SAU 9

Question 1

Beskriv kommunikerende, adhærerende, og okkluderende celle-kontakter

Answer 1

Okkluderende kontakter:
Tight junctions (zonula occludens)
Adhærerende (forankrende) kontakter:
Celle-celle: Adherens junctions (adhæsionsbælter, zonula adhaerens), Desmosomer (Macula adherens)
Celle-ECM: Hemidesmosomer, Fokale adhæsioner
Kommunikerende kontakter:
Gap junctions (nexus).
Transmembrane proteiner er en væsentlig komponent i alle cellekontakter. For adhærerende kontakter forankres det cytosolære domæne af det transmembrane protein til cytoskelettet (enten aktin eller intermediære filamenter) via linkerproteiner (plaque protein).
Tight junctions: Placeret lateralt, lige under den apikale overflade, som et bælte rundt i cellen. De transmembrane proteiner, der kontakter tilsvarende proteiner fra nabocellen betegnes claudiner og occludiner. Hindrer paracellulær transport.
Adherens junctions: Placeret lateralt, ofte tæt på tight junctions, som et bælte rundt i cellen, med kontakt til aktin cytoskelettet. Transmembrane cadheriner associerer til cadheriner på naboceller. Giver mekanisk stabilitet, og indgår i dannelse af invaginationer af epitheliale overflade.
Desmosomer: Typisk placeret lateralt, ’punktvist’ rundt i cellen, med kontakt til intermediære filamenter. Cadheriner (desmoglein og desmocollin) indgår som de transmembrane proteiner. Giver mekanisk styrke.
Gap junctions: Typisk placeret lateralt, ’punktvist’ rundt i cellen. Connexoner opbygget af connexiner indgår. Tillader passage af ioner og små molekyler mellem naboceller.

Question 2

Beskriv cellereceptorer (integriner) for adhæsive ECM glycoproteiner

Answer 2

Den extracellulære matrix (ECM) indeholder forskellige multiadhæsive glykoproteiner, heriblandt fibronectin og laminin. Disse proteiners egenskaber omfatter evnen til at sammenbinde transmembrane receptorer (integriner) fra celler med protein (typisk kollagen) i ECM. Fibronectin er generelt udbredt i bindevæv, mens laminin findes i basallamina.

Integriner er transmembrane proteiner involveret i cellers kontakt til ECM, og indgår bl.a. i hemidesmosomer og fokale adhæsioner. Hemidesmosomer giver forankring af epithelceller til basallamina, mens fokale adhæsioner typisk er involveret til cellers adhæsion i bindevæv, inkl. i forbindelse med cellulær migration. I begge tilfælde forankres cytoskelettet (intermediære filamenter i hemidesmosomer eller aktin i fokale adhæsioner) via linkerproteiner til den cytosolære del af integriner, som extracellulært er forankret til kollagenfibre via multiadhæsivt glykoprotein (laminin i hemidesmosomer eller fibronectin i fokale adhæsioner).

Question 3

Redegør for cellekontakters betydning for opretholdelse af epithelers integritet

Answer 3

Overfladeepitheler danner generelt en beskyttende, og barrrieredannende ’membran’ på legemets ydre og indre overflader. Hovedfunktionen af forskellige typer overfladeepithel kan dog variere, hvilket bl.a. afspejler sig i de forskellige typer udformning epitheler kan have – eksempelvis enlaget vs flerlaget. Et enlaget epithel kan f.eks. mediere transport, mens et flerlaget epithel typisk danner en beskyttende barriere. For at et epithel skal kunne opretholde sin integritet og bevare sine egenskaber skal det danne relevante celle-celle og celle-ECM kontakter

Question 4

Beskriv adhæsive glycoproteiner i ECM

Answer 4

Question 5

Describe shortly how cells are able to interact with the collagen in the extracellular matrix

Answer 5

Cells are able to interact with the collagen in the extracellular matrix
thanks to a family of transmembrane receptor proteins called integrins. The extracellular domain of an integrin binds to components of the matrix, while its intracellular domain interacts with the cell cytoskeleton.

Question 6

Describe how integrins interact directly with collagen fibers in the extracellular matrix

Answer 6

Integrins do not, however, interact directly with collagen fibers in the
extracellular matrix. Instead, another extracellular matrix protein,
fibronectin, provides a linkage: part of the fibronectin molecule binds to collagen, while another part forms an attachment site for integrins. When the extracellular domain of the integrin binds to fibronectin, the intracellular domain binds (through a set of adaptor molecules) to an actin filament inside the cell (Figure 20–14). For many cells, it is the formation and breakage of these attachments on either end of an integrin molecule that allows the cell to crawl through a tissue, grabbing hold of the matrix at its front end and releasing its grip at the rear.

Question 7

Describe how integrin can be activated from the cytosolic side

Answer 7

an intracellular signaling molecule can activate the integrin from the cytosolic side, causing it to reach out and grab hold of an extracellular structure. Similarly, binding to an external structure can switch on a variety of intracellular signaling pathways by activating protein kinases that associate with the intracellular end of the integrin. In this way, a cell’s external attachments can help regulate its behavior—and even its survival.

Question 8

Show how Fibronectin and transmembrane integrin proteins help attach a cell to the extracellular matrix

Answer 8

Question 9

How many integrins do humans make?

Answer 9

Humans make at least 24 kinds of integrins, each of which recognizes distinct extracellular molecules and has distinct functions, depending on the cell type in which it resides.

Question 10

Describe the function of integrins on white blood cells

Answer 10

For example, the integrins on white blood cells (leukocytes) help the cells crawl out of blood vessels at sites of infection so as to deal with marauding microbes. People who lack this type of integrin develop a disease called leucocyte adhesion deficiency and suffer from repeated bacterial infections. A different form of integrin is
found on blood platelets, and individuals who lack this integrin bleed excessively because their platelets cannot bind to the necessary bloodclotting protein in the extracellular matrix.

Question 11

Show how An integrin protein switches
to an active conformation when it binds
to molecules on either side of the plasma
membrane.

Answer 11

Question 12

How are chains og GAGs linked to a core protein?

Answer 12

Chains of GAGs are usually covalently linked to a core protein to form
proteoglycans, which are extremely diverse in size, shape, and chemistry.

Typically, many GAG chains are attached to a single core protein
that may, in turn, be linked to another GAG, creating a macromolecule
that resembles a bottlebrush.

Question 13

Show how Proteoglycans and GAGs can form large aggregates.

Answer 13

Question 14

Describe the proportion of GAGs in dense compact tissues and jellylike substances.

Answer 14

In dense, compact connective tissues such as tendon and bone, the
proportion of GAGs is small, and the matrix consists almost entirely of collagen (or, in the case of bone, of collagen plus calcium phosphate crystals).

The jellylike substance in the interior of the eye consists almost entirely of one particular type of GAG, plus water, with only a small amount of collagen. In general, GAGs are strongly hydrophilic
and tend to adopt highly extended conformations, which occupy a
huge volume relative to their mass. Thus GAGs act as effective “space fillers” in the extracellular matrix of connective tissues.

Question 15

Show how Glycosaminoglycans (GAGs)
are built from repeating disaccharide
units.

Answer 15

Question 16

Describe how GAGs from hydrophilic gels

Answer 16

Even at very low concentrations, GAGs form hydrophilic gels: their multiple negative charges attract a cloud of cations, such as Na+, that are osmotically active, causing large amounts of water to be sucked into the matrix. This gives rise to a swelling pressure, which is balanced by tension in the collagen fibers interwoven with the GAGs. When the matrix is rich in collagen and large quantities of GAGs are trapped in the mesh, both the swelling pressure and the counterbalancing tension are enormous. Such a matrix is tough, resilient, and resistant to compression. The cartilage matrix that lines the knee joint, for example, has this character: it can support pressures of hundreds of kilograms per square centimeter.

Question 17

Show how A sheet of epithelial
cells has an apical and a basal
surface.

Answer 17

Question 18

Describe The basal lamina

Answer 18

The basal lamina consists of a thin, tough sheet of extracellular matrix, composed mainly of a specialized type of collagen (type IV collagen) and a protein called laminin. Laminin provides adhesive sites for integrin molecules in the basal plasma membranes of epithelial cells, and it thus serves a linking role like that of fibronectin in other connective tissues.

Question 19

Describe the apical and basal faces of an epithelium

Answer 19

The apical and basal faces of an epithelium are different: each contains a different set of molecules that reflect the polarized organization of the individual epithelial cells. This polarity is crucial for epithelial function. Consider, for example, the simple columnar epithelium that lines the small intestine. It mainly consists of two intermingled cell types: absorptive cells, which take up nutrients, and goblet cells which secrete the mucus that protects and lubricates the gut lining. Both cell types are polarized. The absorptive cells import food molecules from the gut lumen through their apical surface and export these molecules from their basal surface into the underlying tissues. To do this, absorptive cells require different sets of membrane transport proteins in their apical and basal plasma membranes. The goblet cells also have to be polarized, but in a different way: they have to synthesize mucus and then discharge it from their apical end only; their Golgi apparatus, secretory vesicles, and cytoskeleton are all polarized so as to bring this about. For both types of epithelial cells, polarity depends on the junctions that the cells form with one another and with the basal lamina. These cell junctions in turn control the arrangement of an elaborate system of membrane-associated intracellular proteins that create the polarized organization of the cytoplasm.

Question 20

How is the barrier function of epithelial sheets made possible?

Answer 20

The barrier function of epithelial sheets is made possible by tight junctions. These junctions seal neighboring cells together so that water-soluble molecules cannot easily leak between them.

Question 21

Show how Tight junctions allow epithelial cell sheets to serve as barriers to solute diffusion.

Answer 21

Question 22

Describe what happens without tight junctions and how tight junctions maintain the polarity of epithelial cells

Answer 22

Without tight junctions to prevent leakage, the pumping
activities of absorptive cells such as those in the gut would be futile,
and the composition of the extracellular fluid would become the same on both sides of the epithelium.

Tight junctions also play a key part in maintaining the polarity of the
individual epithelial cells in two ways. First, the tight junctions around the apical region of each cell prevent diffusion of proteins in the plasma membrane and so keep the contents of apical domain of the plasma membrane separate—and different—from the basolateral domain. Second, in many epithelia, the tight junctions are sites
of assembly for the complexes of intracellular proteins that govern the apico-basal polarity of the cell interior.

Question 23

What does all types of junctions provide?

Answer 23

All types of junctions provide mechanical strength to the epithelium by the same strategy: the proteins that form the junctions span the plasma membrane and are linked inside the cell to cytoskeletal filaments. In this way, the cytoskeletal filaments are tied into a network that extends from cell to cell across the whole expanse of the epithelial sheet.

Question 24

Describe how adherens junctions and desmosomes are built

Answer 24

Adherens junctions and desmosomes are both built around transmembrane proteins that belong to the cadherin family: a cadherin molecule in the plasma membrane of one cell binds directly to an identical cadherin molecule in the plasma membrane of its neighbor. Such interaction of like-with-like is called homophilic binding. In the case of cadherins, binding also requires that Ca2+ be present in the extracellular medium.

Question 25

Show how Cadherin proteins mediate mechanical attachment of one cell to another.

Answer 25

Question 26

Describe the importance of epithelial movement

Answer 26

Epithelial movements are crucial during embryonic development, when they create structures such as the neural tube, which gives rise to the brain and spinal cord, and the lens vesicle, which develops into the lens of the eye.

Question 27

Show how Adherens junctions form adhesion belts around epithelial cells in the small intestine.

Answer 27

Question 28

Show how Epithelial sheets can bend to form an epithelial tube or vesicle.

Answer 28

Question 29

Describe blister and hemidesmosomes

Answer 29

Blisters are a painful reminder that it is not enough for epidermal cells
to be firmly attached to one another: they must also be anchored to the underlying connective tissue. As we noted earlier, the anchorage is mediated by integrins in the cells’ basal plasma membranes. The extracellular domains of these integrins bind to laminin in the basal lamina; inside the cell, the integrin tails are bound via linker proteins to keratin filaments, creating a structure that looks superficially like half a desmosome. These attachments of epithelial cells to the basal lamina beneath them are therefore called hemidesmosomes.

Question 30

Show how desmosomes link the keratin intermediate filaments of one epithelial cell to those of another

Answer 30

Question 31

Show how hemidesmosomes anchor the keratin filaments in an epithelial cell to the basal lamina.

Answer 31

Question 32

Describe how extracellular signals can regulate the permeability of gap junctions

Answer 32

The channels allow inorganic ions and small, water-soluble molecules (up to a molecular mass of about 1000 daltons) to move directly from the cytosol of one cell to the cytosol of the other. This flow creates an electrical and a metabolic coupling between the cells.

Gap junctions between cardiac muscle cells, for example, provide the electrical coupling that allows electrical waves of excitation to spread synchronously through the heart, triggering the coordinated contraction of the cells that produces each heart beat.

Gap junctions in many tissues can be opened or closed in response to extracellular or intracellular signals. The neurotransmitter dopamine, for example, reduces gap-junction communication between certain neurons in the mammalian retina when secreted in response to an increase in light intensity. This reduction in gap-junction permeability alters the pattern of electrical signaling and helps the retina switch from using rod photoreceptors, which are good detectors of low light levels, to cone photoreceptors, which detect color and fine detail in bright light.

Question 33

Show how gap junctions provide neighboring cells with a direct channel of intercytosolic communication.

Answer 33