Cell Communication and Signaling

Question 1

General: What is cell communication?

Answer 1

1. Unicellular organisms (such as bacteria and yeast) communicate with each other
   - mating in yeast
2. Cells within a multicellular organism also communicate with each other.
   - Communication between neurons

Question 2

Communication in unicellular organisms (mating in yeast)

Answer 2

1. Yeast have 2 sexes (mating types) - a and alpha- both of which are haploid cells
2. To mate, two sexes fuse and become a diploid cell
3. Cells of mating types “a” and alpha release “a” and alpha mating factors, respectively, which bind to specific receptors on cells of “opposite” sex
4. That is “a” cells bind alpha factor and alpha cells bind “a” factor. This binding causes the cells to fuse and form a diploid a/alpha cell
5. “a” and alpha factors are short peptides (12 amino acids)

Question 3

Local Communication

Answer 3

1. Occurs between cells that are close together
   - Paracrine: signals released into the extracellular fluid. Go to all cells, but are recognized only by specific cells that have receptors for the signal
   - Synaptic: signals released into a synapse (in nerve cells)
   - Direct contact: signals pass through intercellular connections or are transmitted by interactions of cell surface molecules (cell-cell recognition)

Question 4

Long distance communication

Answer 4

1. Occurs between cells that are far apart
   - Hormonal or endocrine: signals move a long distance through vascular system (hormones), or even through air (pheromones)

Question 5

Specificity of multicellular communication

Answer 5

1. Neurotransmitters go only to a specific cell. This prevents other cells from sensing the signal
2. Hormones reach most cells, but are recognized only by specific cells which have receptors to these hormones
3. In direct communication, molecules move to a specific cell or specific cells recognize each other using their membrane receptors.

Question 6

Three stages of cell signaling

Answer 6

1. Reception: cells detect an incoming signal which binds to a receptor molecule, thus the information carried by the signal is received by the cell.
   - Receptors are usually found on the cell surface, but can also be found within cells (in the nucleus)
2. Transduction: binding of signal to its receptor changes the receptor. This change begins a sequence of biochemical events (called pathway) that ends in cellular response. Thus the information carried by the signal is transduced into the cell.
3. Response: almost any cellular activity (growth, movement, synthesis of a molecule, or even death). Thus the cell responds to information.

Question 7

Signaling by epinephrine

Answer 7

Ex: stimulation of glycogen breakdown in skeletal muscles by the hormone epinephrine
- Must occur in the cell, not made in a lab setting. The process must include other molecules in the cell = signal transduction pathway

Question 8

Reception and receptor types

Answer 8

1. Signal binding to a receptor is specific (the receptor does not recognize any other signals)
   - Signals are called ligands - small molecules which bind specifically to larger ones (receptors)
   - Most receptors are membrane proteins (receptors for steroids, however, are often internal)

Question 9

Four Major Types of Receptors

Answer 9

1. G protein-linked (receptors for epinephrine, neurotransmitters, yeast mating factors)
2. Enzymes (tyrosine-kinase receptors)
3. Ligand-gated ion channels
4. Internal (steroid hormone receptors)

Question 10

G protein-linked receptor

Answer 10

1. G protein is inactive when bound to GDP
2. When signal binds to receptor, GDP is displaced by GTP. G protein is now active when bound to GTP. Conformational change in G protein causes its movement along membrane.
3. GTP hydrolysis by G protein which activates another enzyme

Question 11

Enzyme receptors

Answer 11

They have enzymatic activities themselves
- the tyrosine kinase receptor (receptor for growth factors)
- The extracellular part binds the ligan (signal)
- The intracellular part acts as an enzyme
(Compare to G protein-linked receptors, which do not have enzymatic activity, but are linked to enzymes)

Question 12

Tyrosine Kinase receptor

Answer 12

It is a protein kinase enzyme that phosphorylates (attaches a phosphate group) tyrosine residues within proteins

• The phosphate group comes from ATP
  1. Two subunits dimerize
  2. Two subunits phosphorylate each other
  3. Activation of TK receptor
  4. Activation of relay proteins

Question 13

Ligand-gated ion channel

Answer 13

Changes in concentration of ions such as Ca+, and Na+ affect the cell; for example by triggering electrical signals in the nervous system.

Question 14

Internal receptors

Answer 14

• If a signal can pass through the cell membrane, then there is no need for extracellular receptors
• Instead, the cell uses intracellular receptors to receive such signals
• These signals include hydrophobic molecules – such as steroids and thyroid hormones (lipids) of animals, and small gaseous molecules, such as ethylene and nitric oxide, in plants– that can diffuse into cells
  Ex:
  1. Testosterone is distributed through blood, and can enter all cells by diffusion
  2. However, only cells that have testosterone receptor inside can respond to the signal
  3. Activated receptor induces gene expression which leads to development of male sex characteristics

Question 15

Signal transduction pathways

Answer 15

• Membrane receptors: have a multi-step pathway, and must carry information from the outside of the cell to the inside.
• Internal receptors: can carry out the transduction themselves.

Question 16

Multi-step signal transduction pathways

Answer 16

1. Advantages:
   - Amplification of signal: one signal can transmit information to multiple molecules at each step
   - Regulation: more steps means more checkpoints to regulate the final response
2. Mechanism:
   - the signal causes conformational changes in cellular protein.

Question 17

Major Mechanism of signal transduction

Answer 17

The major mechanism of signal transduction is phosphorylation.
Protein kinase is an enzyme that transfers a phosphate group form ATP to a substrate protein. (Phosphate group can be removed from a protein by protein phosphatases)
Substrates include:
1. The protein kinase itself (autophosphorylation)
2. Other proteins

Question 18

Major protein kinases

Answer 18

Tyrosine kinase and serine/threonine kinase

Question 19

Phosphorylation cascade

Answer 19

• Cells have thousands of different protein kinases
• Different protein kinases can phosphorylate each other, regulating enzymatic activity: this is a phosphorylation cascade.
• The cascade can be inhibited by protein phosphatases which remove phosphate groups, inactivating the protein kinases. Thus is no signal is present, phosphatases turn the cascade off.

Question 20

Second messengers

Answer 20

Small molecules = second messengers (ions or water-soluble small molecules). Second messengers rapidly spreads inside the cell.

Question 21

Major second messengers

Answer 21

Ca 2+
Inositol triphosphate (IP3)
Diacyl glycerol (DAG)
Cyclic AMP (cAMP)
-These second messengers participate in signaling pathways initiated by G protein-linked receptors and tyrosine kinase receptors.

Question 22

Cyclic AMP

Answer 22

Adenosine triphosphate gets activated by signal binding to receptor to create adenosine monophosphate.
- Adenylyl cyclase is located in the cell membrane, and it is activated after signal binds to receptor activates G protein that activates adenylyl cyclase.

Question 23

Cholera

Answer 23

1. The bacterium binds to the lining of the small intestine
2. Then, the bacterium produces cholera toxin (an enzyme) that chemically alters the alpha subunit of a heteromeric G protein (which is made up of 3 subunits: alpha, beta, gamma) which is involved in a signaling pathway that results in secretion of water and sodium.
3. The G protein no longer hydrolyzes GTP, resulting in constant activation of adenylyl cyclase and cAMP production and continuous activation of the signaling pathway.
4. Continuous signaling leads to continuous secretion of water and salt into the gut which leads to diarrhea, dehydration, and often death.

Question 24

Ca2+ as Second messengers

Answer 24

1. Calcium ions - is an even more commonly used second messenger than cAMP; it functions as a second messenger in:
   - muscle contraction
   - Cell divisions
   - Secretion of many substances
   - Plant adaptation to cold and heat
   - Plant response to touching
2. Calcium ions function in signaling pathways mediated by both G protein-linked receptors and tyrosine kinases receptors
3. Normally Ca2+ outside the cell > Ca 2+ inside the cell
4. Ca 2+ in cytosol < Ca 2+ in ER &laquo_space;Ca 2+ outside

Question 25

How is Ca 2+ gradient maintained?

Answer 25

1. Ca 2+ pump operates constantly to move Ca 2+ to outside and into ER.
2. Operates when Ca 2+ rises inside; moves Ca 2+ to mitochondrion. Driven by proton force
3. Ca 2+ in cytosol &laquo_space;Ca 2+ in the ER &laquo_space;Ca 2+ outside.
4. Calcium pumps are needed to maintain these concentration gradients.

Question 26

Ca 2+ as second messenger

Answer 26

When signals transduction begins, Ca 2+ rises due to its release from the ER.

• Other messengers are involved as well (IP3 and DAG).
• IP3 and DAG are produced by the cleavage of a phospholipid PIP2
• In reality IP3 and DAG are second messengers, and Ca 2+ is a third messenger, but the term “second messenger” is used anyway.
• Ca 2+ binding protein (present at high levels: 1% of total protein in animal cells) It changes conformations and activates other proteins (phosphatases and kinases)

Question 27

IP3 to Ca2+ release

Answer 27

1. IP3 usually activates Ca 2+ channels to move Ca 2+ from the ER into the cytosol
2. Cytosolic Ca 2+ activates other protein components of transduction pathway either directly or via calmodulin.
3. DAG remains within the plasma membrane. It can also act as a 2nd messenger by activating protein kinase C (PKC).

Question 28

Cytoplasmic Response

Answer 28

• Regulates enzyme activity
• No effect on gene expression
• Ex: epinephrine induces glycogen breakdown in the liver.
• > happens in the cytoplasm; no genes are induced or repressed
• > involves many steps (cascade = signal amplification, about 100 million times)

Question 29

Nuclear Response

Answer 29

• Information is transmitted from the outside (signal) to the inside (cytosol, then nucleus) and causes a change in gene expression
• How changes in gene expression are caused:
• > Special regulators (transcription factors = inducers/repressors) are turned on/off
• > New proteins are made (induction) or some proteins are no longer made (repression)
• > Nuclear responses are typical of hormones or growth factors.

Question 30

Specificity of Cell Signaling

Answer 30

1. Some signals should activate only specific cells/pathways
   - Cells have specific “collections” of receptors on their surface
   - Cells have specific “collections” of relay proteins inside
2. Some signals should elicit multiple responses
   - the transduction pathway branches
3. Sometimes different signals need to elicit the same response
   - Transduction pathways “cross talk”