion". The Journal of Neuroscience. 21 (10): 3515–20. doi:10.1523/JNEUROSCI.21-10-03515.2001. PMC 6762490. PMID 11331380.
41. Kato K, Zorumski CF (September 1996). "Platelet-activating factor as a potential retrograde messenger". Journal of Lipid Mediators and Cell Signalling. 14 (1–3): 341–8. doi:10.1016/0929-7855(96)00543-3. PMID 8906580.
42. Kato K, Clark GD, Bazan NG, Zorumski CF (January 1994). "Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation". Nature. 367 (6459): 175–9. Bibcode:1994Natur.367..175K. doi:10.1038/367175a0. PMID 8114914. S2CID 4326359.
43. Carta M, Lanore F, Rebola N, Szabo Z, Da Silva SV, Lourenço J, et al. (February 2014). "Membrane lipids tune synaptic transmission by direct modulation of presynaptic potassium channels". Neuron. 81 (4): 787–99. doi:10.1016/j.neuron.2013.12.028. PMID 24486086.