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Exocytosis

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Exocytosis is a term for the active transport process that transports large molecules from cell to the extracellular area. Hormones, proteins and neurotransmitters are examples of large molecules that can be transported out of the cell.[1] Exocytosis is a crucial transport mechanism that enables polar molecules to flow through the cell membranes’ hydrophobic lipid bilayer. The transport process is essential to hormone secretion, immune response and neurotransmission.

The process of regulated exocytosis. Secretory vesicles containing molecules, shown as purple orbs, being secreted, forming vesicles in the cytoplasm and moving towards the cell membrane, before the vesicle fuses with the membrane, releasing its contents into the extracellular fluids. The arrows show the secretory vesicles directional movement, as well as labelling key components, such as the cytoplasm, the cell membrane and the extracellular fluid. Made in biorender.com

Both prokaryotes and eukaryotes undergo exocytosis. Prokaryotes secrete molecules and cellular waste through translocons that are localized to the cell membrane. In addition, they secrete molecules to other cells through specialized organs.[2] Eukaryotes rely on multiple cellular processes to perform the exocytosis process. Eukaryotes have several organelles and a nucleus in the cytoplasm that are connected through multiple transport routes, that is formally known as the secretory pathway. This is a complex pathway with multiple processes, including the exclusion of molecules to the extracellular area[3] [4]. This happens where secretory vesicles transport and fuse with the plasma membrane of the cell to release their contents to the extracellular area.

Different molecules will carry different signal sequences. Proteins carry signal sequences at their N-Terminus, which guides them through the secretory pathway.[5] When reaching the plasma membrane, the vesicles bind to porosomes that are embedded in the membrane. This is a process helped by SNARE proteins (Soluble NSF attachment protein receptors) in regulated exocytosis. This is one of tree processes in which exocytosis can be performed, where the two others are constitutive exocytosis[6] and outer-membrane vesicle mediated exocytosis.[7]

Purposes of Exocytosis

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Exocytosis plays a vital role in various biological processes:

  • Neurotransmitter Release – Exocytosis occurs in nerve cells to release neurotransmitters into synapses, this facilitates communication between neurons.
  • Hormone Secretion – Enables the endocrine system to secrete hormones, such as insulin through regulated exocytosis.[8]
  • Immune Response – Exocytosis enables the immune system to release cytokines and cytotoxic molecules to decrease inflammation and combat infections.[9][10]
  • Membrane Growth and Repair – Exocytosis contributes to plasma membrane expansion and the repair of damaged membranes, along with other processes, such as endocytosis.[11]
  • Waste Removal – Cells expel waste products and undigested materials through exocytosis.[6]

History

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The discovery of major principles of cell secretion started between the 1940’s and 50’s, which has helped to understand cellular transport mechanisms. The discovery of lysosome exocytosis in the 1950s was made possible by early research on the endoplasmic reticulum by Keith Porter, Albert Claude, and George Palade, which resulted from the development of electron microscopy.[12]  This has given a greater understanding of the membrane trafficking and vesicle transport, which in turn provides information about cell communication and its environment.

Some important milestones in exocytosis research:

  • 1950s-1960s: The basic elements and functions of the term exocytosis was discovered, and the word exocytosis was used to describe vesicle-mediated secretion processes, with emphasis on the role within neurotransmitter release and hormone secretion[12].
  • 1970s-1980s: The SNARE proteins were identified after a decade of biochemical research, through an in-vitro trafficking assay developed in the 80’s by Rothman et. Al. The synaptic SNAREs identified were discovered in either synaptic vesicles or presynaptic membrane.[13] This led to research that uncovered their critical role in vesicle docking and fusion with the plasma membrane [5] and led to an understanding of the processes that trigger exocytosis, such as increased calcium concentration.[14]
  • 1993: James E. Rothman, Randy W. Schekman, and Thomas C.Südhof made groundbreaking contributions to understanding vesicle transport, earning the Nobel Prize in Physiology or Medicine in 2013. Their research elucidated the mechanisms of vesicle trafficking, fusion, and cargo release[15].
  • 2000s-Present: The development of new and advanced imaging techniques, such as fluorescence imaging allowed for real-time monitoring of exocytosis[6]. This provides new insights into molecular mechanisms, such as multiple pathways, kiss-and-run and the process of exocytosis to a more detailed level.[8]

Types

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Regulated exocytosis

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Regulated exocytosis is usually triggered by an increase in the cytosolic free calcium ions (Ca2+) concentration involving synaptotagmin and mediated by SNARE proteins.[14] SNARE complex is formed by syntaxin-1 and SNAP25 at the presynaptic plasma membrane and Synaptrobrevin (VAMP) at the vesicle membrane. This complex promotes membrane fusion through mechanical force and is driven by adenosine triphosphate (ATP) - dependent cycle.[10] Following the docking and priming processes, the calcium sensors that trigger exocytosis might interact either with the SNARE complex or the phospholipid layer in the attaching membranes. The calcium sensors trigger porosomes to open, allowing neurotransmitters to be released into the synaptic cleft. A small percentage of indocrine and neuron cells have vesicles that are ready to fuse immediately upon stimulation. The majority of cells are kept in reserve pools, like actin filaments in endocrine cells and synapses in neurons.[11] This makes sure the vesicles docked are able to undergo a fusion at a rapid rate. [16]

Constitutive exocytosis

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Constitutive exocytosis is a continuous process that occurs in all cells. It is involved in the addition of new membrane proteins and lipids to the plasma membrane or the extracellular area. This process does not require any additional signalling and is an important part in maintaining the cells membrane by inserting new membrane proteins. The molecular machinery in constitutive exocytosis is under continuous research and proteins such as ELKS and EXOCYST are complexes that contribute to the tethering the vesicles to the plasma membrane. This makes sure there is a proper fusion and secretion of material.

Outer-membrane vesicle mediated exocytosis

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Vesicular exocytosis in prokaryote gram-negative bacteria is another mechanism that has been found in recent years. Exocytosis, in this case, occurs through release of outer-membrane vesicles (OMV). This contributes to the bacteria's functions, such as pathogenicity and communication. OMV's carry toxins and viral factors to host cells to create inflammatory responses and infection. The vesicles carry molecules that can contribute to immune system modulation[17][7]. Outer-membrane vesicles are able to use a process called horizontal gene transfer through carrying DNA and RNA between bacterial organisms. This promotes adaptation in the environment and helps bacteria evolve.[7] This is unique to gram-negative bacteria and challenges the existing view on exocytosis as an eukaryotic process.

Mechanisms in exocytosis

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The mechanisms involved in exocytosis are divided into 6 separate steps:

Mechanism of synaptic vesicle exocytosis at the neuronal synapse. SNARE proteins (syntaxin, SNAP-25, and synaptobrevin) create the SNARE complex, which directs neurotransmitter-filled vesicles to the plasma membrane. The vesicle merges with the membrane and releases its contents into the synaptic cleft when calcium ions (Ca2+) enter the cell, enabling the signal to reach the subsequent neurone. Made in biorender.com

Vesicle trafficking:

Vesicles are transported throughout the cell across relatively short distances with the help of motor proteins and the cytoskeleton. These are usually necessary for moving vesicles from the Golgi apparatus to the plasma membrane for secretion.[1] Motor proteins, such as actin filaments or microtubules, work together with the cytoskeleton and other motor proteins to move the vesicles from the Golgi apparatus and to the plasma membrane.[2]

Vesicle tethering:

Prior to attaching to the cell wall, vesicles are concentrated close to the cell membrane through tethering, which happens more than 1 vesicle diameter from the membrane to prevent premature attachment. When the molecule concentration is significant, the vesicles attach to the plasma membrane.[1]

Vesicle docking:

In the lipid-lined pore theory, both membranes curve toward each other to form the early fusion pore. When the two membranes are brought to a "critical" distance, the lipid head-groups from one membrane insert into the other, creating the basis for the fusion pore.

Proteins like SNAREs help control how the vesicle attaches to the cell membrane. The SNARE complex, which includes proteins like synaptobrevin, SNAP-25 and syntaxin, plays an essential role in ensuring that the vesicles dock correctly, especially in nerve cells.[13]

Through a strong t-/v-SNARE ring complex, secretory vesicles momentarily dock and fuse at the porosome at the cells plasma membrane.

Vesicle priming

Priming is the process in which the vesicle releases a component through so that it can merge with the plasma membrane of the cell wall. Before the merge transpires, a vesicle becomes release-competent. This means that the vesicle responds to a trigger, usually a rise in Ca2+ concentration.[14] Priming refers to the preparation of vesicles to merge with the plasma membrane, wherein two variants of the definitions of the process can occur:

  • Priming in permeabilized cells[12]:
    •  This is based on the studies on permeabilized neurosecretory cells, such as chromaffin and PC12.
    •  These cells vesicle merging capabilities diminish after membrane permeabilization. Priming is defined as a calcium dependent process that restores secretion competence or supports
  • In electrophysical measurements:
    • Priming is often described as the process where vesicles are recycled. The pool of vesicles that are refilled, with molecules, are often referred to as primed vesicles and are ready to release with censoring. The censoring can be triggered by Ca2+ increase in concentration.[11]

Vesicle fusion

Fusion happens when the plasma membrane and vesicle merge, forced by the SNARE proteins. A fusion of the plasma membrane and vesicle results in a release of the contents in the vesicle into the extracellular area. In synapses/neurons, there is a different release which involves the neurotransmitters release into a synaptic cleft.[13]

Vesicle retrieval

After fusion with the plasma membrane, vesicle membranes are often retrieved through endocytosis. This allows them to be recycled and reused for secretion, making the fusion temporarily. This returns the vesicle to cytosol to be reused.[4]

Retrieval of synaptic vesicles occurs by endocytosis. Most synaptic vesicles are recycled without a full fusion into the membrane (kiss-and-run fusion) via porosome. Regulated exocytosis and subsequent endocytosis are ATP-dependent processes, and therefore reliant on the mitochondria.[18]

See also:

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References

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  1. ^ a b c Wu, Ling-Gang; Hamid, Edaeni; Shin, Wonchul; Chiang, Hsueh-Cheng (2014). "Exocytosis and endocytosis: modes, functions, and coupling mechanisms". Annual Review of Physiology. 76: 301–331. doi:10.1146/annurev-physiol-021113-170305. ISSN 1545-1585. PMC 4880020. PMID 24274740.
  2. ^ a b Viotti, Corrado (2016), Pompa, Andrea; De Marchis, Francesca (eds.), "ER to Golgi-Dependent Protein Secretion: The Conventional Pathway", Unconventional Protein Secretion: Methods and Protocols, New York, NY: Springer, pp. 3–29, doi:10.1007/978-1-4939-3804-9_1, ISBN 978-1-4939-3804-9, retrieved 2025-04-11
  3. ^ Schweizer, Felix E; Ryan, Timothy A (2006-06-01). "The synaptic vesicle: cycle of exocytosis and endocytosis". Current Opinion in Neurobiology. Signalling mechanisms. 16 (3): 298–304. doi:10.1016/j.conb.2006.05.006. ISSN 0959-4388.
  4. ^ a b Bonifacino, Juan S.; Glick, Benjamin S. (2004-01-23). "The Mechanisms of Vesicle Budding and Fusion". Cell. 116 (2): 153–166. doi:10.1016/S0092-8674(03)01079-1. ISSN 0092-8674. PMID 14744428.
  5. ^ a b Jahn, Reinhard; Scheller, Richard H. (2006-09). "SNAREs — engines for membrane fusion". Nature Reviews Molecular Cell Biology. 7 (9): 631–643. doi:10.1038/nrm2002. ISSN 1471-0080. {{cite journal}}: Check date values in: |date= (help)
  6. ^ a b c Tran, Duy T.; Ten Hagen, Kelly G. (2017-04-15). "Real-time insights into regulated exocytosis". Journal of Cell Science. 130 (8): 1355–1363. doi:10.1242/jcs.193425. ISSN 0021-9533.
  7. ^ a b c Yáñez-Mó, María; Siljander, Pia R.-M.; Andreu, Zoraida; Zavec, Apolonija Bedina; Borràs, Francesc E.; Buzas, Edit I.; Buzas, Krisztina; Casal, Enriqueta; Cappello, Francesco; Carvalho, Joana; Colás, Eva; Cordeiro-da Silva, Anabela; Fais, Stefano; Falcon-Perez, Juan M.; Ghobrial, Irene M. (2015). "Biological properties of extracellular vesicles and their physiological functions". Journal of Extracellular Vesicles. 4: 27066. doi:10.3402/jev.v4.27066. ISSN 2001-3078. PMC 4433489. PMID 25979354.
  8. ^ a b "Synaptic Vesicle - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2025-04-11.
  9. ^ Song, Ji-hoon; Hanayama, Rikinari (2016), Miyasaka, Masayuki; Takatsu, Kiyoshi (eds.), "Mechanisms of Lysosomal Exocytosis by Immune Cells", Chronic Inflammation: Mechanisms and Regulation, Tokyo: Springer Japan, pp. 369–378, doi:10.1007/978-4-431-56068-5_29#citeas, ISBN 978-4-431-56068-5, retrieved 2025-04-11
  10. ^ a b Südhof, Thomas C.; Rothman, James E. (2009-01-23). "Membrane Fusion: Grappling with SNARE and SM Proteins". Science. 323 (5913): 474–477. doi:10.1126/science.1161748. PMC 3736821. PMID 19164740.
  11. ^ a b c Stojilkovic, Stanko S. (2005-04). "Ca2+-regulated exocytosis and SNARE function". Trends in endocrinology and metabolism: TEM. 16 (3): 81–83. doi:10.1016/j.tem.2005.02.002. ISSN 1043-2760. PMID 15808803. {{cite journal}}: Check date values in: |date= (help)
  12. ^ a b c Verhage, Matthijs; Sørensen, Jakob B. (2008). "Vesicle Docking in Regulated Exocytosis". Traffic. 9 (9): 1414–1424. doi:10.1111/j.1600-0854.2008.00759.x. ISSN 1600-0854.
  13. ^ a b c Ungar, Daniel; Hughson, Frederick M. (2003-11-01). "SNARE Protein Structure and Function". Annual Review of Cell and Developmental Biology. 19 (Volume 19, 2003): 493–517. doi:10.1146/annurev.cellbio.19.110701.155609. ISSN 1081-0706. {{cite journal}}: |issue= has extra text (help)
  14. ^ a b c Stojilkovic, Stanko S. (2005-04). "Ca2+-regulated exocytosis and SNARE function". Trends in endocrinology and metabolism: TEM. 16 (3): 81–83. doi:10.1016/j.tem.2005.02.002. ISSN 1043-2760. PMID 15808803. {{cite journal}}: Check date values in: |date= (help)
  15. ^ Südhof, Thomas C. (2013-10-30). "Neurotransmitter release: the last millisecond in the life of a synaptic vesicle". Neuron. 80 (3): 675–690. doi:10.1016/j.neuron.2013.10.022. ISSN 1097-4199. PMC 3866025. PMID 24183019.
  16. ^ Zhang, Minchuan; Augustine, George J. (2021-03-16). "Synapsins and the Synaptic Vesicle Reserve Pool: Floats or Anchors?". Cells. 10 (3): 658. doi:10.3390/cells10030658. ISSN 2073-4409. PMC 8002314. PMID 33809712.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  17. ^ "https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immune-system-modulator". www.cancer.gov. 2011-02-02. Retrieved 2025-04-11. {{cite web}}: External link in |title= (help)
  18. ^ Ivannikov, M.; et al. (2013). "Synaptic vesicle exocytosis in hippocampal synaptosomes correlates directly with total mitochondrial volume". J. Mol. Neurosci. 49 (1): 223–230. doi:10.1007/s12031-012-9848-8. PMC 3488359. PMID 22772899.
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