Figure 15-3The binding of extracellular signal molecules to either cell-surface receptors or intracellular receptors

Most signal molecules are hydrophilic and are therefore unable to cross the plasma membrane directly; instead, they bind to cell-surface receptors, which in turn generate one or more signals inside the target cell. Some small signal molecules, by contrast, diffuse across the plasma membrane and bind to receptors inside the target cell—either in the cytosol or in the nucleus (as shown here). Many of these small signal molecules are hydrophobic and nearly insoluble in aqueous solutions; they are therefore transported in the bloodstream and other extracellular fluids after binding to carrier proteins, from which they dissociate before entering the target cell.

Figure 15-4Forms of intercellular signaling

(A) Contact-dependent signaling requires cells to be in direct membrane-membrane contact. (B) Paracrine signaling depends on signals that are released into the extracellular space and act locally on neighboring cells. (C) Synaptic signaling is performed by neurons that transmit signals electrically along their axons and release neurotransmitters at synapses, which are often located far away from the cell body. (D) Endocrine signaling depends on endocrine cells, which secrete hormones into the bloodstream that are then distributed widely throughout the body. Many of the same types of signaling molecules are used in paracrine, synaptic, and endocrine signaling; the crucial differences lie in the speed and selectivity with which the signals are delivered to their targets.

Figure 15-5The contrast between endocrine and synaptic signaling

In complex animals, endocrine cells and nerve cells work together to coordinate the diverse activities of the billions of cells. Whereas different endocrine cells must use different hormones to communicate specifically with their target cells, different nerve cells can use the same neurotransmitter and still communicate in a highly specific manner. (A) Endocrine cells secrete hormones into the blood, which signal only the specific target cells that recognize them. These target cells have receptors for binding a specific hormone, which the cells “pull” from the extracellular fluid. (B) In synaptic signaling, by contrast, specificity arises from the synaptic contacts between a nerve cell and the specific target cells it signals. Usually, only a target cell

that is in synaptic communication with a nerve cell is exposed to the neurotransmitter released from the nerve terminal (although some neurotransmitters act in a paracrine mode, serving as local mediators that influence multiple target cells in the area).

Figure 15-6Autocrine signaling

A group of identical cells produces a higher concentration of a secreted signal than does a single cell. When this signal binds back to a receptor on the same cell type, it encourages the cells to respond coordinately as a group.

Figure 15-7Signaling via gap junctions

Cells connected by gap junctions share small molecules, including small intracellular signaling molecules, and can therefore respond to extracellular signals in a coordinated way.

Figure 15-8An animal cell's dependence on multiple extracellular signals

Each cell type displays a set of receptors that enables it to respond to a corresponding set of signal molecules produced by other cells. These signal molecules work in combinations to regulate the behavior of the cell. As shown here, an individual cell requires multiple signals to survive (blue arrows) and additional signals to divide (red arrow) or differentiate (green arrows). If deprived of appropriate survival signals, a cell will undergo a form of cell suicide known as programmed cell death, or apoptosis.

Figure 15-9Various responses induced by the neurotransmitter acetylcholine

Different cell types are specialized to respond to acetylcholine in different ways. (A and B) For these two cell types, acetylcholine binds to similar receptor proteins, but the intracellular signals produced are interpreted differently in cells specialized for different functions. (C) This muscle cell produces a distinct type of receptor protein for acetylcholine, which generates different intracellular signals from the receptor shown in (A) and (B), and results in a different effect. (D) The chemical structure of acetylcholine.

Figure 15-11The role of nitric oxide (NO) in smooth muscle relaxation in a blood vessel wall

Figure 15-15Three classes of cell-surface receptors(A) Ion-channel-linked receptors, (B) G-protein-linked receptors, and (C) enzyme-linked receptors. Although many enzyme-linked receptors have intrinsic enzyme activity, as shown on the left, many others rely on associated enzymes, as shown on the right.

Figure 15-16Different kinds of intracellular signaling proteins along a signaling pathway from a cell-surface receptor to the nucleus

In this example, a series of signaling proteins and small intracellular mediators relay the extracellular signal into the cell, causing a change in gene expression. The signal is amplified, altered (transduced), and distributed en route. Many of the steps can be modulated by other extracellular and intracellular signals, so that the final result of one signal depends on other factors affecting the cell (see Figure 15-8). Ultimately, the signaling pathway activates (or inactivates) target proteins that alter cell behavior. In this example, the target is a gene regulatory protein.

Figure 15-17Two types of intracellular signaling proteins that act as molecular switches

In both cases, a signaling protein is activated by the addition of a phosphate group and inactivated by the removal of the phosphate. (A) The phosphate is added covalently to the signaling protein by a protein kinase. (B) A signaling protein is induced to exchange its bound GDP for GTP. To emphasize the similarity in the two mechanisms, ATP is shown as APPP, ADP as APP, GTP as GPPP, and GDP as GPP.

Figure 15-18Signal integration

(A) Extracellular signals A and B both activate a different series of protein phosphorylations, each of which leads to the phosphorylation of protein Y but at different sites on the protein. Protein Y is activated only when both of these sites are phosphorylated, and therefore it becomes active only when signals A and B are simultaneously present. For this reason, integrator proteins are sometimes called coincidence detectors. (B) Extracellular signals A and B lead to the phosphorylation of two proteins, a and b, which then bind to each other to create the active protein. In both of the examples illustrated, the proteins themselves are phosphorylated. An equivalent form of control can also occur, however, by the exchange of GTP for GDP on GTP-binding proteins (see Figure 15-17).

Figure 15-19Two types of intracellular signaling complexes

(A) A receptor and some of the intracellular signaling proteins it activates in sequence are preassembled into a signaling complex by a large scaffold protein. (B) A large signaling complex is assembled after a receptor has been activated by the binding of an extracellular signal molecule; here the activated receptor phosphorylates itself at multiple sites, which then act as docking sites for intracellular signaling proteins.

Figure 15-20A hypothetical signaling pathway using modular binding domains

Signaling protein 1 contains three different binding domains, plus a catalytic protein kinase domain. It moves to the plasma membrane when extracellular signals lead to the creation of various phosphorylated docking sites on the cytosolic face of the membrane. Its SH2 domain binds to phosphorylated tyrosines on the receptor protein, and its PH domain binds to phosphorylated inositol phospholipids in the inner leaflet of the lipid bilayer. Protein 1 then phosphorylates signaling protein 2 on tyrosines, which allows protein 2 to bind to the PTB domain on protein 1 and to the SH2 domain on an adaptor protein. The adaptor protein then links protein 2 to protein 3, causing the phosphorylation of protein 3 by protein 2. The adaptor protein shown consists of two binding domains—an SH2 domain, which binds to a phosphotyrosine on protein 2, and an SH3 domain, which binds to a proline-rich motif on protein 3.

Figure 15-23One type of signaling mechanism expected to show a steep thresholdlike response

Here, the simultaneous binding of eight molecules of a signaling ligand to a set of eight protein subunits is required to form an active protein complex. The ability of the subunits to assemble into the active complex depends on an allosteric conformational change that the subunits undergo when they bind their ligand. The binding of the ligand in the formation of such a complex is generally a cooperative process, causing a steep response as the ligand concentration is changed, as explained in Chapter 3. At low ligand concentrations, the number of active complexes increases roughly in proportion to the eighth power of the ligand concentration.

Figure 15-24An accelerating positive feedback mechanism

In this example, the initial binding of the signaling ligand activates the enzyme to generate a product that binds back to the enzyme, further increasing the enzyme's activity.

Figure 15-25Five ways in which target cells can become desensitized to a signal molecule

The inactivation mechanisms shown here for both the receptor and the intracellular signaling protein often involve phosphorylation of the protein that is inactivated, although other types of modification are also known to occur. In bacterial chemotaxis, which we discuss later, desensitization depends on methylation of the receptor protein.