1. Some signal molecules can directly enter cells.

• Hydrophobic molecules such as steroid hormones can enter cells because of their hydrophobic character. The receptor molecules for these hormones are inside the cells. (look) , (look)
• Nitric oxide (NO) can also enter cells directly. The discovery of nitric oxide as a signal molecule provides an explanation for the ability of nitroglycerine to provide relief from the pains of angina. NO is released from nitroglycerine and relaxes blood vessels. NO often binds to the enzyme which converts GTP into cyclic GMP, an internal cell signal molecule. (look)

2. Other external cell signals, use one of three mechanisms to pass the "message" into the cell interior - a) An ion channel linked receptor, b) a G-protein linked receptor, c) an enzyme linked receptor. (look)

• G protein receptors are a major pathway for converting an external signal into an intracellular message. (look)
• G proteins consist of three subunits. The large alpha unit dissociates from the rest of the molecule and diffuses along the internal cell surface when a signaling molecule binds to the external receptor binding site. (look) This dissociation is accompanied by release of GDP and binding of GTP. Binding of GTP is common in molecular switches. (look)
• G proteins cause K⁺ channels to open in response to neurotransmitter binding in heart muscle. (look)
• Hormone binding can use a G protein intermediate to produce changes in concentrations of intracellular messengers:
• Cyclic AMP is an important intracellular messenger. Adrenaline, glucagon, and ACTH are important hormones which cause changes in cyclic AMP concentrations within target cells. (look) Remember back to the diagram which described the release of glucose from glycogen and the addition of glucose to a growing glycogen chain? As you can see from here, one of the effects of increased concentrations of cAMP is activation of a kinase. This kinase starts a cascade of changed in enzymes which results in an increase in the rate at which glucose is released from glycogen.
• Other hormones use the inositol phosphate pathway (phospholipase C activation). Examples of these hormones are vasopressin and thrombin. Acetylcholine, a common neurotransmitter, also uses the inositol phosphate pathway. (Do you remember that we noted in a previous lecture that inositol phospholipids were found as part of the the internal layer of the lipid bilayer membrane?) (look) The inositol pathway is involved with release of Ca⁺⁺ from the ER. This release is involved in many important biological processes, including fertilization. Look at this beautiful picture to see what happens when a starfish egg is fertilized. A Ca⁺⁺ sensitive fluorescent dye records rising concentrations of Ca⁺⁺, (look). As we shall see, it is Ca⁺⁺ release from sarcoplasmic reticulum in muscle which activates skeletal muscle contraction. (Do you now know which hormones use the cAMP or the inositol phosphate pathways? Do you know what becomes of the inositol phospholipids?)
• Ca⁺⁺ concentrations in all cells, including skeletal muscle cells are kept extremely low (around 10^-7 M) by active transport pumps which pump from the cytosol into the ER or to the outside of the cell.
• Ca⁺⁺ release affects target proteins by first binding to a Ca⁺⁺ binding protein, the most common of which is calmodulin

• Light absorption by rhodopsin in the eye causes release of the alpha subunit of a G protein. This causes ion channels to close and the electrical potential to change across rod and cone cell membranes. It is this electrical potential change which results an action potential on an adjacent cell and eventually a signal sent to the brain via the optic nerve.

3. Receptors which activate G proteins have multiple segments of protein chain which pass through the membrane. These receptors can change conformation (shape) in response to binding an external messenger and transmit this change across the membrane. However, receptor proteins with a single pass through the membrane apparently can't transmit a shape change across membranes. As a result, these types of receptor proteins work by permitting linking of of receptor subuits by a signal molecule.

• Receptor tyrosine kinases bind a variety of extracellular signals, including growth hormones.(look)

• These kinases activate an important GTP binding protein called Ras. (look) Ras activation leads to a cascade of activation of kinases and eventual changes in gene regulatory proteins. Gene transcription and thus gene expression are changed, causing changes in cell proliferation and cell differentiation. (look)
• Look here to see a very recent view of the Ras signaling pathway.

• About 30% of human cancers have mutation in the ras genes. Since cancer is usually characterized by changes in cell proliferation and loss of the ability to differentiate, ras and related genes are significant factors in the search for a cure for cancer.
• (Do you now know which kinds of hormone receptors are single-pass and which are multiple-pass proteins ?)

All text and images, not attributed to others, including course examinations and sample questions, are Copyright, 2007, Thomas J. Herbert and may not be used for any commercial purpose without the express written permission of Thomas J. Herbert.