Biomedical Engineering Reference
In-Depth Information
To make this possible, most of the internalized plasma membrane components
(proteins and lipids) are continually returned to the cell surface by exocytosis. This
large-scale endocytic-exocytic cycle is mediated largely by clathrin-coated pits
and vesicles. Major trafficking pathways consist of an inward flux of endocytic
vesicles from the plasma membrane and an outward flux of exocytic vesicles to
the plasma membrane. Virtually all eucaryotic cells continually ingest their plasma
membrane in the form of small pinocytic (endocytic) vesicles, which later return
to the cell surface. The same amount of membrane that is being removed by endo-
cytosis is being added to the cell surface by exocytosis. In this sense, endocytosis
and exocytosis are linked processes that can be considered to constitute an endo-
cytic-exocytic cycle (Alberts et al.
2002
). In this paper, we discuss both arms of
the cycle.
Kinetically, three modes of endocytosis can be defined: fluid-phase, adsorptive,
and receptor-or lipid raft mediated endocytosis (Khalil et al.
2006
): (1) Fluid-phase
endocytosis is a low efficiency, nonspecific process that involves the bulk uptake.
(2) Absorptive endocytosis molecules are bound to the cell surface and concen-
trated before internalization, with the molecules interacting with generic comple-
mentary binding sites, such as lectin or charged interaction. (3) Receptor-mediated
endocytosis also involves concentration of the molecules, with certain ligands binding
to receptors on the cell surface and becoming concentrated before internalization.
Typically, clathrin-coated pits are involved. In addition, we consider lipid rafts as a
separate uptake process.
Specific proteins, including receptors, are removed from early endosomes and
recycled to their original plasma membrane domains; some proceed to a different
domain of the plasma membrane, thereby mediating a process called transcytosis;
and some progress to lysosomes, where they are degraded, while both the receptor
and the ligand end up being degraded in lysosomes, resulting in receptor down-
regulation. In other cases, both are transferred to a different plasma membrane
domain, and the ligand is thereby released by exocytosis at a surface of the cell
different from that where it originated (transcytosis). In the case of transcytosis,
nanoparticles specifically fuse with the basolateral domain of the plasma mem-
brane. In our model, we consider transcytosis as one of the key processes.
A central question is whether exocytosis occurs for nanoparticles. This is a little
appreciated area, although it should be separated from endocytosis (see Alberts
et al. above). Experimentally, exocytosis is measured by repeated incubations and
wash (void of external nanoparticles) cycles at various time intervals after the initial
exposure (Panyam and Labhasetwar
2003
). There are several limitations of this
approach, particularly in capturing nanoparticle dynamics and quantifying endocy-
tosis and exocytosis rates simultaneously, in a steady-state fashion.
Likewise, the real magnitude and impact of spatiotemporal dynamics can be
understood only by carrying out mathematical modeling (Kholodenko et al.
2010
).
Our recently developed model allows the incorporation of exocytosis in a virtual
situation, providing more informative nanoparticle dynamics.
We describe the above events phenomenologically, without going into the deepest
details of reaction steps. For simplicity, only the minimal routes are considered in
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