Exocytosis

Exocytosis is an active transport mechanism by which cells move large molecules such as hormones, proteins and neurotransmitters from the intracellular environment to the extracellular space. This process allows polar or hydrophilic substances to cross the lipid-rich plasma membrane, enabling essential physiological functions including endocrine secretion, immune defence, membrane repair and synaptic communication. Exocytosis occurs in both prokaryotic and eukaryotic organisms, although the mechanisms differ significantly between these groups.

Overview and Biological Significance

In prokaryotes, exocytosis involves the secretion of molecules and waste products through membrane-embedded translocons or through specialised structures that deliver substances to other cells. Gram-negative bacteria also perform a unique form of exocytosis through the release of outer membrane vesicles, which play roles in communication, pathogenicity and horizontal gene transfer.
In eukaryotes, the process relies on a complex network of organelles connected by intracellular transport routes collectively known as the secretory pathway. Newly synthesised proteins carrying N-terminal signal sequences pass through the endoplasmic reticulum and Golgi apparatus before being packaged into secretory vesicles. These vesicles subsequently travel to the plasma membrane, bind to specialised structures called porosomes and fuse with the membrane to release their contents. Fusion is facilitated by SNARE proteins, which are critical to regulated exocytosis.
Exocytosis supports numerous essential activities, such as neurotransmitter release at synapses, hormone secretion from endocrine glands, immune responses through the release of cytokines and cytotoxic molecules, and membrane renewal and repair.

Historical Development

The principles underlying cellular secretion became clearer during the mid-twentieth century. In the 1940s and 1950s, work by researchers studying the endoplasmic reticulum and other organelles helped reveal the existence of membrane-mediated transport. The discovery of lysosomal exocytosis in the 1950s marked a major breakthrough enabled by advances in electron microscopy.
From the 1950s to the 1960s, the term ‘exocytosis’ began to be used to describe vesicle-mediated secretion, particularly in contexts involving neurotransmission and endocrine function. During the 1970s and 1980s, SNARE proteins were identified through in vitro trafficking assays, leading to a complete redefinition of vesicle docking and fusion. Throughout the 1980s and 1990s, research established the importance of calcium ions as triggers for vesicle release. Critical work by James Rothman, Randy Schekman and Thomas Südhof on vesicle transport, fusion and cargo release earned the 2013 Nobel Prize in Physiology or Medicine.
Modern imaging techniques developed since the early 2000s, including high-resolution fluorescence microscopy, have made it possible to observe exocytosis in real time. This has allowed scientists to identify various sub-pathways such as ‘kiss-and-run’ fusion, in which vesicles briefly fuse with the plasma membrane without fully collapsing.

Types of Exocytosis

Exocytosis in eukaryotic cells follows three major pathways, each defined by the triggers and cellular machinery involved.
Regulated exocytosisThis pathway is controlled by specific signals, usually a sharp rise in cytosolic calcium concentration. Calcium ions activate synaptotagmin, which interacts with SNARE proteins to initiate vesicle fusion. The core SNARE complex consists of syntaxin and SNAP-25 on the plasma membrane and synaptobrevin (VAMP) on the vesicle membrane. ATP-dependent cycles promote the assembly of this complex, generating the mechanical force required for membrane fusion. This type of exocytosis is prominent in neurons and endocrine cells where rapid, stimulus-dependent secretion is vital. A small subset of vesicles is primed for immediate fusion, while the remainder is stored in reserve pools associated with cytoskeletal structures.
Constitutive exocytosisConstitutive exocytosis occurs continuously in all cell types, independent of specific signals. It delivers new membrane proteins and lipids to the cell surface and releases components into the extracellular space. Protein complexes such as ELKS and the exocyst contribute to vesicle tethering, ensuring accurate targeting and fusion with the plasma membrane. This pathway is essential for maintaining membrane composition and supporting normal cell growth.
Outer membrane vesicle-mediated exocytosisThis mechanism is observed in gram-negative bacteria, where vesicles bud off from the outer membrane. These vesicles carry toxins, signalling molecules, DNA and RNA, contributing to bacterial survival, pathogenicity and communication. They also facilitate horizontal gene transfer, allowing rapid adaptation to environmental pressures. This process challenges the traditional view that exocytosis is limited to eukaryotic cells.

Mechanisms of Exocytosis

Exocytosis in eukaryotic cells involves several coordinated steps, each driven by specific proteins and cytoskeletal components.
Vesicle traffickingSecretory vesicles form at the Golgi apparatus and must be transported across the cytoplasm. This movement relies on motor proteins, including those associated with actin filaments and microtubules, which guide vesicles towards the plasma membrane.
Vesicle tetheringBefore docking, vesicles are loosely tethered near the membrane at distances greater than the vesicle diameter. This prevents premature fusion and concentrates vesicles at the correct release sites. Multiple tethering factors act to maintain vesicle position until docking can occur.
Vesicle dockingDocking involves direct contact between the vesicle and the plasma membrane, mediated by SNARE proteins. The interaction of synaptobrevin, SNAP-25 and syntaxin forms a tightly wound complex known as the trans-SNARE complex, which stabilises the vesicle in position. In many secretory cells, vesicles dock at porosomes—small, cup-shaped structures embedded in the membrane.
Vesicle primingPriming prepares docked vesicles for rapid fusion, rendering them release-competent. This often requires partial ATP-dependent SNARE assembly and sensitivity to calcium influx. In neurosecretory cells, priming has been studied extensively using permeabilised cell preparations such as chromaffin cells and PC12 cells. These models demonstrate that vesicles require biochemical modifications before they can efficiently respond to calcium signals.
Vesicle fusionUpon stimulation, typically via an increase in intracellular calcium, the primed vesicle undergoes rapid fusion with the plasma membrane. Calcium sensors interact with the SNARE complex or the phospholipid bilayer, triggering porosome opening and allowing content release. Fusion can occur as full collapse of the vesicle into the membrane or through transient contact characteristic of kiss-and-run events.
Cargo release and membrane recoveryAfter fusion, the vesicle releases its contents into the extracellular space. Membrane components are recycled through endocytosis and returned to the endomembrane system, maintaining membrane balance.

Biological Roles of Exocytosis

Exocytosis underpins numerous vital processes:

• Neurotransmission: release of neurotransmitters into synapses.
• Endocrine secretion: hormone release, such as insulin from pancreatic cells.
• Immune responses: secretion of cytokines and cytotoxic agents.
• Membrane repair: rapid patching of damaged plasma membrane regions.
• Waste removal: expulsion of debris and undigested material.