Cell Signaling and Communication

15Cell Signaling

and Communication

15 Cell Signaling and Communication

• Signals

• Receptors

• Signal Transduction

• Signal Effects: Changes in Cell Function

• Direct Intercellular Communication

15 Signals

• Both prokaryotic and eukaryotic cells must process information from their environment and respond appropriately.

• Signals may be chemical molecules or physical stimuli such as light.

• Cells must be set up to interpret signals—not all cells can interpret all signals.

• To interpret a signal, a cell must have the appropriate receptor protein.

15 Signals

• Organisms receive many signals from the environment such as light, odors, tastes, temperature, touch, and sound.

• Multicellular organisms’ internal cells are exposed to extracellular fluids and other cells, from which they receive information.

• A few of the many types of signals in animal cells are hormones, neurotransmitters, chemical messages from the immune system, CO2, and H+.

15 Signals

• In large animals, signals reach targets via diffusion as autocrine or paracrine signals when the target is close.

• Autocrine signals are signals generated by the same cells upon which they act.

• Paracrine signals diffuse to and affect nearby cells.

• When the target is distant, signals travel by circulation in the blood.

Figure 15.1 Chemical Signaling Systems (Part 1)

Figure 15.1 Chemical Signaling Systems (Part 2)

15 Signals

• The entire signaling process, from signal detection to final response, is called a signal transduction pathway.

• A signal transduction pathway involves a signal, a receptor, transduction, and effects.

• It is usually described as a series of events but many of the events are actually happening at the same time.

15 Signals

• An example using E. coli:

• The signal is rising solute concentration outside the cell.

• The receptor protein is EnvZ, a transmembrane protein. Rising solute concentration changes the protein’s conformation.

• EnvZ becomes a kinase, and phosphorylates itself.

• A responder is the second component in the pathway. EnvZ now binds to OmpR, which takes the phospate group. OmpR changes shape.

15 Signals

• The signal on the outside of the cell has been transduced to a protein inside the cell, the phosphorylated OmpR.

• Phosphorylated OmpR is a transcription factor. It binds to the promoter for the ompC gene.

• The protein OmpC is inserted into the outer membrane where it blocks pores and prevents solutes from entering.

Figure 15.2 A Model Signal Transduction Pathway (Part 1)

Figure 15.2 A Model Signal Transduction Pathway (Part 2)

15 Signals

• A review of the steps in this signal transduction pathway:

A receptor binds with the signal molecule and changes shape.

Conformational change results in kinase activity.

Phosphorylation alters the functioning of a protein.

The signal is amplified.

Transcription factors are activated.

Altered synthesis of specific proteins occurs.

Protein action alters cell activity.

15 Receptors

• A cell responds to only a few of the many signals it receives.

• The type of receptors each cell makes is genetically determined.

• Receptors have specific binding sites for their signals.

15 Receptors

• A ligand is the signaling molecule that binds the receptor.

• Binding of the ligand causes the receptor to change shape.

• The ligand has no further involvement in the pathway.

• Receptors bind ligands according to the law of mass action, and thus the binding is reversible.

Figure 15.3 A Signal Bound to Its Receptor

15 Receptors

• Inhibitors can bind to the ligand binding sites on receptor molecules.

• Natural and artificial inhibitors are important in medicine.

15 Receptors

• There are two classes of signaling molecules: Ligands with cytoplasmic receptors: small

and/or nonpolar molecules that can cross the plasma membrane, such as steroids.

Ligands with plasma membrane receptors: large and/or polar molecules that can not cross, such as insulin. Receptors are usually transmembrane proteins.

Figure 15.4 Two Locations for Receptors

15 Receptors

• Three well-studied types of transmembrane receptors in complex eukaryotes:

Ion channel receptors

Protein kinases

G protein-linked receptors

15 Receptors

• Some ion channel proteins, acting as “gates,” are signal receptors.

• Channel proteins can open to let certain ions in or out, or close to restrict them.

• The signal to open or close the channel can be chemical, light, sound, pressure, or voltage.

• An example of a gated ion channel is the acetylcholine receptor.

Figure 15.5 A Gated Ion Channel

15 Receptors

• Some eukaryotic receptor proteins become kinases when activated.

• A phosphate is transferred from ATP to a protein, the target protein, changing its shape or activity.

• Sometimes the protein kinase phosphorylates itself. This is called autophosphorylation.

• Insulin receptors are examples of protein kinase receptors.

Figure 15.6 A Protein Kinase Receptor

15 Receptors

• The seven-spanning G protein-linked receptors are proteins with seven regions that pass through the lipid bilayer.

• A ligand binds to the extracellular side and changes the shape of the protein on the cytoplasmic side. This exposes a binding site for the G protein.

• G protein also has a binding site for GTP. The GTP-bound subunit separates and moves along the membrane until it finds an effector protein.

• The effector protein may catalyze many reactions, amplifying the signal.

Figure 15.7 A G Protein-Linked Receptor (Part 1)

Figure 15.7 A G Protein-Linked Receptor (Part 2)

15 Receptors

• G proteins can either activate or inhibit effectors. Epinephrine illustrates both possibilities.

• In the heart, epinephrine causes the G protein to activate an enzyme that produces cAMP, which has a wide range of effects on the cell.

• In smooth muscle cells around blood vessels, epinephrine causes the G protein to inhibit the production of cAMP, muscles relax, and the blood vessels open wide for maximum blood flow.

15 Receptors

• Cytoplasmic receptors which are located inside the cell bind with ligands that can cross the plasma membrane.

• The receptor changes shape and can then enter the nucleus where it acts as a transcription factor.

• Steroid hormones are an example of such signal molecules.

Figure 15.8 A Cytoplasmic Receptor

15 Signal Transduction

• Transducers convert signals from one form to another.

• Direct transduction results from the action of the receptor itself on effector proteins. Direct transduction occurs at the plasma membrane.

• Indirect transduction uses a second messenger to mediate the interaction between receptor binding and cellular reaction.

• In both direct and indirect transduction the signal initiates a series of events that eventually lead to a final response.


• A protein kinase cascade is direct signal transduction that catalyzes the phosphorylation of target proteins.

• Details of a certain protein kinase cascade were discovered from the investigation of Ras protein inhibition as treatment for bladder cancer.

• Ras is part of a protein kinase cascade that influences cell division. The pathway is called a cascade because each kinase phosphorylates the next.

Figure 15.9 A Protein Kinase Cascade


• There are at least three advantages to having many kinase steps in signal transduction:

Each activated protein kinase can phosphorylate many target proteins, so amplification of the signal occurs at each step.

A signal at the cell membrane is transferred to the nucleus.

Having many steps affecting different target proteins allows for a variety of responses by different cells to the same signal.


• Indirect transduction is more common than direct transduction.

• Scientists investigating the effects of epinephrine on the liver enzyme phosphorylase discovered cyclic AMP (cAMP) as a second messenger.

• The second messenger carries the signal from the membrane receptor to the cytoplasm.

• Second messengers affect many cell processes, amplifying the signal.


• The cAMP molecule is a small cyclic nucleotide generated from ATP.

• The enzyme adenylyl cyclase produces cAMP using ATP as a substrate. Adenylyl cyclase is activated by an activated G protein subunit.

• Like other second messengers, cAMP is not an enzyme. Second messengers act as cofactors or allosteric regulators of target proteins.

• cAMP has two major kinds of targets: ion channels and protein kinases.

Figure 15.10 The Formation of Cyclic AMP


• Phospholipids can be hydrolyzed into components that act as second messengers.

• Phosphatidyl inositol-bisphosphate (PIP2) is hydrolyzed into inositol triphosphate (IP3) and diacylglycerol (DAG).

• The two parts each become second messengers, with IP3 moving into the cytoplasm and DAG remaining in the membrane.

• These second messengers trigger many cellular events.

Figure 15.11 The IP3 and DAG Second Messenger System


• Calcium ions are also second messengers.

• Ca2+ concentration in the cytoplasm is usually only about 0.1 M.

• The concentration is kept low via active transport, both out of the cell and into the ER.

• Unlike cAMP, Ca2+ cannot be manufactured in the cell; it must be imported.

• Many different signals cause Ca2+ channels to open, including IP3.


• Once a signal triggers Ca2+ channels to open, Ca2+ concentration rapidly rises to 100 times the resting concentration.

• The calcium ions then affect the activities of cellular proteins, including protein kinase C.

• Ca2+ also binds to Ca2+ channel proteins, triggering additional releases of Ca2+.

• Calcium ions bind to a calcium-binding protein called calmodulin, which can activate certain proteins.


• The gas nitric oxide (NO) was found to be a second messenger by scientists studying the effects of acetylcholine, which causes the relaxation of smooth muscles of the blood vessels.

• Acetylcholine stimulates the IP3 pathway to produce an influx of Ca2+, which leads to an increase in the level of another second messenger, cGMP.

• This messenger stimulates a kinase cascade leading to muscle relaxation.


• However, the pathway does not work in isolated artery tissue, which lacks an endothelial lining.

• It was discovered that NO, produced by the endothelial cells, was also needed.

• Acetylcholine causes increased Ca2+ levels in the endothelial cells, which causes the activation of NO synthase, the enzyme that makes NO.

• NO diffuses rapidly from the endothelial cells to the nearby smooth muscle cells.

• In the smooth muscle cells, NO activates the enzyme guanylyl cyclase, which stimulates the formation of cGMP.

Figure 15.13 Nitric Oxide as a Second Messenger


• Cells must regulate the activity of transducers.

• NO is unstable and breaks down quickly, so NO is regulated by how much of it is made.

• Ca2+ concentrations are restored by mechanisms such as membrane pumps and ion channels.

• Protein kinase cascades are interrupted by protein phosphatases that remove the added phosphates, deactivating the kinases.

• GTPases deactivate G proteins by converting GTP to GDP.

• Both cAMP and cGMP are converted to AMP and GMP by their respective phosphodiesterases.

15 Signal Effects: Changes in Cell Function

• Signal effects may include:

The opening of membrane channels

Changes in enzyme activity

Differences in gene transcription


• Sensory nerve cells of the sense organs are stimulated through the opening of ion channels.

• Each of the thousands of nerve cells in the nose expresses just one of these receptors.

• When an odorant molecule binds to its receptor, a G protein becomes activated, which leads to formation of the second messenger, cAMP.

• The cAMP binds to ion channels, causing them to let in Na+.

• The change in Na+ ion concentration stimulates the neuron to send a signal to the brain.

Figure 15.14 A Signal Transduction Pathway Leads to the Opening of Ion Channels (Part 1)

Figure 15.14 A Signal Transduction Pathway Leads to the Opening of Ion Channels (Part 2)


• The effects of epinephrine on liver cells results in altered enzyme activity.

• The binding of epinephrine to a G protein-linked receptor results in synthesis of cAMP, which in turn initiates a series of kinase reactions.

• Two enzymes are altered:

Glycogen synthase is deactivated by phosphorylation.

Glycogen phosphorylase is activated, catalyzing the release of glucose molecules from glycogen.

Figure 15.15 A Cascade of Reactions Leads to Altered Enzyme Activity (Part 1)

Figure 15.15 A Cascade of Reactions Leads to Altered Enzyme Activity (Part 2)


• Plasma membrane receptors are involved in initiating a broad range of gene expression responses.

• Ras signaling pathways end in the nucleus where genes involved in cell division are transcribed.

• Steroid hormones bind to receptors in the cytoplasm, which then influence gene transcription.

• In plants, light activates phytochrome, which then binds to cytoplasmic regulatory proteins. These then move to the nucleus and influence genes that lead to synthesis of chloroplasts.

15 Direct Intercellular Communication

• Some cells send signals directly from their interior to the interior of adjacent cells.

• This transfer occurs by way of specialized structures called gap junctions in animal cells, and plasmodesmata in plant cells.


• Gap junctions permit metabolic cooperation among linked animal cells.

• Gap junctions are complexes of proteins that make channels, called connexons in adjacent cell membranes.

• The channel is large enough for small signal molecules and ions to pass.

• Signal molecules such as hormones and second messengers such as cAMP and PIP2 also can move through gap junctions.

Figure 15.16 Gap Junctions Connect Animal Cells


• Plant cells communicate through plasmodesmata, membrane-lined channels spanning the thick cell walls between adjacent cells.

• A tube called the desmotubule fills most of the channel; generally only small molecules move through.

• Plasmodesmata are important to C4 plants, helping them to move fixed carbon between mesophyll and bundle sheath cells.

• Plasmodesmata pore size can be regulated.

Figure 15.17 Plasmodesmata Connect Plant Cells

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Cell Signaling and Communication