Introduction and Cell Membrane
- Classify the type of molecules whose diffusion is restricted by membranes.
- Draw the structure of a phospholipid and membrane bilayer and label the hydrophilic and hydrophobic regions.
- Describe the consequence of damage to the cell membrane on the viability of cells.
- Compare the structure of proteins that function as channels to proteins that function as receptors.
Overview of the course
- Describe the basic mechanisms and systems that are common to most cells that allow them to survive, grow and adapt.
- Describe how these mechanisms and systems are employed and modified in different cells to generate unique functions and activities.
- Describe how specific defects in these mechanisms and systems lead to certain diseases.
- In microscope images, identify key structural features of a cell and describe what the presence or absence of those features implies about the function of the cell.
- Identify changes in cell structure that lead to disease
General understanding of how cells work as individuals and in groups
We will describe the major systems, structures and pathways in cells that allow them to survive, grow and adapt. These incude
- General organization of cells
- Secretion and endocytosis
- Morphology and motility
- Cell communication
- Cell quality control
- Cell division and regulation of growth
We will first look at the systems, structures and pathways in a general cell and then explore how these are employed and altered in specific types of cells to generate unique functions and activities. We will highlight cellular mechanisms whose breakdown leads to disease.
In histology, we will explore the structure-function relationship of cells to determine how the shape, size and content of a cell facilitate its function and activity. You will learn how to identify the structural features of cells and how these clues can be used to determine the function and type of cell. You will also learn to identify changes in these structural features and the underlying molecular defect. Finally, you will begin to learn how these changes lead to disease.
Why study cell biology as a physician
The cell is the fundamental unit of life. The vast majority of living organisms (e.g. bacteria and yeast) on Earth are single cells that survive, grow, proliferate and adapt to their environments. Although the cells in our body are more complex and live with billions of other cells, they share many of the same features as single-celled organisms. In fact, some of our cells can, under the right conditions, grow and proliferate as individual cells. For example, in 1951 cervical cancer cells were taken from Henrietta Lacks and grown as individual cells in culture. Descendants of these cells are growing today in labs throughout the world. Thus, even in multicellular organisms, the cell is the fundamental unit of life.
One of the challenges of biomedicine is to understand how the cells in our bodies give rise to all the activities that allow us humans to survive, grow, proliferate and adapt to our environments. We are made entirely of cells and the material that cells produce, and therefore, all the biological events that are required to sustain our lives are generated by cells. For example, as we eat our food, we are always at the risk of ingesting toxins. Most toxins that we accidentally or purposefully ingest are metabolized by the liver into less harmful molecules. If we search a section of the liver to find where this detoxifying activity resides, we discover that the liver contains mostly large masses of cells called hepatocytes. Consequently, the ability to inactive harmful molecules must reside with the hepatocytes. Today, we know that each of these hepatocytes contains enzymes that catalyze the chemical breakdown of toxins.
From a physician's perspective the idea that all human activities are mediated by cells means that when he or she sees a disease, there is usually a breakdown in some cellular event that leads to the development of that disease. For example, atherosclerosis or thickening of the walls of arteries is associated with elevated levels of low-density lipoprotein (LDL) in the serum. LDL is taken up from serum by hepatocytes in the liver. Mutations that reduce hepatocytes' ability to ingest LDL lead to higher serum levels of LDL, increasing the risk of developing atherosclerosis. Knowing how cells work helps understand how diseases arise. Further, by learning how cells take up and process LDL and regulate the amount of cholesterol, we've been able to devise drugs that help reduce the levels of serum LDL. Thus, an understanding of cells creates the potential to development treatments for disease.
Cell membranes function as a border to prevent the loss of critical cellular material. This includes proteins, nucleic acids and carbohydrates and also the building blocks for those macromolecules: amino acids, nucleotides and sugars, respectively. In addition, cell membranes also prevent the loss of ATP, the cellular currency for energy.
To inhibit the loss of cellular material, cell membranes act as a diffusion barrier. All molecules within a cell diffuse due to thermal energy. Without the cell membrane, those molecules would quickly diffuse away from the cell and be lost. The cell membrane forms a barrier across which certain molecules and chemicals cannot diffuse.
The structure of the cell membrane determines the type of molecule or chemicals it prevents from diffusing. Cell membranes contain outer surfaces that are hydrophilic and an inner layer that is hydrophobic. The outer hydrophilic surfaces allow membranes to be soluble in water, whereas the inner hydrophobic layer inhibits the passage of most water-soluble chemicals and molecules.
Membranes contain a large amount of phospholipids. Phospholipids have two chemically distinct structures: a hydrophilic head group and a hydrophobic C-tails. In a mixture of phospholipids and water, the C-tails cluster to avoid interacting with water, whereas the head groups readily interact with water. Consequently, the most stable structure for phospholipids in water is a hollow sphere. Water is found outside and inside the sphere and the phospholipids are arranged into a bilayer that separates the two aqueous environments. Note that a cell is essentially a large membrane sphere with a lot of critical components inside and on the surface of the sphere.
How does the structure of the membrane determine which chemicals it prevents from diffusing across it? The tight packing of phospholipids in a membrane prevents larger molecules (amino acids, carbohydrates) from diffusing across. But even small ions such as sodium, potassium and calcium cannot diffuse across a cell membrane. In this case, the hydrophobic layer within the membrane inhibits the diffusion of ions.
Phospholipids are a class of molecules with each member having different structure and function. Phospholipids differ from each other primarily in the head domains (hydrophilic domain), whereas the C-tails are similar in structure. Phospholipids are classed into different groups based on the structure and composition of the head domain. The details have been discussed in biochemistry.
Why use phospholipids with different head groups? Proteins can differentiate between the head groups. Some proteins will associate with the head groups of specific phospholipids, allowing cells to recruit certain proteins to the cell membrane. The importance of this will be more apparent when we discuss cell communication.
The C-tail of phospholipids are similar in structure with one major difference. The C-tails are fatty acids that contain one or two long chains of hydrocarbons. The individual hydrocarbons can be linked to each other with a single or double bond. A chain with all single bonds generates a straight hydrocarbon chain. These are referred to as saturated lipids. A double bond introduces a kink in the chain resulting in a bent chain. These are called unsaturated lipids.
Cell membranes contain a mix of saturated and unsaturated phospholipids. Because saturated hydrocarbons are straight, these phospholipids can pack more tightly. Unfortunately, a membrane of all saturated phospholipids would be a solid at physiological temperature. The presence of unsaturated phospholipids in a membrane introduces space between phospholipids, making the membrane more fluid-like at physiological temperature.
Not only can different membranes contain different types of phospholipids, but the leaflets in a single membrane can differ in their composition of phospholipid. For example, the outer leaflet of the cell membrane faces the external environment and needs certain types of phospholipids. In contrast, the inner leaflet of the cell membrane faces the cytoplasm of the cell and contains phospholipids that interact with proteins.
A membrane of only phospholipids would form an effective diffusion barrier but would lack many of the functions that are necessary for cell survival. For example, membranes restrict the diffusion of most of the small molecules that cells need to generate energy and build larger macromolecules. These molecules are ofter readily available outside the cell but need a way to get across the membrane into the cell. In addition, to adapt to changing conditions, cells must sense their external environments and respond accordingly. A membrane of only phospholipids lacks the ability to detect external molecules or conditions. Finally, in multicellular organisms, cells must adhere to each other. Phospholipids in membranes do not provide a way to form attachments between two membranes.
To generate the functions described above, membranes rely on proteins. Proteins form channels in membranes that allow the passage of specific molecules or ions. Proteins function as receptors that detect the presence of specific molecules or ions in the external environment. Finally, proteins in membranes interact with proteins in other membrane, generating sites of attachment between membranes and cells.
Proteins can associate with membranes in a variety of ways. The proteins that form channels, receptors or adhesion points are usually integral membrane proteins. These proteins span membrane at least once and can cross the membrane several times (> 10). These proteins are permanently embedded in the membrane and can only be removed through expenditure of large amounts of energy or digestion.
In contrast to integral membrane proteins are peripherally-associated proteins. These proteins associate with the head groups of specific phospholipids or portions of integral membrane proteins. The association of these proteins with membranes is transient. The interaction can be reversed by changing the composition of the membrane or the morphology or charge of the protein. These proteins often provide structural support to membranes, participate in transmitting cell signaling events or alter the topology of membranes in the secretory pathway.
One more important type of interaction between protein and membrane is mediated by a covalent link between a protein and phospholipid. The interaction occurs between an amino acid in the C-terminus of the protein and the head group of a phospholipid. These proteins are found on the outer leaflet of the cell membrane with the protein facing the external environment. Many of these proteins are enzymes that modify proteins in blood or extracellular space.
Fluidity of membranes
The cell membrane is dynamic in that the individual phospholipids and proteins that constitute the membrane are moving rapidly within the membrane. Thermal energy causes lipids and proteins to diffuse within membranes. Scientists have measured the rate at which lipids and proteins diffuse and one estimate is that a lipid can circumnavigate a bacterial membrane in one second.
The diffusive nature of membranes has important biological and medical consequences. Without any other system acting on a membrane, the lipids and proteins in the membrane will be randomly distributed throughout that membrane. As we will see, cells expend a considerable amount of energy to create domains with in membranes that contain a specific set of proteins and sometimes lipids. These domains play important roles in cell adhesion and communication.
Structural support of the cell membrane
Cell membranes require structural support to maintain shape and prevent damage to the phospholipid bilayer. In most cells the cytoskeleton sits underneath the cell membrane in the cytoplasm to provide structural support. Actin filaments are the most common but some cells will employ microtubules to form unique structures (e.g. cilia). Actin filaments form a mesh of filaments under the cell membrane.
The cytoskeleton provides structural support in part by interacting with integral membrane proteins. The interaction with the cytoskeleton limits the diffusion of the membrane proteins and provides a stable framework to which membrane proteins attach. This interaction prevents damage to membranes when external forces pull or push on integral membrane proteins.
Cell membrane and cell potential
It makes sense why cell membranes restrict the diffusion of small molecules such as amino acids, ATP, etc. The cell does not want to lose these critical molecules to the surrounding environment. But why is it important that the cell membrane restrict the diffusion of ions?
Because ions cannot diffuse across the cell membrane, cells can establish a different concentrations of ions in the cytosol compared to the external environment. For example, the intracellular concentration of sodium is much lower than the extracellular concentration. In contrast, the intracellular concentration of potassium is much higher than the extracellular concentration. Similar to sodium, the intracellular concentration of calcium is very low. Cells can establish and maintain these ion gradients because the ions cannot diffuse across the membrane. Ions can only cross through specific proteins that form channels or pumps in the membrane. Cells precisely regulate the activity of channels and pumps. The net distribution of ions makes the cytosol of cells electronegative compared to the external environment.
What is the biological role of these ion gradients? One important role is in cell communication, in particular the communication between neurons and their targets. Active neurons send signals down their axons by allowing sodium ions to enter the cytosol, thereby depolarizing the axon. Cells also use ion gradients to regulate the activity of enzymes. Many enzymes require calcium for their activity. Because the cytosolic concentration of calcium is low, most of these enzymes are inactive. When cells want to activate these enzymes, they allow the cytosolic concentration of calcium to rise.