Chapter 11

It is often necessary for cells to communicate with each other. This may involve transmitting secretory molecules called local regulators to nearby cells. Animals produce local regulators called growth factors that stimulate target cells to grow and multiply. They also produce neurotransmitters in nerve cells to diffuse to target cells (usually other nerve cells or muscle). Local communication systems are said to be part of the paracrine system

Animals and plants produce hormones for long distance chemical communication. Hormones are produced by the endocrine system. Hormones may or may not pass through cell membranes depending on whether they can cross the phospholipid bilayer.

Signaling depends on reception, transduction, and response.

Reception usually involves the signal binding to a transmembrane protein.

Transduction converts the signal to a form that can bring about a cellular response. This often involves a pathway of relay proteins being activated.

The response may involve rearrangement of the cytoskeleton, activation or inhibition of an enzyme or a gene.

Signal molecules behave as ligands. Ligands are small molecules that specifically bind to larger ones such as receptor proteins. As a result of this binding the receptor changes its shape.

Many specific receptor/transduction systems can be categorized as using either G protein-linked receptors or tyrosine kinase receptors. We will consider the general form of the two categories.

G protein-linked receptors are all transmembrane proteins having seven alpha-helix regions that span the hydrophobic region of the cell membrane. They have an extracellular domain that can be recognized and bound by a ligand. They have a domain on their cytosolic side that when in a particular configuration can react with a G protein. The G protein is a membrane bound protein that is activated if it is bound to a GTP molecule (Guanosine triphosphate) and inactivated if it is bound instead by a GDP (Guanosine diphosphate). When a ligand binds to the G protein-linked receptor the receptor changes shape so that in its new conformation the cytosolic domain interacts with the G protein causing it to in turn bind an ATP and become active. The active G protein usually then activates another membrane bound enzyme that causes a reaction to occur inside the cell. The G protein has its own GTPase activity and replaces the GTP with a GDP thereby inactivating itself. It is very important in these communication systems that the signal not only be capable of turning on the transduction system, but that the system be soon turned off so that it can respond to another appropriate signal.

G protein systems are extremely widespread and 60% of all medicines used today exert their effects by influencing G protein pathways.

Receptor tyrosine kinases (RTKs) are often the type receptors for growth factors. RTKs are composed of a single alpha helix region that extends through the membrane. A receptor binding site exists on the extracellular side which can bind to a ligand. On the cytosol side of the receptor are tyrosine kinases that cause ATPs to transfer their phosphates to tyrosines (one of the 20 amino acids in biological proteins) on the cytosolic domain of the RTK. The RTK are found in pairs, and the binding of ligands to each RTK causes the receptors to bind to each other forming a dimer. The cytosolic domain of each RTK acts as tyrosine kinase for the cytosolic domain of the other member of the pair hence phosphorylating its tyrosines. These activated tyrosines because of their specific locations in the RTK each activate a different relay molecule. In this way, one message can simultaneously activate several different relay pathways.

A couple of terms are worthwhile remembering.

Kinases are a general class of enzyme that activates other enzymes through phosphorylation.

Phosphatases are enzymes that remove phosphates from other enzymes thereby deactivating them.

Changes in the concentration of some ions in the cytosol can also often serve as a signal. The passage of ions across the membrane is often controlled by ligand-gated ion channels. When ligands bind to receptor regions of the channel proteins, the channels open allowing the flow of ions. Two ions whose cytosolic concentrations are often important are: Na⁺, and Ca⁺⁺.

Some signals are capable of moving across the cell membrane. These bind to intracellular receptors. Such signals may be steroids, or small gaseous molecules like nitric oxide (NO). The intracellular receptors may be enzymes that are activated by these signals or they may be molecules that when activated can bind to DNA turning on specific genes.

One of the characteristic features of signal transduction pathways is that many of the relay proteins are kinases that activate other enzymes. Since enzymes are unchanged after they stimulate a reaction, they may stimulate many such reactions. This results in the number of activated molecules being amplified at each step of the relay pathway.

Second messengers are small nonprotein water-soluble molecules or ions that can spread rapidly throughout the cell via diffusion. These second messengers are produced as a result of primary messengers (that are unable to cross the membrane) binding to membrane bound proteins. Ca⁺⁺ and cyclic AMP are the two most common second messengers and may result from ligands binding to G protein-linked receptors or RTKs.

Cyclic AMP is made from ATP under the influence of a membrane bound protein adenyl cyclase. Cyclic AMP can then activate other enzymes. Calcium ions may directly bind to some molecules activating them or it may act through an intermediate calmodulin. When calmodulin binds to Ca⁺⁺ it changes shape and binds to other proteins (usually kinases or phosphatases) activating or deactivating them.

The end result of signal transduction is to activate an enzyme or to cause the synthesis of an enzyme by interacting with DNA.

Signals have different effects on different cells because the cells have different proteins (i.e., receptors, relay transducers).

Every activated intermediate must potentially be inactivated.