EUKARYOTIC

o Secretory vesicles head straight to the membrane as soon as they've left the golgi immediately releasing their cargo.

o These have little control mechanisms in place as the secreted proteins are in constant demand extracellularly such as interleukins from whiteblood cells, and other secreted proteins such as collagen needed in the extracellular matrix.

o This secretion pathway also maintains the cell membrane when the vesicles fuse with the membrane in order to release the cargo, constantly adding lipids to the membrane.

o Most constitutively secreted proteins undergo acidification in their journey through the secretory system, as the environment gradually becomes more acidic through the secretory system. This could be due to many reasons:

o Observations from the mannose 6 phosphate receptors present on secretory vesicles suggest that the pH gradient may allow for vectoral transport of proteins in a unidirectional manner, where one side of the carrier will bind to the cargo protein and the other end is pH sensitive, moving to a more acidic environment heading towards the plasma membrane, stimulating dissociation of the cargo protein to occur and the carrier and receptor can be recycled. This would not be possible without a pH gradient

o The change in pH stimulates a conformational change in the protein which is needed before the protein can leave the trans golgi network. There is increasing evidence that protein subunits must firstly be assembled in order to leave the secretory system. This has been shown in viral membrane proteins where proteins are altered structurally within the golgi due to the change in pH

o All membrane traffic is slowed to the membrane via acidotropic drugs such as chloroquine

Regulated secretion

o this type of secretion occurs when cargo vesicles remain near the cell surface until there is a trigger that stimulates the immediate release of cargo. This is controlled by external factors causing a cascade of intracellular pathways to release the proteins, meaning there are many regulatory steps that can control the release of these secreted proteins compared to those in constitutive secretion.

o Examples include; the release of insulin in response to glucose or something from calcium. Once the transport vesicles have reached the cell surface, they then fuse together to form large mature secretory vesicles which can remain there for days. Characteristics of regulatory secretion include:

o The release of cargo is coupled to an extracellular stimulus, such as the binding of a receptor stimulating a second messenger such as intracellular calcium increase.

o Cargo is packaged and highly concentrated in secretory granules -up to 200 fold increase, whereas constitutive vesicles are concentrated at a maximum of 2 fold.

o Secretory vesicles are stored within the cell for varying amounts of time, forming a large pool of mature secretory products. There mature vesicles are released rapidly to a specific stimulation. This means the protein is accessible when it is needed, regardless of new protein synthesis.

As well as constitutive secretion having a pH sensitive role, it is supported that the regulatory system is as well where acidotropic drugs severely inhibit the regulatory pathway 14

Unconventional protein secretion (UPS)

o there are two types of UPS depending on the nature of the protein; those that do not posses the ER signal peptide and those that posses the signal but avoid the route taken through the golgi.

o Proteins synthesised and secreted via the UPS are typically involved in disease and inflammation in conditions cuh as; starvation, mechanical stress and er stress. Genetic disease such as alzheimers related inflammation, autoimmune diseases and immunomodulation via heat shock proteins that advance the invasiveness of cancer, can cause cell stress and therefore is likely that UPS pathway is used in cellular diseases, making this secretion pathway a new possible target for disease. (ILB1)