Cell-to-Cell communication is absolutely essential for multicellular organisms. The billions of cells of a human or an oak tree must communicate in order to develop from a fertilized egg and then survive and reproduce in turn. Communication among cells is also important for many unicellular organisms that must locate food and find mates in order to sexually reproduce.

Studies of cell signaling are helping to answer some of the most important questions in biology and medicine – in areas ranging from embryological development to hormone action to the development of cancer and other kinds of disease.

The signals received by cells, whether originating from another cell or from some change in the organism's physical surroundings, take various forms. Cells can sense and respond to electromagnetic signals, such as light, and to mechanical signals, such as touch. However, cells most often communicate with each other using chemical signals. We will deal here with the main mechanisms by which cells detect, process, and respond to chemical signals sent from other cells.

The process by which a signal on a cell's surface is converted into a specific cellular response, a series of steps called a signal-transduction pathway, has been extensively studied in many types of cells. The molecular details of signal transduction in most cells are strikingly similar, even though the last common ancestor of these different types of cells lived over a billion years ago. These similarities suggest that early versions of the cell-signaling mechanisms used today evolved well before the first multicellular creatures appeared on Earth.

Example: cell communication between two yeast cells. Cells of the yeast Saccharomyces cerevisiae use chemical signaling to identify cells of opposite mating type and to initiate the mating process. First cells of mating type A release a-factor, which binds to receptors on nearby cells of mating type B. Meanwhile, B cells release b-factor, which binds to specific receptors on A cells. Both these "factors" are small proteins of about 20 amino acid in length. Binding of these factors to the receptors induces changes in the cells that lead to their fusion, or mating. The resulting A/B cell combines in its nucleus all the genes from both A and B cells, (diploid).

Cells usually communicate by releasing chemical messengers targeted for cells that may not be immediately adjacent. Some messengers travel only short distances. Such molecules are called local regulators: a substances that influences cells in vicinity. E.g. animal growth factors, which are compounds that stimulate nearby target cells to grow and multiply. Numerous cells can simultaneously receive and respond to the molecules of growth factors produced by a single cell in their vicinity. This type of local signaling in animals is called paracrine signaling.

Another specialized type of local signaling occurs between nerve cells. One nerve cell produces a neurotransmitter, that diffuses (across a synapse) to a single target cell that is touching the first cell.

Both animals and plants use chemicals called hormones for signaling at greater distances. Cells may also communicate by direct contact. Both animals and plants have cell junctions that provide cytoplamic continuity between adjacent cells. Also, animal cells may communicate via direct contact between molecules on their surfaces. This sort of signaling is important in embryonic development and in the operation of the immune system.

From the perspective of the cell receiving the message, cell signaling can be divided into three stages: Signal reception, Signal transduction, and Cellular response. When reception occurs at the plasma membrane, the transduction stage is usually a pathway of several steps, with each molecule in the pathway bringing about a change in the next. The last molecule in the pathway triggers the cell's response.

A signal molecule binds to a receptor protein, causing the protein to change shape. A cell targeted by a particular chemical signal has molecules of a receptor protein that recognizes the signal molecule. The signal molecule is complementary in shape to a specific site on the receptor and attaches there, like a key in a lock. The signal molecule behaves as a ligand, the term for a small molecule that specifically binds to a larger one. Ligand binding causes a receptor protein to undergo a change in conformation, that is a change in shape. For many receptors, this shape change directly activates the receptor so that it can interact with another cellular molecule. For other receptors the immediate effect of the ligand binding causes the aggregation of two or more receptor molecules.

Most signal receptors are plasma-membrane proteins.

G-Protein-Linked Receptors. This ia a plasma-membrane receptor that works with the help of a protein called a G protein and another protein, usually an enzyme. In the absence of the extracellular signal molecule specific for the receptor, all three proteins are in inactive form. The inactive G protein has a GDP molecu;e bound to it. When the signal molecule binds to the receptor protein, the receptor changes shape in such a way that it binds and activates the G protein. A molecule of GTP replaces the GDP on the G protein. The active G protein (moving freely along the membrane) binds to and activates the enzyme, which triggers the next step in the pathway leading to the cell's response. The G protein then catalyzes the hydrolysis of its GTP and dissociates from the enzyme, becoming available for reuse. All three proteins remain attached to the plasma membrane.

Ion-Channel Receptors. Some membrane receptors of chemical signals are Ligand-gated ion channels. These channels are protein pores in the plasma membrane that open or close in response to the binding of a chemical signal, allowing or blocking the flow of specific ions, such as Na⁺ or Ca²⁺ into the cell. Often the change in the concentration of a particular ion inside the cell directly affects cell function.

Intracellular Receptors. Not all signal receptors are membrane proteins. Some are proteins located in the cytoplasm or nucleus of target sells. To reach such a receptor, a chemical messenger must be able to pass through the target cell's plasma membrane. A number of important signaling molecules can do just that, either because they are small enough to pass between the membrane phospholipids or because they are themselves lipids and therefore soluble in the membrane.

The trasnductionstage of cell signaling is usually a multistep pathway. One benefit of such a pathway is signal amplification. If some of the molecules in a pathway transmit the signal to multiple molecules of the next component in the series, the result can be a large number of activated molecules at the end of the pathway. That is a very small number of extracellular signal molecules can produce a major cellular response.

Pathways relay signals from receptors to cellular responses. Like falling dominoes, the signal-activated receptor activates another protein, which activates another molecule, and so on, until the protein that produces the final cellular response is activated. The molecules that relay a signal from the receptor to response, sometimes called relay molecules, are mostly proteins.

Protein phosphorylation, a common mode of regulation in cells, is a major mechanism of signal transduction. A signaling pathway begins when a signal molecule binds to a membrane receptor. The receptor then activates a relay molecule, which activates a protein kinase (1). Active protein kinase 1 transfers a phosphate from ATP to an inactive molecule of another protein kinase molecule (2), thus activating this second kinase. In turn, active protein kinase 2 catalyzes the phosphoralation (and activation) of protein kinase 3. Finally, active protein kinase 3 phosphorylates a protein that brings about the cell's final response to the signal. Each activated protein kinase molecule is inactivated by the removal of tha phosphate group by enzymes called phosphatases. This make the protein kinases available for reuse.

Certain small molecules and ions are key components of signaling pathways (second messengers). The extra cellular signal molecule that binds to the membrane receptor is a pathway's "first messenger". Because second messengers are both small and water-soluble, they can readily spread throughout the cell by diffusion. Second messangers participate in pathways initiated by both G-protein-linked receptors and tyrosine-kinase receptors. The two most widely used second messengers are cyclic AMP and calcium ions, Ca²⁺. A large variety of relay proteins are sensitive to the cytosolic concentration of one or the other of these second messengers.

Cyclic AMP (cAMP) Cyclic AMP is a component of many G-protein-signaling pathways. The signal molecule - the "first messanger" - activates a G-protein-linked receptor, which activates a specific G protein. In turn, the G protein activates adenylyl cyclase, which catalyzes the conversion of ATP to cAMP.

Calcium Ions and Indositol Triphosphate Calcium ions (Ca²⁺) are actively transported out of the cytosol by a variety of protein pumps. Pumps in the plasma membrane move Ca²⁺ into the extracellular fluid, and ones in the ER membrane Ca²⁺ into the lumen of the ER. Consequently, the Ca²⁺ consentration in the cytosol is usually muth lower than in the extracellular fluid and ER. Additional Ca²⁺ pumps in the mitochondrial inner membrane operate when the calcium level in the cytosol rises significantly. These pumps are driven by the proton-motive force generated across the membrane by mitochondrial electron transport chains.

Calcium ions (Ca²⁺) and indositol trisphosphate (IP₃) functions as second messengers in many signal-transduction pathways. The process is initiated by thebinding of a signal molecule to either a G-linjed receptor or a Tyrosine-kinase receptor. In The following figure the circled numbers trace the former pathway. 1- Asignal molecule binds to a receptor, leading to 2- activation of an enzyme celled phospholipase C. 3- This enzyme cleaves a plasma-membrane phospholipid called PIP₂ into DAG and IP₃. Both can function as second messangers. 4- IP#, a small molecule, quickly diffuses through the cytosol and binds to a ligand-gated calcium channel in the ER membrane, causing it to open. 5- Calcium ions flow out of the ER (down their gradient), raising the Ca²⁺ level in the cytosol. 6- The calcium ions activate the next protein in one or more signaling pathways, often acting via calmodulin, a ubiquitous Ca²⁺-binding protein. DAG functions as a second mesanger in still other pathways.

Ultimateley, a signal-transduction pathway leads to the regulation of one or more cellular activities. The regulated activities may occur in the cytoplasm, such as a rearrangment of the cytoskeleton, the opening or closing of an ion channel in the plasma membrane, or some aspect of cell metabolism. Many other signaling pathways ultimately regulate not the activity of an enzyme but the synthesis of enzymes or other proteins, usually by turing specific genes on or off.