Selectively (semi) permeable barrier for materials moving into or out of cell

Cells are organized into three main regions

Phospholipid bilayer

Hydrophilic heads / Hydrophobic tails ---> amphipathic

What’s permeable?: small, polar, uncharged (CO2, …) hydrophobic (O2, hydrocarbons)

impermeable: large (sugars, proteins); all ions

Cholesterol- stabilizes structure.Increases permeability to water soluble molecules.Makes up 5-33% of animal cell membranes.

Cell-Cell Recognition

Cell Membranes (cont.)• Differences in membranes from different cell types? % proteins,

types and # of each protein• Ex. Myelin, which insulates nerve fibers, contains only 18% protein

and 76% lipid. • Mitochondrial inner membrane contain 76% protein and only 24%

lipid.• Plasma membranes of human red blood cells and mouse liver

contain nearly equal amounts of proteins (44, 49% respectively) and lipids (43, 52% respectively)

Cellular Membrane Protein Functions

Membrane Junctions:

•Tight junctions

•Leakproof sheets

•Adjacent membranes fuse together.

• Desmosomes (anchoring junctions)

•Prevent cells from being pulled apart (ex: skin cells)

• Gap junctions (connexons- water filled protein channels)

•Allow for communication/movement of molecules.

Plasma Membrane Specializations: microvilli, cilia

Cytoplasm

Material outside the nucleus and inside the plasma membrane

Cytosol

Fluid that suspends other elements

Organelles:

Ribosomes

Made of protein and RNA; Sites of protein synthesis; Found at two locations -free in the cytoplasm, attached to rough endoplasmic reticulum

Endoplasmic reticulum (ER)

Rough Endoplasmic Reticulum - Studded with ribosomes; Site where building materials of cellular membrane are formed

Smooth Endoplasmic Reticulum - Functions in cholesterol synthesis and breakdown, fat metabolism, and detoxification of drugs

Golgi apparatus - Modifies and packages proteins; Produces different types of packages: secretory vesicles, cell membrane components, lysosomes

Endomembrane system

Tight JunctionsEpithelia are sheets of cells that provide the interface between masses of cells and a cavity or space (a lumen). * The portion of the cell exposed to the lumen is called its apical surface. * The rest of the cell (i.e., its sides and base) make up the basolateral surface.

Tight junctions seal adjacent epithelial cells in a narrow band just beneath their apical surface. Tight junctions perform two vital functions: * They prevent the passage of molecules and ions through the space between cells. So materials must actually enter the cells (by diffusion or active transport) in order to pass through the tissue. This pathway provides control over what substances are allowed through. * They block the movement of integral membrane proteins (red and green ovals) between the apical and basolateral surfaces of the cell. Thus the special functions of each surface, for example receptor-mediated endocytosis at the apical surface and exocytosis at the basolateral surface can be preserved.

The Epithelia of the Human Lung: an exampleA report by Vermeer, et al., in the 20 March 2003 issue of Nature provides a striking example of the role of tight junctions.The epithelial cells of the human lung express a growth stimulant, called heregulin, on their apical surface and its receptors on the basolateral surface. (These receptors also respond to epidermal growth factor (EGF), and mutant versions have been implicated in cancer. As long as the sheet of cells is intact, there is no stimulation of its receptors by heregulin thanks to the seal provided by tight junctions. However, if the sheet of cells becomes broken, heregulin can reach its receptors. The result is an autocrine stimulation of mitosis leading to healing of the wound.

Several disorders of the lung * the chronic bronchitis of cigarette smokers * asthma * cystic fibrosisincrease the permeability of the airway epithelium. The resulting opportunity for autocrine stimulation may account for the proliferation (piling up) of the epithelial cells characteristic of these disorders.

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/J/Junctions.html

Adherens JunctionsAdherens junctions provide strong mechanical attachments between adjacent cells. * They hold cardiac muscle cells tightly together as the heart expands and contracts. * They hold epithelial cells together. * They seem to be responsible for contact inhibition. * Some adherens junctions are present in narrow bands connecting adjacent cells. * Others are present in discrete patches holding the cells together.

Adherens junctions are built from: * cadherins — transmembrane proteins (shown in red) whose extracellular segments bind to each other and whose intracellular segments bind to catenins (yellow). Catenins are connected to actin filaments

Inherited mutations in a gene encoding a cadherin can cause stomach cancer. Mutations in a gene (APC), whose protein normally interacts with catenins, are a common cause of colon cancer. Loss of functioning adherens junctions may also lead to tumor metastasis.

Gap JunctionsGap junctions are intercellular channels some 1.5–2 nm in diameter. These permit the free passage between the cells of ions and small molecules (up to a molecular weight of about 1000 daltons). They are cylinders constructed from 6 copies of transmembrane proteins called connexins. Because ions can flow through them, gap junctions permit changes in membrane potential to pass from cell to cell.Examples: * The action potential in heart (cardiac) muscle flows from cell to cell through the heart providing the rhythmic contraction of the heartbeat. * At some synapses in the brain, gap junctions permit the arrival of an action potential at the synaptic terminals to be transmitted across to the postsynaptic cell without the delay needed for release of a neurotransmitter. * As the time of birth approaches, gap junctions between the smooth muscle cells of the uterus enable coordinated, powerful contractions to begin.

Several inherited disorders of humans such as certain congenital heart defects and certain cases of congenital deafness have been found to be caused by mutant genes encoding connexins.

DesmosomesDesmosomes are localized patches that hold two cells tightly together. They are common in epithelia (e.g., the skin). Desmosomes are attached to intermediate filaments of keratin in the cytoplasm.

Pemphigus is an autoimmune disease in which the patient has developed antibodies against proteins (cadherins) in desmosomes. The loosening of the adhesion between adjacent epithelial cells causes blistering. Carcinomas are cancers of epithelia. However, the cells of carcinomas no longer have desmosomes. This may account for their ability to metastasize.

Lysosomes - Contain enzymes that digest nonusable materials within the cell

Peroxisomes - Membranous sacs of oxidase enzymes; Detoxify harmful substances;

break down free radicals (highly reactive chemicals); breaks down fats (ALD)

Mitochondria - Carry out reactions where oxygen is used to break down food; Provides

ATP for cellular energy

Inclusions

stored nutrients, pigments, secretory products, etc. specific to each cell type

Cytoskeleton - Network of protein structures that extend throughout the cytoplasm;

Provides the cell with an internal framework:

Microfilaments - movement w/in cell

Intermediate filaments - cell scaffolding

Microtubules - cell spindle, cilia, distribute organelles

Cell Diversity***structure and function

Cell Diversity (cont).

Membrane Transport – movement of substance into and out of the cell

1. by DISSOLVING in a membrane  2. by membranes ENGULFING particles  3. by CARRIER PROTEINS 4. by CHANNEL PROTEINS via diffusion

Passive transport

No energy is required; substance moves down concentration gradient

Active transport

The cell must provide metabolic energy (ATP), protein carrier/pump used; substance

moves against its concentration gradient

Solution – homogeneous mixture of two or more components

Solvent – dissolving medium

Solutes – components in smaller quantities within a solution

Intracellular fluid – nucleoplasm and cytosol

Interstitial (intercellular) fluid – fluid on the exterior of the cell

Passive Transport:

Diffusion

Solutes are lipid-soluble materials or small enough to pass through membrane pores

Types of diffusion

Osmosis – simple diffusion of water

Highly polar water moves through protein channels - aquaporins

Facilitated diffusion

Substances require a protein channel for passive transport because of size, charge or lipid insoluble

Solutions surrounding cells:

isotonic (.9% saline)

hypertonic ---> crenation

hypotonic ----> lysis

Filtration

Water and solutes are forced through a membrane by fluid, or hydrostatic pressure

A pressure gradient must exist

Solute-containing fluid is pushed from a high pressure area to a lower pressure area

Receptor-mediated endocytosis

phagocytosis

EndocytosisExocytosis

Active TransportTransport substances that are unable to pass by diffusion: they may be too large; they may not be able to dissolve in the fat core of the membrane; they may have to move against a concentration gradient

*Solute pumping:

Amino acids, some sugars and ions are transported by solute pumps

ATP or energy stored in previously established solute gradient energizes protein carriers, which causes them to change their shape

Co-transport (Na-K pump, Na-glucose pump). - uses energy directly from ATP or from energy stored in gradient formed previously. Symport, anti-port

Bulk transport -

Exocytosis

Endocytosis (phagocytosis, pinocytosis, Receptor-mediated endocytosis)

Problems with channels or pumps

Ex. Ca channels and heart disease: http://www.cell.com/content/article/fulltext?uid=PIIS0092867404008426

Sodium channels and cystic fibrosis

ORAL REHYDRATION THERAPY (http://rehydrate.org/index.html)

Viruses, bacteria and parasites --> diarrhea in 16 million US children under 5/year. 3 million people (1.9 million children under 5) worldwide die/year; 600 in US and hospitalizes 360,000; ORT still under utilized! sodium-glucose cotransport system: The sodium-glucose cotransport system establishes a sodium ion gradient based on the hydrolysis of ATP. The transport protein binds both glucose and Na+; glucose moves up its concentration gradient using the energy from sodium moving down its gradien and changing the shape of the transport protein.Also: sodium-amino acid pumps http://www.pbs.org/wgbh/rxforsurvival/series/video/index.html

Endocytosis

Exocytosis

http://www.time.com/time/magazine/article/0,9171,1543876-1,00.html

Selectivity is a central property of the channel. Water molecules worm their way through the narrow channel by orienting themselves in the local electrical field formed by the atoms of the channel wall. Protons (or rather oxonium ions, H3O+) are stopped on the way and rejected because of their positive charges.

 Cholesterol bound to Low density lipoproteins (LDL) is taken up by cells so that cholesterol can be used in construction of membranes, etc.  In this case the receptor is recycled and the ligand (LDL-cholesterol) is metabolized so the free cholesterol can be released and used by the cell. There are two genetic mutations that cause either no uptake of LDL receptors or uptake and accumulation of cholesterol in late endosomes.

HOW DOES NEXIUM WORK??The proton pump being referred to here is a H+/K+ ATPase found on the apical membrane of gastric gland epithelia (specifically, the parietal cells). This ATPase pumps H+ out of the cell in exchange for bringing in a K+ from the gland lumen.

Nexium is administered as an inactive prodrug in a pH resistant form, allowing it to pass through the stomach to the small intestine, where it is absorbed into the blood stream. From there, this lipophilic molecule will easily cross cellular membranes. In gastric parietal cells, due to their slightly lower pH (a byproduct of acid production?), Nexium becomes activated.

Activated Nexium (esomeprazole) will irreversibly inhibit the proton pump by covalently binding to it (via disulfide linkages). That protein will be inactive until it is naturally degraded by the cell ( these proteins have a half life of a couple of days).

Cancer and Cells

CANCER: mulistage, multifactor process

Cancers vary in their site of origin and cell types & in their survival rates

3 main categories: 1. carcinoma (90% of cancers) from epithelial cells 2. sarcomas from connective tissues

and muscle cells 3. lymphomas and leukemias from blood and lymphatic tissue *within these categories, cancers are named from the cell type involved

Causes: 1. lifestyle - smoking, diet

2. radiation - X-rays, UV rays, radon?

3. chemicals - pollutants, workplace

4. Virus 5. Inherited 6. Spontaneous

Incidence? (http://apps.nccd.cdc.gov/uscs/)

Effects: 1. proto-oncogene -----> oncogene 3. DNA repair gene mutated

2. tumor suppressor gene -----> inactivated 4. wrong # chromosomes or genes

Cancer cells have certain properties that distinguish them from normal cells:1. * Altered Growth Factor Requirements of Cancer Cells * Malfunction of Cellular Regulatory Systems * Defective Differentiation 2. * Loss of Density-Dependent Inhibition of Cell Proliferation* Altered Associations with Neighboring Cells and the Extracellular Matrix * Loss of Anchorage Dependence * Loss of Contact Inhibition of Movement3. * Decreased Programmed Cell Death - Apoptosis4. * Increased Angiogenesis5. * Increased Production of Proteases-->can dissolve cellular material -->metastasis

What do cancer cells look like??trait benign tumor vs. malignant (metastasis) nuclear size small large, irregular shape, prominent nucleoliN/C ratio low high(nucleus/cytoplasmic volume)Nuclear shape regular irregularMitotic index low high(relative # dividing cells)Tissue organization normal disorganizedDifferentiation well differentiated poorly differentiated (anaplastic)Tumor boundary encapsulated poorly defined

Tumor Grading: Grade1(resemble normal tissue in structure and organization, w/modest abnormalities) --> 4 (rapidly dividing, poorly differentiated)

Anaplastic - highest grade, in which cells so poorly differentiated and abnormal in appearance that no longer resemble cell of origin

Tumor Staging: determines how far cancer has progressed. “TMN” system - Tumor size? Are lymph Nodes +? Extent of spreading to other organs-Metastasis?

Treatments:

1. surgery 2. chemotherapy(stops cell division) 3. Radiation 4. other?? ex. anti-angiogenesis drugs

Prevention? Anti-oxidants? Lifestyle?

US Mortality, 2004

Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.

• 1. Heart Diseases 652,486 27.2• • 2. Cancer 553,888 23.1

• 3. Cerebrovascular diseases 150,074 6.3• • 4. Chronic lower respiratory diseases 121,987 5.1• • 5. Accidents (Unintentional injuries) 112,012 4.7• • 6. Diabetes mellitus 73,138 3.1• • 7. Alzheimer disease 65,965 2.8• • 8. Influenza & pneumonia 59,664 2.5• 9. Nephritis 42,480 1.8

• 10. Septicemia 33,373 1.4

Rank Cause of DeathNo. of deaths

% of all deaths

2007 Estimated US Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2007.

Men289,550

Women270,100

•26% Lung & bronchus

•15% Breast

•10% Colon & rectum

• 6% Pancreas

• 6% Ovary

• 4% Leukemia

• 3% Non-Hodgkin lymphoma

• 3% Uterine corpus

• 2% Brain/ONS

• 2% Liver & intrahepaticbile duct

•23% All other sites

Lung & bronchus 31%

Prostate 9%

Colon & rectum 9%

Pancreas 6%

Leukemia 4%

Liver & intrahepatic 4%bile duct

Esophagus 4%

Urinary bladder 3%

Non-Hodgkin 3% lymphoma

Kidney 3%

All other sites 24%

Trends in the Number of Cancer Deaths Among Men and Women, US, 1930-2004

0

50,000

100,000

150,000

200,000

250,000

300,000

1930 1940 1950 1960 1970 1980 1990 2000

Women

Men

Nu

mb

er o

f C

ance

r D

eath

s

265,000

270,000

275,000

280,000

285,000

290,000

2000 2001 2002 2003 2004

Men

Women

Source: US Mortality Public Use Data Tape, 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.

Ch. 3: Cells and Tissues• Download CellPhysio ppt from the Cell

Physiology and Histology Tab on Haiku. All cells share general structures but have

different shapes & structures due to different functions

HW: Read/Review! p. 61-75, answer questions: #1-16 in the reading.

Thu. 10.6.11

• Download Cell Structure Lab (Cell Physio Tab on Haiku)

• Physio Current Events (choose article)

• Finish workbook p. 34-37 ex 2-7.

• HW: Read p. 75-81, #17-22 (dropbox)

• Dropbox Diet Dilemma by Friday!

Tuesday 10/16/12• Open Osmosis and Transport document

• Open Great Rehydration Race

• Download Biology Lab Report Form from the first page on Haiku

• Take the practice quiz on Haiku (look on the calendar for today!)

• HW: Bring in a liquid(s) for the rehydration lab. Work on transport document and rehydration pre lab.

• Rehydration lab + Transport work due next Thu 10/25/12

Wed. 10.10.12• Open Cell Structure Lab.

• Open Physio Current Events (It’s at the bottom of the first Haiku Page if you don’t already have it saved).

• Download Osmosis and Transport document (cell physio tab).

• Cell Structure Lab, Diet Dilemma Letter.

• HW: p.75-81 #17-22

Tuesday 10.11.11• Download Does Form Matter Article and

Questions and “A Visual Guide to Pronation” from “Cell Physio Tab”

• Dates To Remember:– Thu 10.13.11: Bryn Mawr Running Co. Speaker: 10:45

a.m. Room 124 (Ms. Keiser’s Room)– Fri. 10.14.11: Current Events Article write up due in

dropbox– Thu 10.27.11: Mutter Museum Trip (8:30a.m.-2:30p.m.)

• HW/Missing Work (Dropbox/email ASAP):– Due last Friday: Diet Dilemma Letter, Cell Structure Lab

• Buy a Pink Bracelet! $3, dress down day: Thursday!

Your Task (Groups of 4)• Create a visual guide to pronation including:

– Image of Underpronation, Overpronation and normal pronation.

– Image of wear pattern (on bottom of shoes) for each type of pronation.

– Include a written description of each type of pronation (what happens anatomically with the muscles/bones/arches)

– What type of shoe is best for each type of pronation? Include a specific example shoe.

– Injuries associated with under/overpronation.

Wrap It Up!

• Remember to come to Rm 124 at 10:45-10:50 a.m. on Thu!

• HW: finish the Does Form Matter article and questions.

• Bring in an old pair of running shoes to determine whether your type of pronation.