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Membrane & Signaling Processes
As they relate to Terms 1 and 4 of System 4

Robert Campbell, April 2011

Introduction to Membrane Processes & Signaling Cascades

Animal cells are enclosed in a phospholipid bi-layer membrane. The 'head' of a phospholipid is hydrophilic (attracted to water), while the hydrophobic 'tails' are repelled by water and are forced to aggregate toward the center between th two heads. The hydrophilic head contains the negatively charged phosphate group, and many contain other polar groups. The hydrophobic tail consists of fatty acid hydrocarbon chains. The hydrophobic tails line up toward each other, forming a membrane with hydrophilic heads on both sides facing the water inside and outside the cell membrane. This mosaic of lipid cell membrane can act as a solvent for many other substances and proteins embedded within it so that they can migrate laterally over the membrane.

The many proteins and other substances embedded, attached, or adjacent to the cell membrane play essential roles in initiating chemical signaling cascades within the cell. Some act as chemical pumps to move potassium, sodium, calcium, and hydrogen ions against a concentration gradient. Figures 2 and 3 illustrate typical arrangements of a great diversity of membrane related chemicals.

Fig. 1

The outer leaflet consists predominantly of phosphatidylcholine, sphingomyelin, and glycolipids. The inner leaflet contains phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. Cholesterol is distributed in both leaflets and adjusts the fluidity of the membrane. The phosphate heads have a net negative charge. Many proteins and other chemicals are also embedded as below.

Fig. 2 [Above]

Some membrane proteins penetrate only part of the way through the membrane. Peripheral membrane chemicals attach to other proteins and do no penetrate.

Fig. 3 [Above]

A few simplified examples of signaling pathways:

Calcium ions (Ca2+) previously pumped into and stored into the ER are rapidly released when Inositol triphosphate (IP3) opens the channel. There are over 300 kinds of transport channels, many acting as pumps to move ions and other chemicals against a concentration gradient.

Fig. 4 [Above]

Steroid hormones derive from lipids and phospholipids mainly in the gonads and adrenal glands. They are lipid soluble and can pass through the membrane to receptors in the cell. Protein hormones such as insulin and growth hormone, as well as monoamine hormones such as adrenaline, cannot pass through the membrane. They must bind to a membrane receptor to initiate a signaling cascade to the nucleus.

Fig. 5 [Above]

G proteins communicate signals from many hormones, neurotransmitters, and other signaling factors. The chemical signals are called ligands when they dock on a receptor. The ligand binding employs electronic forces, not covalent chemical bonds and docking is reversible.

When signal molecules dock on a receptor domain outside of the cell, it causes the embedded protein receptor to alter shape in an intracellular domain that activates a "peripheral" G protein at the inner membrane. The G protein activates a cascade of further compounds, and finally causes a change downstream in the cell.

G protein complexes bind to phosphate groups. G proteins (guanine nucleotide-binding protein family) respond to many signaling factors to activate signaling cascades downstream. They function as molecular switches. When attached to a complex with three phosphate groups (Guanosine triphosphate GTP), they turn on. When they are attached to a complex with only two phosphate groups (Guanosine diphosphate GDP), they turn off.

G proteins regulate metabolic enzymes, ion channels, transporters, and other parts of the cell machinery, controlling transcription, motility, contractility, and secretion, which in turn regulate systemic functions such as embryonic development, learning, memory, and homeostasis. PKA is a protein kinase that is activated by cyclic adenosine mono-phosophate (cAMP).
Cyclic AMP (adenosine monophosphate) is a second messenger, used for intracellular signal transduction, such as transferring the effects of hormones like glucogon and adrenaline, which cannot pass through the cell membrane. It is involved in the activation of protein kinase enzymes (PKA) that regulate the effects of adrenaline and glucagon. It also regulates the passage of Ca2+ through ion channels. cAMP is synthesized from ATP on the inner side of the plasma membrane.
Fig. 6

Phosphorylation

Phosphorylation is the addition of a phosphate (PO4) group to a protein or other organic molecule and plays a critical role in cell signaling. (The agent of exchange is commonly Adenosine Tri-Phosphate (ATP) which can be reduced to ADP or AMP.) It activates or deactivates a great many protein enzymes, including some causing or preventing diseases such as cancer and diabetes. Each amino acid in protein contains a side chain, which distinguishes it from other amino acids. Phosphates are negatively charged so that their addition to a protein will change its characteristic shape through ionic (electronic) forces. Enzymes called kinases (phosphorylation) and phosphatases (dephosphorylation) are involved in switching other enzymes on or off by changing their shape. Within a protein, phosphorylation can occur on several amino acids, usually serine, threonine, and tyrosine. Histidine and aspartate phosphorylation sometimes occurs as part of two component pathways (analagous to stimulus-response to the environment common in prokaryotes). It is relatively uncommon in eukaryotic pathways.

There are thousands of different kinds of proteins in a cell and up to one half of them may be phosphorylated in some cellular state. Phosphorylation often occurs on multiple distinct sites on a given protein to alter its shape. Upon the deactivating signal, the protein enzyme becomes dephosphorylated again and stops working. This is a global mechanism in complex signaling cascades.

Phosphorylation and Energy

Adenosine tri-phosphate (ATP) is the "high-energy" exchange medium in the cell. It is synthesized in mitochondria organelles by adding a third phosphate group to ADP (adenosine di-phosphate) in a process called oxidative phosphorylation. ATP is also synthesized by glycolysis that converts glucose into pyruvate, releasing free energy to form ATP and NADH (reduced nicotinamid adenine dinucleotide). Glucose is synthesized by solar energy in plant cells. Glycolysis in the cytoplasm produces pyruvate which is employed by mitochondria to convert the bulk of the energy originally in glucose to ATP via the citric acid (Krebs) cycle.

Figure 7 shows a couple of steps employing enzymes in a more complex process of energy conversion. Enzymes are proteins that fold into a highly specific shape. Various molecules are attracted and fit in such a way that they are brought into intimate contact and can bond together much more rapidly and accurately than they would at random. Enzymes are highly specific catalysts tailored to each chemical reaction. Enzymes can be turned on and off by attaching or removing phosphate groups. In some cases, other molecules can attach to turn them off or turn them back on by their release in a reverse manner to phosphate groups.

[image]
Fig. 7

Phosphorylation of sugars, such as glucose, is often the first stage of their catabolism in cells because the phosphate group prevents them from diffusing back outside through the membrane transporter. Catabolism is a metabolic process where complex organic compounds are broken down into simpler compounds, for instance, converting glucose into carbon dioxide and water with the release of energy into ATP. Anabolism is the metabolic steps requiring energy to make complex compounds, such as proteins, by assembling simple compounds such as amino acids.

Figure 8 below gives a general picture of how the process works to provide the energy needed by cells to operate.

The adding and subtracting of a phosphate to ADP is a metabolic process. Metabolic processes can be separated into two phases; catabolism is the process of breaking down (breaking down food to make ATP), and anabolism is the process of building up (using the energy created in converting ATP to ADP to build up cells or move molecules around the cell). (CoQ10 is a coenzyme.)
Fig. 8

Endocrine, Autocrine, Paracrine, and Juxtacrine Signaling

Endocrine signaling cascades are initiated by chemical messengers released from the endocrine glands. They circulate in the blood stream and bind to chemical receptors embedded in the membranes of various cells throughout the body that, in turn, initiate a series of events that results in a signaling cascade to the nucleus. Chemical messengers can also inhibit signaling cascades or the cascade may depend on their concentration or other factors.

Autocrine signaling releases a chemical messenger to the outside of a cell that binds to a receptor in the same cell to initate or modify a signaling cascade in that cell.

Juxtacrine signaling docks a signaling chemical directly with the chemical receptor on an adjacent cell. The signaling chemical remains attached to the sending cell. An example of juxtacrine signaling is shown in the "Notch" signal represented above right in Figure 9.

Paracrine signaling releases chemical messengers that rapidly degrade or are reabsorbed over very small distances, such as at synaptic junctions between neurons.

Fig. 9

Other Signaling Mechanisms

Because calcium ions (Ca2+) are an important "second messenger" that affects all cell signaling, it is essential to keep concentrations very low in the cytosol so as not to interfere with other signaling cascades unless it is needed rapidly. PMCA is a membrane transport protein that employs ATP to