Summary of Chapter 11, BIOLOGY, 11TH ED Campbell, by J.B. Reece Et Al. 2014

Chapter 11CELL COMMUNICATION

Summary of Chapter 11, BIOLOGY, 11TH ED Campbell, by J.B. Reece et al. 2014.

Cell-to-cell communication is essential in multicellular organisms.

Cells must communicate in order to coordinate their activities in order to develop, grow and reproduce.

Apoptosis integrates input from many signaling pathways and causes cell death.

CONCPET I. EXTERNAL SIGNALS ARE CONVERTED TO RESPONSES WITHIN THE CELL.

1. EVOLUTION OF CELL SIGNALLING

The example of yeast.

Yeast has two sexes or mating types called a and α.

Cells of type a secrete a signal called the a factor; those of type α secrete a signal called the α

factor.

Each factor is secreted to the environment and binds to receptors on the other cell type, e. g. a type cells have receptors for α factors and vice versa.

This causes the cells to move and grow towards one another and eventually fuse. The new cell has now all the genes of both parents, a combination that provides greater advantage of adaptation.

The process by which a signal on a cell's surface is converted to a specific response is a series of steps called signal-transduction pathway.

2. LOCAL AND LONG-DISTANCE SIGNALING.

1) Paracrine signaling: The signals are molecules secreted by a cell called local regulators. These local regulators influence cells in the vicinity. These chemical signals are released into the extracellular fluid and adjacent cells respond to a local regulator. The influenced, responding cells are called target cells.

2) Synaptic signaling: a nerve cell releases neurotransmitter molecules into a synapse, the narrow space between the transmitting nerve cell and the target cell.

3) Endocrine or Hormonal signaling: Is a long distance signaling. The specialized secreting cells, endocrine cells, release the chemical signals or regulators into the blood, which distributes the hormones throughout the body.

Animal and plant cells have cell junctions and plasmodesmata that allow direct communication between adjacent cells by letting signals flow from one cell to the next through these channels.

The target cell must have the proper type of receptors in order to recognize the signal.

3. STAGES IN CELL SIGNALING: A PREVIEW

Receptors are located in the plasma membrane of the target cells.

When reception occurs at the plasma membrane, a pathway of several steps is initiated, which brings a change in a molecule which in turn causes a change in an adjacent molecule and so on. The last molecule in the sequence brings about the response.

1) Reception: the signal molecule binds to an integral protein in the plasma membrane.

2) Transduction: the binding of the signal causes a configurational change in the membrane protein, which initiates the process. Transduction can occur in one step or several steps. The intermediate molecules in the transduction pathway are called relay molecules.

3) Response: in the final stage, an enzyme is activated that causes a response. The response could the catalysis of a reaction, the rearrangement of the cytoskeleton or the activation of a gene.

CONCEPT II. RECEPTION: A SIGNALING MOLECULE BINDS TO A RECEPTOR PROTEIN, CAUSING IT TO CHANGE SHAPE.

The signal protein matches the shape of a specific site on the receptor protein.

The signal protein acts as a ligand, a small protein that specifically binds to a large one.

The binding of the signal protein causes a conformational change in the receptor protein, which in turn can now activate another molecule.

Most signal proteins are water soluble and too large to pass through the plasma membrane.

A. Receptors in the plasma membrane

Most signal receptors are plasma membrane proteins.

These receptors transmit information from the extracellular environment to the inside of the cell by changing shape or aggregating when a specific ligand binds to it.

G-proteins are guanine nucleotide binding proteins. They are peripheral proteins that arebound to a transmembrane protein or attached to the membrane.

1. G-protein-linked receptors

a. The G-protein-coupled receptors are plasma membrane receptor proteins that work with the help of protein called the G proteins.

These receptor proteins have signal-binding sites facing the extracellular fluid, and G-binding sites facing the cytosol.

The G protein is inactive when the nucleotide guanosine diphosphate, GDP, is attached and active when the guanosine triphosphate, GTP, is attached.

• Remember that guanine is nitrogenous base also found in nucleic acids.

When the signal ligand binds to the extracellular site of the receptor protein, it changes shape and its cytoplasmic side binds to an inactive G protein.

b. When the appropriate signaling molecule binds to the extracellular side of the receptor, the receptor is activated and changes shape.

• The G protein is inactive when bound to GDP. When the G protein binds to the receptor, the G protein then releases the attached GDP, which is replace by a GTP from the cytosol, and becomes activated.

c. The active G protein travels through the plasma membrane and binds to and activates an enzyme.

d. The active enzyme triggers the next step in the pathway, and GTP hydrolyses a phosphate and returns to the inactive GDP.

All these changes occur in the plasma membrane.

GPCR-based signaling systems are very widespread and diverse in their functions.

Similarities in the structure of G proteins and GPCR in diverse organism suggests that these proteins and their receptors evolved very early among eukaryotes.

See page 215.

1. Tyrosine-kinase receptors (RTKs)

RTKs are transmembrane proteins that have enzymatic activity.

A receptor tyrosine kinase (RTKs) can trigger more than one signal transduction pathway at once, helping the cell regulate and coordinate many aspects of cell growth and reproduction.

• A kinase is an enzyme that catalyses the transfer of phosphate groups.

a. Tyrosine kinase receptors are transmembrane proteins consisting of an extracellular signal (ligand) binding site, a transmembrane α helix and an intracellular tail containing many tyrosines, an amino acid.

The cytoplasmic portion of the receptor functions as the enzyme tyrosine kinase.

In the absence of a signal, tyrosine-kinase receptors exist as single polypeptides in the plasma membrane referred to as monomers. These monomers are inactive.

b. The receptor is activated in two steps:

• The ligand binding causes the receptor polypeptides to aggregate and form a dimer.
• The aggregation causes the activation of the tyrosine-kinase part of both polypeptides by adding phosphates to the tyrosine AAs on the tail of the polypeptides.
• ATP supplies the phosphates.

c. Relay proteins in the cytoplasm of the cell recognize and bind to the activated tyrosine kinases, and become activated in turn.

One dimer may activate ten or more relay proteins. The relay proteins may or may not become phosphorylated.

d. The activated relay proteins in turn trigger many transduction pathways and responses.

1. Ligand-gated ion channel receptors

a. Ion channels are transmembrane proteins that open forming pores that allow the flow of a specific kind of ion across the membrane.

When a ligand binds to the ligand-gated ion-channel receptor protein, the gated channel opens.

b. The ligand-gated ion-channel receptors change their configuration and open or close in response to a specific signal.

This response of the channel protein leads to change in the ion concentration inside the cell.

At a synapse between nerve cells, the ion concentration may trigger an electrical signal that is propagated down the receiving cell.

c. When the ligand dissociates from the ligand-gated ion-channel receptors, the gate closes and ions cannot longer enter the cell.

B. Intracellular receptors

Some signal receptors are proteins found in the cytosol or in the nucleus of target cells.

To reach these receptors, a signaling molecule must pass through the plasma membrane of the target cell.

Small or hydrophobic signal molecules can pass through the plasma membrane.

Steroid and thyroid hormones are small hydrophobic lipid soluble hormones that pass through the plasma membrane.

Nitric oxide (NO) is very small molecule that can readily pass through the plasma membrane.

The hormone binds to an intracellular receptor protein in the cytosol and activates it.

The hormone-receptor complex enters the nucleus and binds to specific genes.

Genes are activated and messenger RNA is synthesized.

mRNA codes for a protein that causes changes in the body.

mRNA is translated into a specific protein.

See the example of the steroid hormone aldosterone on page 218.

CONCEPT III. SIGNAL TRANSDUCTION

Cascades of molecular interactions relay signals from receptors to target molecules in the cell

1. Signal Transduction Pathways

The binding of a specific signaling molecule to a receptor in the plasma membrane triggers the first step in the chain of molecular interactions – the signal transduction pathway.

• A domino effect or a cascade of molecular interactions

At each step in a pathway, the signal is transduced into a different form, commonly a conformational change in a protein.

2. Protein Phosphorylation and Dephosphorylation

The addition of a phosphate in order to activate an enzyme is a widespread mechanism in regulating protein activity.

The general name of an enzyme that transfers phosphate groups from ATP to a protein is protein kinase.

Most cytoplasmic protein kinases act on substrate molecules different from themselves.

Most kinases phosphorylate their substrate on either of two amino acids, serine or threonine.

Many of the relay protein in the signaling pathway are protein kinases, and often act on other protein kinases along the pathway.

The addition of a phosphate changes the protein from inactive to active.

Activation is always associated with change in conformation.

A cascade of protein phosphorylation transmits the signal.

In a phosphorylation cascade, a series of different proteins in a pathway are phosphorylated in turn, each protein adding a phosphate group to the next one in line.

Each phosphorylation causes a conformational change that brings about the next phosphorylation and change inactivity.

At the end of the cascade, a protein is activated that brings about the response.

Protein phosphatases remove phosphate, dephosphorylation, groups from active proteins making them available for reuse.

See Fig. 11.10, p. 219.

2. Small Molecules and Ions as Second Messenger

May signaling pathways also involve small, no-protein, water-soluble molecules or ions called second messengers.

The extracellular signal is the "first messenger."

First messenger (signal) combines with receptors on the plasma membrane of the target cell.

A. Cyclic AMP

The plasma membrane has G-protein linked receptors.

Steps:

1. The first messenger activates a G-protein linked receptor

2. G-protein linked receptor activates a G protein in turn..

3. G protein releases GDP and then binds with GTP.

4. Binding GTP produces a conformational change in the G protein and binds it to adenylyl cyclase, an enzyme embedded in the plasma membrane.

- Another external signal is epinephrine.

5. The activated adenylyl cyclase catalyzes the conversion of ATP to cyclic AMP (cAMP) a secondary messenger.

- The phosphate group in cAMP is attached to both the 5’ and the 3’ carbons of the ribose.

6. Cyclic AMP (cAMP) activates one or more enzymes (protein kinases) in the cytosol that alter the activity of the cell.

7. Protein kinases phosphorylate a specific protein.

These activated proteins then trigger a chain reaction leading to a metabolic effect, a cellular response.

In the absence of a signal, e.g. epinephrine, Cyclic AMP is quickly converted to AMP by the enzyme phosphodiesterase. This happens very quickly.

There are G-protein systems that inhibit rather than activate adenylyl cyclase in the plasma membrane.

A signal molecule activates a different receptor that in turns activates an inhibitory G protein.

Cholera:

• The cholera bacterium forms a biofilm on the lining of the intestine and produces a toxin, an enzyme that modifies the G proteins that regulates the secretion of water and salts into the intestine.
• The modified G protein is unable to hydrolyze the GTP into GDP and phosphate, it remains stuck in its active form and continues to produce camp.
• The large concentration of cADP causes the cells to secrete large amounts of water and salts into the intestine.
• This results in diarrhea and dehydration followed by death if left untreated.

Check fig. 11.11, p. 220, and fig. 11.12, p. 221.

B. Calcium ions and inositol triphosphate, IP3.

Cytosolic Ca2+ concentration is increase by several signals like neurotransmitters, some hormones, and growth factors.

Ca2+ is a common second messenger. Increasing the concentration of Ca2+ brings about many cell responses, e. g. muscle contraction, cell division and secretion of certain substances in animals; greening in response to light, in plants.

Ca2+ is used as a second messenger in G-protein pathways and tyrosine pathways.

The concentration of Ca2+ is much lower in the cytosol than in the extracellular environment of the cell.

Ca2+ are actively concentrated in the ER and sometimes into the mitochondria and chloroplasts.

1. Signaling molecules bind to receptors, leading to activation of phospholipase C.

• Hormone-receptor complex activates the G-protein.
• G-proteins then activate the membrane bound enzyme phospholipase C.

2. Phospholipase C splits the phospholipid PIP2 into IP3 (inositol triphosphate) and DAG (diacylglycerol). Both act as second messengers.

3. IP3 stimulates the ER to release calcium, which combines with calmodulin in the cytosol of the cell.

• IP3 quickly diffuses through the cytosol and binds to an IP3-gated calcium channel in the ER membrane, causing it to open.
• DAG is the second messenger of other pathways.

4. Ca2+ ions flow out of the ER, down their concentration gradient, raising the Ca2+ level in the cytosol.

5. Calmodulin-Ca complex stimulates protein kinase C to phosphorylate certain proteins.

• Calcium is a third messenger in this case.

In summary: Ca2+ and inositol triphosphate, IP3.

• When a hormone binds to a receptor, Ca2+ channels open and calcium ions move into the cell.
• Certain receptors are linked by a G protein to calcium ion channels.
• Calcium in the cell binds to the protein calmodulin and changes conformation.
• The activated calmodulin then activates certain enzymes.

ANOTHER EXPLANATION.

Phospholipase C Pathway

Phospholipase C cleaving PIP2 into IP3 and DAG

Specific signals can trigger a sudden increase in the cytoplasmic Ca2+ level up to 500–1,000 nM by opening channels in the endoplasmic reticulum or the plasma membrane. The most common signaling pathway that increases cytoplasmic calcium concentration is the phospholipase C pathway.

• Many cell surface receptors, including G protein-coupled receptors and receptor tyrosine kinases activate the phospholipase C (PLC) enzyme.
• PLC hydrolyses the membrane phospholipid PIP2 to form IP3 and diacylglycerol (DAG), two classical second messengers.
• DAG recruits protein kinase C (PKC), attaching it to the plasma membrane
• IP3 diffuses to the endoplasmic reticulum, and binds to an IP3 receptor,
• The IP3 receptor serves as a Ca2+ channel, and releases Ca2+ from the endoplasmic reticulum.
• The Ca2+ ions bind to PKC, activating it.[2]

ROLES OF CALCIUM

“Important physiological roles for calcium signaling range widely. These include muscle contraction, neuronal transmission as in an excitatory synapse, cellular motility (including the movement of flagella and cilia), fertilization, cell growth or proliferation, learning and memory as with synaptic plasticity, and secretion of saliva.[6] High levels of cytoplasmic calcium can also cause the cell to undergo apoptosis.[7] Other biochemical roles of calcium include regulating enzyme activity, permeability of ion channels, activity of ion pumps, and components of the cytoskeleton.[8]”

6Berridge, Michael J.; Lipp, Peter; Bootman, Martin D. (October 2000). "The versatility and universality of calcium signalling". Nature Reviews Molecular Cell Biology 1 (1): 11–21.

7Joseph, Suresh K.; Hajnóczky, György (2007-02-06). "IP3 receptors in cell survival and apoptosis: Ca2+ release and beyond". Apoptosis 12 (5): 951–968.

8Koolman, Jan; Röhm, Klaus-Heinrich (2005). Color Atlas of Biochemistry. New York: Thieme.

See fig. 11.14, p. 222.

CONCEPT IV. RESPONSES TO SIGNALS

1. Nuclear and Cytoplasmic Responses.

Signal transduction leads to the regulation of transcription or cytoplasmic activities.

The response may occur in the cytoplasm or may involve action in the nucleus.

• Enzymatic activity
• Cytoskeleton rearrangement
• Gene activity and mRNA synthesis

Many signaling pathways regulate not the activity of the enzyme but the synthesis of the enzymes or other proteins by turning certain genes on or off.

The final activated molecule may function as a transcription factor that turns a gene on. This increases the production of mRNAs, which will be translated in the cytoplasm into specific proteins. See fig. 11.15, p. 223.

The activity of a protein may be regulated by directly affecting the protein that functions outside the nucleus.

Growth factors and certain animal and plant hormones regulate the activity of genes.

2. REGULATION AND RESPONSE

• Signaling pathways general amplify the cell’s response to a single signaling event.
• The many steps in a multistep pathway provide control points at which the cell’s response can be further regulated.
• Scaffolding proteins affect the overall efficiency of the response.
• The termination of the signal has to be regulated.

1. Signal amplification

Signal amplification occurs when in a cascading pathway, the number of activated molecules is much greater than in the previous step.

The activated proteins persist in their active form long enough to act on many substrate molecules before they become inactive. This has a multiplying effect at each step of the transduction process.

In this way, a small number of signal molecules, e.g. epinephrine, can lead to the release of hundreds of millions of molecules.

See fig. 11.16, p. 224.

2. Specificity of cell signaling

The particular combination of proteins in a cell gives the cell great specificity in both the signals it detects and the responses it carries out.

Cells in different tissues will respond or not to a particular signal molecule; cells in different tissues may respond to the same signal but the response is different in each tissue.

• Epinephrine causes the heart to contract and the liver to break down glycogen.

The response depends on the collection proteins found in each cell.

Two cells that respond differently to the same signal differ in one or more proteins that handle and respond to the signal.