Chapter 5Chapter 5

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Dee Unglaub Silverthorn, Ph.D.

H ^UMAN P ^HYSIOLOGY H ^UMAN P ^HYSIOLOGY

PowerPoint^® Lecture Slide Presentation by

Dr. Howard D. Booth, Professor of Biology, Eastern Michigan University

AN INTEGRATED APPROACH

T H I R D E D I T I O N

Chapter 5 Chapter 5

Membrane Dynamics

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About this Chapter About this Chapter

• Cell membrane structures and functions

• Membranes form fluid body compartments

• Membranes as barriers and gatekeepers

• How products move across membranes

• Distribution of water and solutes in cells &

the body

• Chemical and electrical imbalances

• Membrane permeability and changes

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• Membranous tissues:

• Example: pericardial membrane

• Epithelial tissues: one to many cells thick

• Cell Membranes (plasmalemma) enclose cells

Membranes: two meanings Membranes: two meanings

Figure 5-1: Membranes in the body

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• Cell structure & support

• Barrier isolates cell (impermeable)

• Chemically

• Physically

• Regulates exchange (semipermeable)

• Cell communication

Cell Membranes: Overview

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Cell Membranes: Overview Cell Membranes: Overview

Figure 5-2: The fluid mosaic model of the membrane

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• Phospholipid bilayer and cholesterol

• Membrane proteins

• Peripheral (associated)

• Integral

Membrane Structure

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• Structure

• Cell polarity

• Phosphorylation

• Extracellular matrix

Structural Membrane Proteins:

Membrane-Spanning

Structural Membrane Proteins:

Membrane-Spanning

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Structural Membrane Proteins:

Membrane-Spanning

Structural Membrane Proteins:

Membrane-Spanning

Figure 5-4: The cytoskeleton is anchored to the cell membrane

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Structural Membrane Proteins:

Membrane-Spanning

Structural Membrane Proteins:

Membrane-Spanning

Figure 5-5: Membrane-spanning proteins

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• Membrane associated enzymes

• External reactions

• Internal reactions

• Receptors bind specific ligand

• Example:

Hormones

• Cell recognition molecules

Membrane Proteins that Bind Molecules Membrane Proteins that Bind Molecules

Figure 5-6: Cell membrane receptor

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• Channel proteins

• Open

• Gated

• Carrier proteins

• Bind to substrate

• Slower transport Transporter Proteins:

Move Products Through Membrane Transporter Proteins:

Move Products Through Membrane

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Transporter Proteins:

Move Products Through Membrane Transporter Proteins:

Move Products Through Membrane

Figure 5-7: Transport proteins of the cell membrane

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Transporter Proteins:

Move Products Through Membrane Transporter Proteins:

Move Products Through Membrane

Figure 5-9: Gating of channel proteins

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• The term was initially applied to the polysaccharide matrix excreted by epithelial cells forming a

coating on the surface of epithelial tissue

• Includes Glycoproteins and Glycolipids

Membrane Carbohydrates:

Form External Glycocalyx Membrane Carbohydrates:

Form External Glycocalyx

Figure 5-11: Map of cell membrane structure

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The Glycocalyx The Glycocalyx

• glycocalyx — carbohydrate-rich peripheral zone of the external surface coating of the membrane in most eukaryotic cells.

• Description

• The outer surface of cells is covered with lipopolysaccharide "hairs"

consisting of proteoglycans, glycoproteins and glycolipids, which are called “glycocalyx” Carbohydrate components of the glycocalyx

include both compounds covalently bound to proteins or, to a lesser extent, to lipids on the cell surface, and additional glycoproteins and polysaccharides which are non-covalently attached to them. Some of the adsorbed macromolecules are components of the

extracellular matrix, which makes it difficult to distinguish between such matrices and the glycocalyx with the cell membrane. Glycocalyx is considered as a protective layer on the vessel wall against

pathogenic effects, a network barrier to the movement of molecules.

It is assumed that the endothelial glycocalyx has a definite

ultrastructure and may be connected with the cytoskeleton to serve as a mechanochemical transducer of blood flow effects (shear stress) into other processes of cell signaling.

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Functions of the Glycocalyx Functions of the Glycocalyx

•Protection: Cushions the plasma membrane and protects it from chemical injury

•Immunity to infection: Enables the immune system to recognize and selectively attack foreign organisms

•Defense against cancer: Changes in the glycocalyx of cancerous cells enable the immune system to recognize and destroy them

•Transplant compatibility: Forms the basis for compatibility of blood transfusions, tissue grafts, and organ transplants

•Cell adhesion: Binds cells together so that tissues do not fall apart

•Inflammation regulation: Glycocalyx coating on endothelial walls in blood vessels prevents leukocytes from rolling/binding in healthy states

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•Fertilization: Enables sperm to recognize and bind to eggs

•Embryonic development: Guides embryonic cells to their destinations in the body

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Membrane Proteins and Functions Reviewed Membrane Proteins and Functions Reviewed

Figure 5-12: Map of membrane proteins

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• Intracellular (ICF)

• Extracellula r (ECF)

• Interstitial

• Plasma

Body Fluid Compartments Body Fluid Compartments

Figure 5-13: Body fluid compartments

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Why does water move through the cell membrane?

• Water can diffuse through the lipid bilayer even though it's polar because it's a very small molecule.

• Water can also pass through the cell membrane by osmosis, because of the high osmotic pressure difference between the inside and the outside the cell.

• That doesn't mean that it's an easy process, because the solubility of water in lipid is about 1 molecule of water per million molecules of lipid.

• But the outside concentration of water is very high (about 50 mol/L), and the surface area to volume ratio of the cell is very large, so this is an important cellular process.

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• Energy

requirements

• Physical

requirements

Overview of Movement Across Membranes Overview of Movement Across Membranes

Figure 5-14: Map of the ways molecules move across cell membranes

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• Stops at equilibrium

• Rate factors: membrane, temperature, distance, & size

Diffusion:

Passive & down a concentration gradient Diffusion:

Passive & down a concentration gradient

Figure 5-16: Fick’s law of diffusion

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• Uniport

• Cotransport

• Symport

• Antiport

Carrier Mediated Transport:

Can be Passive or Active

Carrier Mediated Transport:

Can be Passive or Active

Figure 5-17: Types of carrier-mediated transport

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• Uses transport proteins

• Passive Diffusion to Equilibrium Facilitated Diffusion

Facilitated Diffusion

Figure 5- 21: Diffusion stops at equilibrium (panoramic lower left 66%)

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Facilitated Diffusion Facilitated Diffusion

Figure 5-22: Diffusion of glucose into cells

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• Uses ATP to move

products

• Up a

concentratio n gradient

Primary Active Transport: Pumps Products Primary Active Transport: Pumps Products

Figure 5-23: The Na⁺ - K⁺ -ATPase

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Basal Metabolism Basal Metabolism

In their review, Rolfe and Brown (1997) concluded that

•∼10% of the oxygen consumed during BMR is consumed by nonmitochondrial processes,

•∼20% is consumed by mitochondria to counteract the mitochondrial proton leak, and

•the remaining 70% is consumed for mitochondrial ATP production.

At a whole-animal level, ATP production can be divided into

•20%–25% for Na+,K+-ATPase activity,

•20%–25% for protein synthesis, ∼

•5% for Ca2+-ATPase activity,

•∼7% for gluconeogenesis,

•∼2% for ureagenesis,

•∼11% for all other ATP-consuming processes.

These estimates are averages over the entire animal, and the relative contribution of the different processes varies between tissues. For example, it is estimated that although Na+,K+-ATPase activity constitutes only ∼10% of cellular energy

turnover in the liver, it is responsible for ∼60% in brain and kidney (Clausen et al.

1991). It can be seen from these estimates that membrane-associated activities constitute a significant portion of resting metabolic activity (and thus BMR) in higher animals.

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Primary Active Transport: Pumps Products Primary Active Transport: Pumps Products

Figure 5-24: Mechanism of the Na⁺ - K⁺ -ATPase (75%)

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• Cotransports

• [Ion ] restored

• using ATP

Secondary Active Transport:

Uses Kinetic Energy of [ion]

Secondary Active Transport:

Uses Kinetic Energy of [ion]

Figure 5-25: Sodium-glucose symporter

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• Cell

metabolis m (Chapter 4)

• Membrane transport (Chapter 5)

Energy Transfer: Review Energy Transfer: Review

Figure 5-26: Energy transfer in living cells

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Endocytosis Pathways Endocytosis Pathways

• Clathrin-mediated endocytosis is mediated by small (approx. 100 nm in diameter) vesicles that have a morphologically characteristic coat made up of a complex of proteins that are mainly associated with the cytosolic protein clathrin. Clathrin-coated vesicles (CCVs) are found in virtually all cells and form domains of the plasma membrane termed clathrin-coated pits. Coated pits can concentrate large extracellular molecules that have different receptors responsible for the receptor-mediated endocytosis of ligands, e.g.

low density lipoprotein, transferrin, growth factors, antibodies and many others.

• Caveolae are the most common reported non-clathrin-coated plasma membrane buds, which exist on the surface of many, but not all cell types. They consist of the cholesterol- binding protein caveolin (Vip21) with a bilayer enriched in cholesterol and glycolipids.

Caveolae are small (approx. 50 nm in diameter) flask-shape pits in the membrane that resemble the shape of a cave (hence the name caveolae). They can constitute up to a third of the plasma membrane area of the cells of some tissues, being especially

abundant in smooth muscle, type I pneumocytes, fibroblasts, adipocytes, and endothelial cells.Uptake of extracellular molecules is also believed to be specifically mediated via receptors in caveolae.

• Macropinocytosis, which usually occurs from highly ruffled regions of the plasma

membrane, is the invagination of the cell membrane to form a pocket, which then pinches off into the cell to form a vesicle (0.5–5 µm in diameter) filled with a large volume of

extracellular fluid and molecules within it (equivalent to ~100 CCVs). The filling of the pocket occurs in a non-specific manner. The vesicle then travels into the cytosol and fuses with other vesicles such as endosomes and lysosomes.

• Phagocytosis is the process by which cells bind and internalize particulate matter larger than around 0.75 µm in diameter, such as small-sized dust particles, cell debris, micro- organisms and even apoptotic cells, which only occurs in specialized cells. These

processes involve the uptake of larger membrane areas than clathrin-mediated endocytosis and caveolae pathway.

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• Transcytosis: Moves some molecules and large proteins and particles via endocytosis and exocytosis across cell membrane

• Phagosome: The vesicle formed via internalization, in phagocytic cells.

Binds and internalizes particles >

0.75 microns

• Phagocytes: An Actin-mediated process. Examples, immune cells

• Clatherin-Mediated Endocytosis

• Caveolae: Non-Clatherin coated but have caveolin

Vesicles in Membrane Transport

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• Pinocytosis: non-selective

• Receptor mediated: specific substrate

Endocytosis and Exocytosis: VacuoleTransport

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Caveolae and Clathrin-coated Pits Caveolae and Clathrin-coated Pits

• Caveolae and clathrin-coated vesicles are both specialized regions of the plasma

membrane, crucial to the endomembrane system within the cell. They are involved in the internalization of proteins and lipids, as well as other membrane trafficking

between cellular organelles.

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Caveolin Caveolin

• Caveolae are implicated in the sequestration of a variety

of lipid and protein molecules. It has been suggested that these important cellular organelles have a pivotal role in such diverse biochemical processes as lipid metabolism, growth regulation, signal transduction, and apoptosis. Caveolin interacts with and regulates heterotrimeric G-proteins.

• Currently, there are three members of the caveolin multigene family which are known to encode 21-24 kDa integral

membrane proteins that comprise the major structural component of the caveolar membrane in vivo. Caveolin-2 protein is abundantly expressed in fibroblasts and

differentiated adipocytes, smooth and skeletal muscle, and

endothelial cells. The expression of caveolin-1 is similar to that of caveolin-2 while caveolin-3 expression appears to be limited to muscle tissue types Membrane vesicle formation is a process required for the endocytosis and biosynthesis of various

secreted and membrane bound proteins.

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Clathrin Clathrin

• Clathrin is a protein which assembles into a

polyhedral network on the cell membrane as the

membrane invaginates. It forms a coated pit which is essential to endocytosis. Clathrin is composed of

three polypeptides, a 180 kDa heavy chain and two

32-38 kDa light chains, which combine to create a

distinct three-legged triskelion. It is this morphology

which allows clathrin to form its unique polyhedral

network.

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Endocytosis and Exocytosis: VacuoleTransport Endocytosis and Exocytosis: VacuoleTransport

Figure 5-28: Receptor-mediated endocytosis and exocytosis

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CAVEOLAE

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CAVEOLAE

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Transcytosis Transcytosis

Figure 5-31: Transcytosis across the capillary endothelium

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Transepithelial Transport Transepithelial Transport

Figure 5-30: Transepithelial transport of glucose

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• About 60% of body weight is water

• 67% water -intracellular

• 33% water -extracellular

• 8% plasma

• 25% interstitial

• % varies slightly with sex and age

Distribution of Water and Solutes in the Body Compartments

Figure 5-32: Distribution of volume in the body fluid compartments

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• The 60, 40, 20 rule is useful to know that 60% of the body weight is water, 40% is in the intracellular fluid, and 20% is in the

extracellular fluid. The extracellular

compartment contents the interstitial and

the plasma fluids.

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Molarity vs Molality Molarity vs Molality

• Molarity is defined as the number of moles of solute per liter of solution. This means that if you have a 1 M solution of some compound, evaporating one liter will cause one mole of the solute to precipitate.

• Molality is defined as the number of moles of solute per kilogram of solvent. To make a 1 m solution, you'd take one mole of a

substance and add it to 1 Kg of solvent. As a

result, the final volume of a 1 m solution will

be somewhat more than 1 L if the solvent is

Water.

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Molality Molality

• Molalities are more convenient than molarities in experiments that involve

significant temperature changes. Because the volume of a solution increases when its temperature increases, heating makes the solutions molarity go down- but the molality, which is based on masses rather than

volumes, remains unchanged

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Osmolarity vs Osmolality Osmolarity vs Osmolality

• Osmolarity is distinct from molarity because it measures moles of solute particles rather than

moles of solute. The distinction arises because some compounds can dissociate in solution, whereas

others cannot,

• Plasma osmolality is affected by changes in water content. In comparison, the plasma osmolarity is slightly less than osmolality, because the total

plasma weight (the divisor used for osmolality)

excludes the weight of any solutes, while the total plasma volume (used for osmolarity) includes solute content. Otherwise, one liter of plasma would be

equivalent to one kilogram of plasma, and plasma osmolarity and plasma osmolality would be equal.

However, at low concentrations, the weight of the

solute is negligible compared to the weight of the

solvent, and osmolarity and osmolality are very

similar.

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• Water freely

crosses membranes

• Osmotic pressure (mmHg)

• Osmolarity

• Osmolality

• Comparing two solutions

• Isosmotic

• Hyperosmotic

• Hyposmotic

Osmosis and Osmotic Equilibrium Osmosis and Osmotic Equilibrium

Figure 5-34: Osmosis and osmotic pressure

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• Penetrating solute

• Non-penetrating solute

• Isotonic

• Hypertonic

• Hypotonic

Tonicity: How a Cell Reacts in a Solution Tonicity: How a Cell Reacts in a Solution

Figure 5-35a, b: Tonicity depends on the relative concentrations of nonpenetrating solutes

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• Penetrating solute

• Non-penetrating solute

• Isotonic

• Hypertonic

• Hypotonic

Tonicity: How a Cell Reacts in a Solution Tonicity: How a Cell Reacts in a Solution

Figure 5-35a, b: Tonicity depends on the relative concentrations of nonpenetrating solutes

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Tonicity: How a Cell Reacts in a Solution Tonicity: How a Cell Reacts in a Solution

Figure 5-35c, d: Tonicity depends on the relative concentrations of nonpenetrating solutes

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• Separation of charged ions

• Membrane insulates

• Potential

• Conduction of signal

• Electrochemical gradient Electrical Disequilibrium

Electrical Disequilibrium

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Electrical Disequilibrium Electrical Disequilibrium

Figure 5-36a, b: Separation of electrical charge

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Understanding the paradox of electroneutrality on either side of the membrane and having a Resting Membrane Potential of -70 Understanding the paradox of electroneutrality on either side of the membrane and having a Resting Membrane Potential of -70

• Neurons have an overall negative charge on the inside, with DNA (proteins and more K+ than Na+) and there's an overall positive charge outside with more Na+ than K+. But the diagram suggests that both the intracellular fluid and the extracellular fluid is electrically neutral... I'm confused. Am I missing something?

• Overall, the inside is electrically neutral, but because the region just outside of the membrane is positive (because of K+ leak) it attracts the negative ions to the inner membrane surface. So overall, there is neutrality, but locally at the membrane there is not.

• The sum overall charge is neutral both inside and outside the cell. The resting membrane potential of -70 is just right beneath the membrane. As soon as you travel more inward in the cell it becomes more neutral overall. It’s crazy how much energy is devoted to the Na+/K+ pumps just to make that small area beneath the membrane temporarily negative.

• The charge is positive near the outside of the membrane and negative near the inside of the membrane.

It’s like magnets attracting one another through a sheet of paper.

• The Faraday constant (10e5 coulombs/mole) is a big number, the membrane capacitance (10e-6

coulombs/volt sq cm) is quite small. Furthermore any excess charge on either side of the membrane is localized to the immediate vicinity of the membrane by electrostatic attraction to its oppositely charged complement across the membrane. Collectively this means that a very, very small ionic concentration difference across the membrane can result in a significant transmembrane voltage. Another way of

conceptualizing this is that a ratio of 1,000,001 negative charges to 999,999 positive charges on the inside and the inverse ratio on the outside both equal 1.00000 (electroneutrality), while those 4 extra negative charges inside relative to outside would simultaneously produce a quite measurable transmembrane voltage across the small membrane capacitance. So both electroneutrality on each side of the membrane and a resting voltage gradient across the membrane are simultaneously valid and highly accurate

approximations. The same attention to relative scale is why all the way through an action potential you can regard internal and external ionic concentrations and the resultant ionic equilibrium potentials to be

constant, for all but the smallest internal or external compartment volumes

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• Resting

• Equilibrium

• Channel opening

• Voltage gated

• ATP gated (leak)

Membrane Potentials: Change with Permeability

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Membrane Potentials: Change with Permeability Membrane Potentials: Change with Permeability

Figure 5-38a, b: Potassium equilibrium potential

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Membrane Potentials: Change with Permeability Membrane Potentials: Change with Permeability

Figure 5-38c: Potassium equilibrium potential

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Membrane Potentials: Change with Permeability Membrane Potentials: Change with Permeability

Figure 5-39: Sodium equilibrium potential

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Figure 5-42a: Insulin secretion and membrane transport processes

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Figure 5-42b: Insulin secretion and membrane transport processes

Chapter 5Chapter 5

H UMAN P HYSIOLOGY H UMAN P HYSIOLOGY

Chapter 5 Chapter 5

Membrane Dynamics

About this Chapter About this Chapter

• Cell membrane structures and functions

• Membranes form fluid body compartments

• Membranes as barriers and gatekeepers

• How products move across membranes

• Distribution of water and solutes in cells &

the body

• Chemical and electrical imbalances

• Membrane permeability and changes

• Membranous tissues:

• Example: pericardial membrane

• Epithelial tissues: one to many cells thick

• Cell Membranes (plasmalemma) enclose cells

Membranes: two meanings Membranes: two meanings

• Cell structure & support

• Barrier isolates cell (impermeable)

• Chemically

• Physically

• Regulates exchange (semipermeable)

• Cell communication

Cell Membranes: Overview

Cell Membranes: Overview

Cell Membranes: Overview Cell Membranes: Overview

• Phospholipid bilayer and cholesterol

• Membrane proteins

• Peripheral (associated)

• Integral

Membrane Structure

Membrane Structure

• Structure

• Cell polarity

• Phosphorylation

• Extracellular matrix

Structural Membrane Proteins:

Membrane-Spanning

Structural Membrane Proteins:

Membrane-Spanning

Structural Membrane Proteins:

Membrane-Spanning

Structural Membrane Proteins:

Membrane-Spanning

Structural Membrane Proteins:

Membrane-Spanning

Structural Membrane Proteins:

Membrane-Spanning

• Membrane associated enzymes

• External reactions

• Internal reactions

• Receptors bind specific ligand

• Example:

Hormones

• Cell recognition molecules

Membrane Proteins that Bind Molecules Membrane Proteins that Bind Molecules

• Channel proteins

• Open

• Gated

• Carrier proteins

• Bind to substrate

• Slower transport Transporter Proteins:

Move Products Through Membrane Transporter Proteins:

Move Products Through Membrane

Transporter Proteins:

Move Products Through Membrane Transporter Proteins:

Move Products Through Membrane

Transporter Proteins:

Move Products Through Membrane Transporter Proteins:

Move Products Through Membrane

• The term was initially applied to the polysaccharide matrix excreted by epithelial cells forming a

coating on the surface of epithelial tissue

• Includes Glycoproteins and Glycolipids

Membrane Carbohydrates:

Form External Glycocalyx Membrane Carbohydrates:

Form External Glycocalyx

The Glycocalyx The Glycocalyx

Functions of the Glycocalyx Functions of the Glycocalyx

Membrane Proteins and Functions Reviewed Membrane Proteins and Functions Reviewed

H ^UMAN P ^HYSIOLOGY H ^UMAN P ^HYSIOLOGY