1. Cell Communication and Multicellularity

2. 7 Cell Communication and Multicellularity
7.1 What Are Signals, and How Do Cells Respond to Them?
7.2 How Do Signal Receptors Initiate a Cellular Response?
7.3 How Is the Response to a Signal Transduced through the Cell?
7.4 How Do Cells Change in Response to Signals?
7.5 How Do Cells in a Multicellular Organism Communicate Directly?

3. 7 Cell Communication and Multicellularity
In prairie voles, oxytocin and vasopressin released by brain cells bind to other brain cells and trigger life-long bonding and extensive care of offspring.
Opening Question:
Does oxytocin affect caring behavior in humans?

4. 7.1 What Are Signals, and How Do Cells Respond to Them?
All cells process information from the environment. The information can be a chemical or a physical stimulus, such as light. Signals can come from outside the organism or from neighboring cells.

5. 7.1 What Are Signals, and How Do Cells Respond to Them?
To respond to a signal, a cell must have a specific receptor that can detect it.
A signal transduction pathway is the sequence of events that lead to a cell’s response to a signal.

6. 7.1 What Are Signals, and How Do Cells Respond to Them?
In large multicellular organisms, signals reach target cells by diffusion or by circulation through the blood.
Chemical signals often in low concentrations.

7. 7.1 What Are Signals, and How Do Cells Respond to Them?
Autocrine signals affect the cells that made them.
Juxtacrine signals affect only adjacent cells.
Paracrine signals affect nearby cells.
Hormones travel to distant cells, usually via the circulatory system.

8. Figure 7.1 Chemical Signaling Systems
(A) A signal molecule can diffuse to and act on the cell that produces it, an adjacent cell, or a nearby cell. (B) Many signals act on distant cells and must be transported by the organism’s circulatory system.

9. 7.1 What Are Signals, and How Do Cells Respond to Them?
A signal transduction pathway involves a signal, a receptor, and responses.
Only cells with the necessary receptors can respond to a signal.
Responses may involve enzymes and transcription factors that are activated or inactivated to bring about the response.

10. Figure 7.2 A Signal Transduction Pathway
This general pathway is common to many cells and situations. The ultimate effects on the cell are either short-term or long-term molecular changes, or both.

11. 7.1 What Are Signals, and How Do Cells Respond to Them?
Crosstalk: signal transduction pathways can be interrelated.
Pathways can branch; one activated protein may activate multiple pathways.
Multiple pathways can converge on a single transcription factor.
One pathway may be activated while another is inhibited.

12. 7.2 How Do Signal Receptors Initiate a Cellular Response?
Receptor proteins have very specific binding sites for chemical signal molecules, or ligands.
Binding the ligand causes the receptor protein to change shape.
The binding is reversible and the ligand is not altered.

13. Figure 7.3 A Signal and Its Receptor
(A) The adenosine 2A receptor occurs in the human brain, where it is involved in inhibiting arousal. (B) Adenosine is the normal ligand for the receptor. Caffeine has a similar structure to that of adenosine and can act as an antagonist that binds the receptor and prevents its normal functioning.

14. 7.2 How Do Signal Receptors Initiate a Cellular Response?
Receptors (R) bind to their ligands (L) according to the law of mass action:
R + L ↔ RL
Binding and dissociation (de-binding) have rate constants (K1 and K2).

15. 7.2 How Do Signal Receptors Initiate a Cellular Response?
A rate constant relates the rate of a reaction to the concentration of the reactants:
Rate of binding = K1[R][L]
Rate of dissociation = K2[R][L]

16. 7.2 How Do Signal Receptors Initiate a Cellular Response?
At equilibrium, the rate of binding equals the rate of dissociation:
K1[R][L] = K2[R][L] or

17. 7.2 How Do Signal Receptors Initiate a Cellular Response?
KD is the dissociation constant, a measure of the affinity of the receptor for its ligand. The lower the KD, the higher the binding ability of the ligand and receptor. Very low KD values allow receptors to bind their ligands at very low ligand concentrations.

18. 7.2 How Do Signal Receptors Initiate a Cellular Response?
Many drugs function as ligands. The KD value of a drug’s binding can be taken into consideration when determining dosage levels.

19. 7.2 How Do Signal Receptors Initiate a Cellular Response?
Inhibitors (or antagonists) can also bind to receptor proteins.
Caffeine is similar to adenosine and binds to the same receptors. Adenosine initiates a signal transduction pathway in nerve cells that reduces brain activity.
Caffeine “ties up” the adenosine receptors, allowing continued nerve cell activity.

20. Figure 7.3 A Signal and Its Receptor
(A) The adenosine 2A receptor occurs in the human brain, where it is involved in inhibiting arousal. (B) Adenosine is the normal ligand for the receptor. Caffeine has a similar structure to that of adenosine and can act as an antagonist that binds the receptor and prevents its normal functioning.

21. 7.2 How Do Signal Receptors Initiate a Cellular Response?
Receptors can be located in the cytoplasm or in the cell membrane.
Intracellular receptors: Small or nonpolar ligands can diffuse across the cell membrane (e.g., estrogen).
Membrane receptors: Large or polar ligands bind to cell membrane receptors (e.g., insulin).

22. Figure 7.4 Two Locations for Receptors
Receptors can be located inside the cell (in the cytoplasm or nucleus) or in the plasma membrane.

23. 7.2 How Do Signal Receptors Initiate a Cellular Response?
Types of plasma membrane receptors in eukaryotes:
Ion channels
Protein kinase receptors
G protein-linked receptors

24. 7.2 How Do Signal Receptors Initiate a Cellular Response?
Ion channel receptors: Channel proteins that allow ions to enter or leave a cell.
Signals can be chemical ligands such as hormones, sensory stimuli such as light, or electric charge differences.
The acetylcholine receptor on muscle cells is a gated ion channel.

25. Figure 7.5 A Gated Ion Channel
The acetylcholine receptor (AChR) is a ligand-gated ion channel for sodium ions. It is made up of five polypeptide subunits. When acetylcholine molecules (ACh) bind to two of the subunits, the gate opens and Na+ flows into the cell. This channel helps regulate membrane polarity (see Chapter 45).

26. 7.2 How Do Signal Receptors Initiate a Cellular Response?
Protein kinase receptors:
Some receptors become protein kinases—they catalyze phosphorylation of themselves and/or other proteins.
The insulin receptor phosphorylates itself and other insulin response substrates, which initiates insertion of glucose transporters into the plasma membrane.

27. Figure 7.6 A Protein Kinase Receptor
The mammalian hormone insulin binds to a receptor on the outside surface of the cell and initiates a response.

28. 7.2 How Do Signal Receptors Initiate a Cellular Response?
G protein-linked receptors: Ligand binding changes the shape of the cytoplasmic region, which binds to a G protein.
G proteins: Mobile membrane proteins with three subunits. They bind GDP (guanosine diphosphate) and GTP (guanosine triphosphate).

29. Figure 7.7 A G Protein-Linked Receptor
The G protein is an intermediary between the receptor and its effector.

30. 7.2 How Do Signal Receptors Initiate a Cellular Response?
GTP-subunit separates from G protein and moves through plasma membrane until it encounters an effector protein.
Binding activates the effector, which causes a change in cell function.
GTP is hydrolyzed to GDP.

31. 7.2 How Do Signal Receptors Initiate a Cellular Response?
Intracellular receptors respond to physical signals such as light or chemicals that can cross the cell membrane. Many are transcription factors. After binding their ligands, they move to the nucleus, bind to DNA, and alter gene expression.

32. Figure 7.8 An Intracellular Receptor
The receptor for cortisol is in the cytoplasm bound to a chaperone protein that is released when cortisol binds to the receptor.

33. 7.3 How Is the Response to a Signal Transduced through the Cell?
Signals sometimes initiate a chain or cascade of events. Thus, the initial signal can be amplified and distributed and result in several different responses.

34. 7.3 How Is the Response to a Signal Transduced through the Cell?
Protein kinase receptors bind signals called growth factors that stimulate cell division. One signal transduction pathway was worked out using bladder cancer cells.

35. 7.3 How Is the Response to a Signal Transduced through the Cell?
Bladder cancer cells have an abnormal form of a G protein called Ras. The protein is permanently bound to GTP, causing continuous cell division. If the abnormal Ras is inhibited, the cells stop dividing. This led to the development of Ras inhibitors for cancer treatment.

36. Figure 7.9 Signal Transduction and Cancer
(A) Ras is a G protein that regulates cell division. (B) In some tumors, the Ras protein is permanently active, resulting in uncontrolled cell division.

37. 7.3 How Is the Response to a Signal Transduced through the Cell?
Other cancers have abnormalities in other parts of signal transduction pathways. By comparing defective and normal cells, complete signaling pathways have been worked out.

38. 7.3 How Is the Response to a Signal Transduced through the Cell?
A protein kinase cascade is a pathway in which one protein kinase activates the next, and so on.

39. Figure 7.10 A Protein Kinase Cascade
In a protein kinase cascade, a series of proteins are sequentially activated.

40. 7.3 How Is the Response to a Signal Transduced through the Cell?
In a protein kinase cascade:
The signal is amplified at each step.
Information that arrived at the plasma membrane is communicated to the nucleus.
Multiple steps provide specificity.
Different target proteins provide variation in the response.

41. 7.3 How Is the Response to a Signal Transduced through the Cell?
Some signal transduction pathways include small non-protein molecules called second messengers that mediate some steps. They were discovered in research on the liver enzyme glycogen phosphorylase, which is activated by epinephrine.

42. Figure 7.11 The Discovery of a Second Messenger (Part 1)
Glycogen phosphorylase is activated in liver cells after epinephrine binds to a membrane receptor. Sutherland and his colleagues observed that this activation could occur in vitro only if fragments of the plasma membrane were present. They designed experiments to show that a second messenger caused the activation of glycogen phosphorylase.

43. Figure 7.11 The Discovery of a Second Messenger (Part 2)
Glycogen phosphorylase is activated in liver cells after epinephrine binds to a membrane receptor. Sutherland and his colleagues observed that this activation could occur in vitro only if fragments of the plasma membrane were present. They designed experiments to show that a second messenger caused the activation of glycogen phosphorylase.

44. Working with Data 7.1: The Discovery of a Second Messenger
Experiments showed that glycogen phosphorylase could only be activated by epinephrine when the entire contents of liver cells were present. Hypothesis: a cytoplasmic messenger must transmit the message from the epinephrine receptor at the membrane to glycogen phosphorylase in the cytoplasm.

45. Working with Data 7.1: The Discovery of a Second Messenger
Glycogen phosphorylase activity was measured in liver cell fractions, with or without incubation with epinephrine.

46. Working with Data 7.1: The Discovery of a Second Messenger
Question 1: As part of Sutherland’s research, the activity of glycogen phosphorylase was measured in various liver cell fractions, with or without incubation with epinephrine. The table shows the results. Explain how these data support the hypothesis that there is a soluble second messenger that activates the enzyme.

47. Working with Data 7.1: The Discovery of a Second Messenger
Question 2: Propose an experiment to test whether the factor (second messenger) that activates the enzyme is stable on heating (and therefore probably not a protein), and give predicted data.

48. Working with Data 7.1: The Discovery of a Second Messenger
Question 3: The second messenger, cAMP, was purified from the hormone-treated membrane fraction. Propose experiments to show that cAMP could replace the membrane fraction and hormone treatment in the activation of glycogen phosphorylase, and create a table to show possible results.

49. 7.3 How Is the Response to a Signal Transduced through the Cell?
These experiments confirmed a second messenger—cyclic AMP (cAMP). cAMP is produced from ATP by the enzyme adenylyl cyclase. Adenylyl cyclase is activated via a G protein-linked epinephrine receptor.

50. Figure 7.12 The Formation of Cyclic AMP
The formation of cAMP from ATP is catalyzed by adenylyl cyclase, an enzyme that is activated by G proteins.

51. 7.3 How Is the Response to a Signal Transduced through the Cell?
Second messengers serve to amplify and distribute the signal. Binding of one epinephrine molecule leads to production of many of cAMP. The cAMP molecules activate many enzyme targets.

52. 7.3 How Is the Response to a Signal Transduced through the Cell?
Second messengers are also involved in crosstalk.

53. 7.3 How Is the Response to a Signal Transduced through the Cell?
Other second messengers are formed when phospholipids in the plasma membrane are hydrolyzed by phospholipases.
Example: hydrolysis of PIP2 (phosphatidyl inositol- bisphosphate)

54. 7.3 How Is the Response to a Signal Transduced through the Cell?
PIP2:
Hydrophobic portion is diacylglycerol (DAG) embedded in plasma membrane.
Hydrophilic portion is inositol triphosphate (IP3) projecting into cytoplasm.
PIP2 is hydrolyzed by phospholipase C.

55. Figure 7.13 The IP3/DAG Second-Messenger System
Phospholipase C hydrolyzes the phospholipid PIP2 into its components, IP3 and DAG, both of which are second messengers. Lithium ions (Li+) block this pathway and are used to treat bipolar disorder (red type).

56. 7.3 How Is the Response to a Signal Transduced through the Cell?
IP3 and DAG are both second messengers that activate protein kinase C (PKC). PKC is a family of protein kinases that can phosphorylate many proteins, leading to a variety of cell responses.

57. 7.3 How Is the Response to a Signal Transduced through the Cell?
An overactive IP3/DAG signal transduction pathway in the brain leads to excessive brain activity in bipolar disorder. Lithium ions (Li+) inhibit G protein activation of phospholipase C and synthesis of IP3.

58. 7.3 How Is the Response to a Signal Transduced through the Cell?
Low Ca2+ concentrations in the cytoplasm are maintained by active transport proteins at plasma and ER membranes. IP3 and other signals can open Ca2+ channels and Ca2+ concentrations in the cytoplasm increase rapidly. Entry of a sperm into an egg cell also opens Ca2+ channels.

59. Figure 7.14 Calcium Ions as Second Messengers
The concentration of Ca2+ can be measured using a dye that fluoresces when it binds the ion. Here, fertilization in a starfish egg causes a rush of Ca2+ from the environment into the cytoplasm. Areas of high Ca2+ concentration are indicated by the red color, and the events are photographed at 5-second intervals. Calcium signaling occurs in virtually all animal groups and triggers cell division in fertilized eggs, initiating the development of new individuals.

60. 7.3 How Is the Response to a Signal Transduced through the Cell?
Ca2+ acts as a second messenger. It activates protein kinase C, controls other channels, and stimulates secretion by exocytosis.

61. 7.3 How Is the Response to a Signal Transduced through the Cell?
Nitric oxide (NO) gas is a second messenger between acetylcholine (a neurotransmitter) and the relaxation of smooth muscle in blood vessels, allowing more blood flow. Binding of acetylcholine to a receptor releases IP3, which opens Ca2+ channels.

62. 7.3 How Is the Response to a Signal Transduced through the Cell?
The influx of Ca2+ activates NO synthase, which catalyzes production of NO from arginine. NO diffuses to nearby smooth muscle cells where it stimulates synthesis of cGMP, another second messenger.

63. 7.3 How Is the Response to a Signal Transduced through the Cell?
Signal transduction is highly regulated. Concentration of NO is regulated by how much is made. Concentration of Ca2+ depends on activity of membrane pumps and ion channels.

64. 7.3 How Is the Response to a Signal Transduced through the Cell?
Protein kinases, G proteins, and cAMP are regulated by enzymes that convert the activated form back to inactive form. The balance between enzymes that activate and enzymes that inactivate transducers determines the cellular response to a signal.

65. Figure 7.16 Regulation of Signal Transduction
Some signals lead to the production of active transducers such as (A) protein kinases, (B) G proteins, and (C) cAMP. Other enzymes (shown in red) inactivate or remove these transducers.

66. 7.3 How Is the Response to a Signal Transduced through the Cell?
Cells can alter the balance by:
Synthesis or breakdown of the enzymes
Activation or inhibition of the enzymes by other molecules

67. 7.4 How Do Cells Change in Response to Signals?
Effects of signals:
Opening ion channels
Changing enzyme activity
Differential gene expression

68. 7.4 How Do Cells Change in Response to Signals?
Ion channels:
Ion channels can function as receptors and other components of signal transduction pathways.
Sometimes the opening of an ion channel is itself the response to a signal.

69. 7.4 How Do Cells Change in Response to Signals?
Sensory cells have receptors that respond to external stimuli such as light, sound, taste, odor, or pressure. Alteration of the receptor results in the opening of ion channels.

70. Figure 7.17 A Signal Transduction Pathway Leads to the Opening of Ion Channels (Part 1)
The signal transduction pathway triggered by odorant molecules in the nose results in the opening of ion channels. The resulting influx of Na+ and Ca2+ into the neuron cells of the nose stimulates the transmission of a scent message to a specific region of the brain.

71. Figure 7.17 A Signal Transduction Pathway Leads to the Opening of Ion Channels (Part 2)
The signal transduction pathway triggered by odorant molecules in the nose results in the opening of ion channels. The resulting influx of Na+ and Ca2+ into the neuron cells of the nose stimulates the transmission of a scent message to a specific region of the brain.

72. Figure 7.17 A Signal Transduction Pathway Leads to the Opening of Ion Channels (Part 3)
The signal transduction pathway triggered by odorant molecules in the nose results in the opening of ion channels. The resulting influx of Na+ and Ca2+ into the neuron cells of the nose stimulates the transmission of a scent message to a specific region of the brain.

73. Figure 7.17 A Signal Transduction Pathway Leads to the Opening of Ion Channels (Part 4)
The signal transduction pathway triggered by odorant molecules in the nose results in the opening of ion channels. The resulting influx of Na+ and Ca2+ into the neuron cells of the nose stimulates the transmission of a scent message to a specific region of the brain.

74. 7.4 How Do Cells Change in Response to Signals?
Enzyme activities:
Covalent bonding of a phosphate group by a protein kinase changes the enzyme’s shape.
cAMP binds noncovalently to enzymes to change their shapes.
In both, an active site is exposed, and the enzyme catalyzes new reactions.

75. 7.4 How Do Cells Change in Response to Signals?
In the protein kinase cascade in liver cells stimulated by epinephrine, two enzymes are phosphorylated:
1. Glycogen synthase is inhibited— preventing glucose from being stored as glycogen.

76. 7.4 How Do Cells Change in Response to Signals?
2. Phosphorylase kinase is activated—stimulating a protein kinase cascade. Activation of glycogen phosphorylase catalyzes break down of glycogen to glucose.
Both events lead to more glucose available for “flight or fight” response.

77. Figure 7.18 A Cascade of Reactions Leads to Altered Enzyme Activity (Part 1)
Liver cells respond to epinephrine by activating G proteins, which in turn activate the synthesis of the second messenger cAMP. Cyclic AMP initiates a protein kinase cascade, greatly amplifying the epinephrine signal, as indicated by the blue numbers. The cascade both inhibits the conversion of glucose to glycogen and stimulates the release of previously stored glucose.

78. Figure 7.18 A Cascade of Reactions Leads to Altered Enzyme Activity (Part 2)
Liver cells respond to epinephrine by activating G proteins, which in turn activate the synthesis of the second messenger cAMP. Cyclic AMP initiates a protein kinase cascade, greatly amplifying the epinephrine signal, as indicated by the blue numbers. The cascade both inhibits the conversion of glucose to glycogen and stimulates the release of previously stored glucose.

79. 7.4 How Do Cells Change in Response to Signals?
The signal is amplified in this pathway. For each molecule of epinephrine that arrives at the plasma membrane, 10,000 molecules of blood glucose result.

80. 7.4 How Do Cells Change in Response to Signals?
Gene expression:
Signal transduction plays an important role in determining which DNA sequences are transcribed.
For example: In the Ras signaling pathway, the final protein kinase, MAPK, enters the nucleus and stimulates transcription of genes for cell division.

81. 7.5 How Do Cells in a Multicellular Organism Communicate Directly?
Cells within a tissue can communicate directly via specialized intercellular junctions:
Gap junctions in animals
Plasmodesmata in plants

82. 7.5 How Do Cells in a Multicellular Organism Communicate Directly?
Gap junctions: channels between adjacent cells traversed by proteins called connexons:
Connexons of two cells come together to form a channel only nm wide.
Too small for proteins, but wide enough for small molecules and ions.

83. Figure 7.19 Communicating Junctions (Part 1)
(A) An animal cell may contain hundreds of gap junctions connecting it to neighboring cells. The pores of gap junctions allow small molecules to pass from cell to cell, ensuring similar concentrations of important signaling molecules in adjacent cells so that the cells can coordinate their activities. (B) Plasmodesmata connect plant cells. The desmotubule, derived from the smooth endoplasmic reticulum, fills up most of the space inside a plasmodesma, leaving a tiny gap through which small metabolites and ions can pass.

84. 7.5 How Do Cells in a Multicellular Organism Communicate Directly?
In some tissues, chemicals must be passed to cells in the interior of the tissue.
Example: Lens cells of mammalian eyes have many gap junctions. Only cells at periphery are close to blood vessels.

85. 7.5 How Do Cells in a Multicellular Organism Communicate Directly?
Some hormones and second messengers can pass through gap junctions. Only a few cells would need to have signal receptors, as the signal can spread through entire tissue for a coordinated response.

86. 7.5 How Do Cells in a Multicellular Organism Communicate Directly?
Plant cells have several thousand plasmodesmata (tunnels) that traverse the cell walls. The lining is the fused plasma membranes from both cells. A tubule, the desmotubule, derived from the ER, fills the space in the plasmodesmata channels.

87. Figure 7.19 Communicating Junctions (Part 2)
(A) An animal cell may contain hundreds of gap junctions connecting it to neighboring cells. The pores of gap junctions allow small molecules to pass from cell to cell, ensuring similar concentrations of important signaling molecules in adjacent cells so that the cells can coordinate their activities. (B) Plasmodesmata connect plant cells. The desmotubule, derived from the smooth endoplasmic reticulum, fills up most of the space inside a plasmodesma, leaving a tiny gap through which small metabolites and ions can pass.

88. 7.5 How Do Cells in a Multicellular Organism Communicate Directly?
Plasmodesmata are important in circulation of materials—similar in function to capillaries in animals. Plants rely on rapid diffusion of hormones through plasmodesmata to ensure that all cells respond to a signal at the same time.

89. 7.5 How Do Cells in a Multicellular Organism Communicate Directly?
Some larger molecules and particles can pass through plasmodesmata. Plant viruses can move through plasmodesmata by making “movement proteins” to assist their passage.

90. 7.5 How Do Cells in a Multicellular Organism Communicate Directly?
Evolution from single-celled to multi- cellular organisms took up to a billion years and probably occurred in steps:
Aggregation of cells into a cluster
Intercellular communication
Specialization of some cells
Organization of specialized cells into tissues

91. 7.5 How Do Cells in a Multicellular Organism Communicate Directly?
The “Volvocine line” of aquatic green algae (Chlorophyta) illustrates how multicellularity might have evolved. They range from single-celled Chlamydomonas, to clusters of increasing numbers of cells.

92. Figure 7.20 Multicellularity
The evolution of intercellular interactions in a multicellular organism can be inferred from these green algae.

93. 7.5 How Do Cells in a Multicellular Organism Communicate Directly?
Volvox has 1,000 cells, with somatic and reproductive cells in separate tissues. An intercellular signaling mechanism coordinates the activities of the separate tissues within the organism.

94. 7 Answer to Opening Question
Oxytocin is released during sexual activity in humans and results in bonding behaviors. Experiments have shown that oxytocin affects other human behaviors as well, such as trust.