This text is divided into seven major sections:

Overview of membranes
The chemical components of membranes
Membrane structure
Membranes and compartmentalization
Membrane receptors
Some receptors involve second messengers
Insulin and growth factor receptors

Overview of membranes.

The cell is not an amorphous sack of components, but a complex structure filled with organelles. Examples include:
  1. endoplasmic reticulum
  2. mitochondria
  3. nucleus

Membranes are not passive barriers.

  1. They control the structures and environments of the compartments they define, and thereby the metabolism of these compartments.
  2. The membrane itself is a metabolic compartment with unique functions.

Membranes are dynamic.

  1. They can move.
  2. Their components are continuously synthesized and degraded.
  3. The primary event in cell death (e.g. myocardial infarction) may be damage to the cell membrane, leading ultimately to cell death.

Preview: In the following sections we will look at membranes from the perspectives of

  1. chemical components
  2. structure
  3. function

The chemical components of membranes

General composition.
  1. The components
  2. Differences in composition among membranes (e.g. myelin vs. inner mitochondrial membrane)

Distribution of lipids in membranes

  1. There can be large membrane to membrane differences in lipids (compare phosphoglycerides and cholesterol in plasma membrane vs. inner mitochondrial membrane).
  2. There can be large differences within classes of lipids (compare the cardiolipin of the inner mitochondrial membrane to other membranes).
  3. There are also patterns of differences among the fatty acyl groups of the lipids of various membranes
The reasons for these variations are not known.

The proteins of membranes.

  1. Classification of membrane proteins is operational.
  2. Roles of membrane proteins.

Carbohydrates of membranes are present attached to protein or lipid as glycoprotein or glycolipid.

  1. Typical sugars in glycoproteins and glycolipids include glucose, galactose, mannose, fucose and the N-acetylated sugars like N-acetylglucosamine, N-acetylgalactosamine and N-acetylneuraminic acid (sialic acid).
  2. Membrane sugars seem to be involved in identification and recognition.

Membrane structure

The amphipathic properties of the phosphoglycerides and sphingolipids are due to their structures.
  1. The hydrophilic head bears electric charges contributed by the phosphate and by some of the bases.
  2. The long hydrocarbon chains of the acyl groups are hydrophobic, and tend to exclude water.
  3. Phospholipids in an aqueous medium spontaneously aggregate into orderly arrays.
  4. The properties of phospholipids determine the kinds of movement they can undergo in a bilayer.

Membranes are currently pictured according to the fluid mosaic model.

  1. A lipid bilayer composed of phospholipid and cholesterol
  2. Proteins. Integral proteins are shown; peripheral proteins may be loosely attached to the surface.

The difficulty with which flip-flop movement of membrane components occurs relates to the sidedness of membranes. Membrane surfaces have asymmetry -- different characteristics on the two sides.

  1. There are differences in lipid composition between the sides of a membrane. The mechanism for generating this sidedness is unknown.
  2. Membranes also show sidedness with respect to protein composition
  3. The erythrocyte membrane provides a good model of membrane sidedness.

Membrane fluidity -- according to the fluid mosaic model, proteins and lipids diffuse in the membrane.

Membranes separate and maintain the chemical environments of the two sides of the membrane.

Introduction: there are ion gradients across the mammalian plasma membrane. Here is a comparison of the mean concentration of selected ions outside and inside a typical mammalian cell, giving the ion, the concentration in the extracellular fluid, the intracellular fluid and the difference betwen the two.

	Na+		140 mM			10 mM		14-fold

K+ 4 mM 140 mM 35-fold

Ca++ 2.5 mM 0.1 microM 25,000-fold

Cl- 100 mM 4 mM 25-fold

Cell membranes maintain these gradients by

Some substances can cross membranes by passive (simple) diffusion.

  1. Types of molecules that can cross membranes by diffusion:
  2. Direction relative to the concentration gradient: movement is DOWN the concentration gradient ONLY (higher concentration to lower concentration).
  3. Rate of diffusion depends on
  4. Direction relative to the membrane: molecules may cross the membrane in either direction, depending only on the direction of the gradient.

Protein channels transport specific ions.

  1. Ion channels exist for Na+, K+ and Ca++ movement. These channels are specific for a given ionic species.
  2. Channels consist of protein, which forms a gate that opens and closes under the control of the membrane potential.
  3. Ion movement through channels is always down the concentration gradient.

Transport of molecules across membranes by carriers (mediated transport).

  1. A carrier must be able to perform four functions in order to transport a substance.
  2. Terminology: Carriers are also variously called "porters,""porting systems,""translocases,""transport systems" and "pumps."
  3. Carriers resemble enzymes in some of their properties.
  4. A general model for transport is that the carrier is a protein which changes conformation during the transport process.
  5. Sometimes carriers move more than one molecule simultaneously. Nomenclature:

Passive mediated transport, or facilitated diffusion.

  1. The characteristics of a carrier operating by passive mediated transport.
  2. Examples of passive mediated transport.

Active mediated transport involves transport against a concentration gradient, and requires energy.

  1. There are two sources of energy for active transport.
  2. The characteristics of a carrier operating by active transport.
  3. How can the substance be released from the carrier into a higher concentration than the concentration at which it bound in the first place?
  4. Examples of active mediated transport.

Membrane receptors

Cell-cell communication is by chemical messenger.
  1. There are four types of signals.
  2. There are four types of messenger molecules.
  3. The messenger may interact with the cell in either of two ways.
  4. The events associated with communication via these molecules may include the following.

Messenger molecules which diffuse into the cell -- example: steroid hormones.

  1. Steroids are lipid soluble, and can diffuse through the plasma membrane.
  2. Cells which are sensitive to steroid hormones have specific receptor proteins in the cytosol or nucleus which bind the steroid.
  3. The receptor-hormone complex then somehow causes changes in the cell's metabolism, typically by affecting transcription or translation.
  4. The mechanism of termination is unclear, but involves breakdown of the hormone.

Plasma membrane receptors.

  1. Membrane receptors bind specific messenger molecules on the exterior surface of the cell. Either of two types of response may occur.
  2. A variety of messengers can bind to various tissues.
  3. The response of a cell to a messenger depends on the number of receptors occupied.

The acetylcholine receptor of nervous tissue exemplifies a direct response type of receptor.

  1. The receptor is a complex pentameric protein which forms a channel through the membrane.
  2. Mechanism of action.

Some receptors involve second messengers.

Sometimes the binding of an effector to a receptor leads to the formation of an intracellular molecule which mediates the response of the effector.
  1. Definition: This intracellular mediator is called a second messenger.
  2. Effect of second messenger formation: Since a receptor usually forms many molecules of second messenger after being stimulated by one molecule of the original effector, second messenger formation is a means of amplifying the original signal.
  3. The formation and removal of the second messenger can be controlled and modulated.

Cyclic AMP (cAMP) is a second messenger that mediates many cellular responses.

  1. Structure of cAMP: an internal (cyclic) 3', 5'-phosphodiester of adenylic acid.
  2. The mechanism of action of cAMP is to activate an inactive protein kinase.

  3. cAMP is synthesized by the enzyme, adenyl cyclase.
  4. Adenyl cyclase is controlled by two membrane protein complexes, Gs and Gi.
  5. The action of the G-proteins.
  6. Termination of the signal occurs at several levels.

Inositol triphosphate (IP3) and diacylglycerol (DG) are also second messengers.

  1. Animated activation sequence.
  2. IP3 and DG are synthesized by the enzyme, phospholipase C, which has phosphatidylinositol 4,5-bisphosphate (PIP2) phosphodiesterase activity. PIP2 is a normal minor component of the inner surface of the plasma membrane.
  3. The phosphodiesterase is controlled by a G-protein in the membrane, which activates the phosphodiesterase.
  4. Mechanism: IP3 and DG have separate effects.
  5. Termination of the signal occurs at several levels.
  6. Many systems respond to changes on IP3 and DG. Be aware of the large number of systems affected.

Insulin and growth factor receptors.

The insulin receptor exemplifies receptors for which no second messenger has yet been identified.

Structure: The insulin receptor is a tetramer with two kinds of subunits, alpha and beta. Disulfide bridges bind them together.

The mechanism of signal transmission is unclear.

Many of the cellular responses are well known, e.g.

  1. Glucose transport
  2. Protein phosphorylation -- Insulin and many growth factors activate a protein kinase which phosphorylates a tyrosyl residue in the target proteins, including the receptor itself.

Termination of the insulin and certain growth factor signals involves internalization and degradation of the hormone within the cell.

  1. The receptor-insulin complex migrates to a region of the plasma membrane with the protein clathrin coating its inner surface.
  2. This region forms a "coated pit," a region that invaginates and pinches off, forming an intracellular "coated vesicle."
  3. The coated vesicle fuses with a lysosome; the lysosomal proteases degrade the hormone specifically, leaving the clathrin and the receptor unharmed.
  4. The receptor and clathrin recycle, and are returned to the plasma membrane.

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Last modified 1/5/95