1. Cell to Cell Communication

2. Cell Communication Introduction
A typical free-living cell must be able to
Sniff out nutrients
Sense the difference between light and dark
Detect and avoid poisons and predators
Example {Plants}
Respond to temperature, conditions of light and dark, guide the cycle of growth, flowering and fruiting
The cells must be able to communicate with each other

3. Other Reasons for Cell Communication
Provides long range integration of metabolism

4. Methods of Communication Private vs. Public
The message is sent out to the entire body
Private
Only a select few cells receive the message

5. Yeast Cells
When a yeast cell is ready to mate, it secretes a small protein called a mating factor to which other yeast cells are sensitive
They detect the mating factor
They put out a protrusion toward the source of the factor
Halt the cell cycle

6. Players of Cell Signaling
Signaling Cell
Cell sending the message
Target Cell
Cell receiving the message
Ligand
Molecule such as a hormone or a neurotransmitter what binds to a specific site on a protein
Receptor Protein*
Recognizes and responds specifically to the signal molecule
Performs the first step in a series of transduction processes at the receiving end

7. Target Cell Contain receptor proteins in the cell membrane
Recognizes and responds specifically to the signal molecule
Performs the first step in a series of transduction processes at the receiving end

8. Molecules Used As Signals
Proteins
Peptides
Amino Acids
Nucleotides
Steroids
Fatty Acid Derivatives
Dissolved Gases

9. Cell Signaling
Three Steps
Signal reception
Transduction
Response

10. Overview

11. Reception Cells are stimulated by an extracellular signal
Signal binds to, and activates, a receptor protein
Each receptor protein recognizes a specific signal molecule
Once signal is recognized, a new intracellular signal is generated.
This is the first step of transduction

12. Signal Transduction
In society, people use different techniques to transmit messages from one person to the next
Ink & paper
Telephone
Until eventually the signal is expressed in the brain in the form of nerve impulses

13. Signal Transduction
Like society, cells use different forms of signals to represent the same information
Nerve cell
Electrical impulse changes to neurotransmitter signal {chemical signal}
The process of changing signals conversion (information) from one form to the next is called signal transduction

14. Transduction Remember, signal transduction occurs after reception
The receptor protein must be activated.
Allows the message to be passed through the cell membrane
The message is then passed through a set of intracellular signaling molecules.

15. Signal Transduction

16. Public vs. Private Long Distance vs. Local
Amtrak vs. Tri-Rail
Signals can act over long or short ranges
Signals use include
Proteins, peptides, amino acids, nucleotides, steroids, fatty acid derivatives and even dissolved gases
But there are only a handful of basic styles of communication

17. Public & Long Distance Signal sent over the entire body
Signal secreted into the bloodstream of an animal or the sap of a plant
Signal secreted into the sap of a plant
Signal used is called a hormone
In animals, the cells that produce hormones are called endocrine cells
Hence the name of the body system known as the Endocrine System

18. Public and Short Distance
Paracrine Signaling
Signal molecules diffuse locally through the extracellular medium
Signal remains in the neighborhood of the cell that secretes them
Signal acts as local mediators
Regulate inflammation at sites of infection
Regulate cell proliferation in wound healing
Growth factors
Stimulate target cells to grow and multiply
The Immune System
Used in the healing process

19. Private & Long Distance Neuronal Signaling
Messages are delivered over long distances
Head to foot for example
Messages are delivered over private lines to individual cells very quickly (telephone call)

20. Private & Long Distance Neuronal Signaling II
Axon of a neuron, nerve cell, terminates at specialized junctions, synapses, on target cells far away from the neuronal cell body.
When activated by signals from the environment or from other nerve cells, the neuron sends electrical impulses along its axon at speeds up to 100 m/s.

21. Neuronal Signaling III
Signal reaches axon terminal
Intracellular electrical signals are converted into an extracellular chemical form
Electrical impulse stimulates the terminal to secrete a chemical signal known as a neurotransmitter
Neurotransmitter crosses a small gap between axon-terminal membrane and membrane of target cell
Occurs in less than a millisecond

22. Private & Short Distance Intimate Messaging
Most short range of all
Face to face conversation
No molecules are released
Different in comparison to the other three.
Cells make direct contact, through signaling molecules, in their plasma membrane
Message is delivered by the binding of a signal molecule anchored in the plasma membrane of the signaling cell to a receptor molecule embedded in the plasma membrane of the target cell
Cell to cell connection
Remember from Packet #12 the 6 functions of proteins found in the cell membrane

23. Private & Short Distance Intimate Messaging II
In embryonic development, this type of signaling has an important role in tissues where adjacent cells that are initially similar have to become specialized in different ways
Plays role in determining what type of cell a stem cell becomes.

24. Private & Short Distance Intimate Messaging II

26. Intercellular Junctions Animal Cells
Gap Junctions
Communicating cell to cell junction that allows ions and small molecules to pass from the cytoplasm of one cell to the cytoplasm of the next

27. Intercellular Junctions Animal Cells**
Tight Junctions
Cell to cell junction that seals adjacent epithelial cells together, preventing dissolved molecules in the extracellular medium from passing from one side of the epithelial sheet to the other

28. Intercellular Junctions Animal Cells**
Desmosomes
Specialized to cell to cell junction, usually formed between two epithelial cells, mediated by cadherin molecules and characterized by dense plaques of protein into which intermediate filaments in the two adjoining cells insert

29. Types of Signaling/Messaging

30. Questions How do cells receive the signal?
Where do the cells receive the signal?
What do cells do once they have received the signal?
How do cells respond to the signals received?
Among all the hundreds of signals being sent, and received, how do cells determine which signal was sent to them?

31. Signal Reception Details

32. Receptors I
There are two basic mechanisms by which chemical signals cause a biologic effect within the cell
Hence there are two types of receptors
Intracellular receptors
Inside the cell
Cell surface receptors
Found on the surface of the cell
We have already covered the cell surface receptors

33. Types of Receptors

34. Intracellular Receptors
Used for molecules that are sufficiently small and hydrophobic to diffuse across the membrane
Best known hydrophobic signal molecules
Steroid hormones
Cortisol
Estradiol
Testosterone
Thyroid hormones
Thyroxine
Vitamin D
Retinoic Acid

35. Intracellular Receptors
Receptors lie in the interior of the target cell
Cytosol or nucleus
When steroid hormone binds, receptor undergoes large conformational change that enables it to bond to its corresponding sequence in the DNA
Promotes or inhibits transcription of a set of genes
Generally regulatory proteins or enzymes

36. Intracellular Signaling Process I
Signal crosses membrane
Binds to receptor protein
Forms receptor-agonist complex
Complex is transported into the nucleus through the nuclear pores
Complex activates the receptor protein
Activated receptor protein binds at specific regulatory sequences on the DNA strand

37. Intracellular Signaling Process II
Transcription is initiated
Effects are not immediate because the processes of transcription, and translation, must be completed
Complex binds to specific region of DNA causing increased expression of specific genes
The complex behaves as a transcription factor that turns on specific genes
Effects are not immediate
Because of time required for gene transcription and subsequent translation
Furthermore, the duration of effects depends on the half-life of mRNA and protein

38. Steroid Hormone Details
There are different receptor proteins for each hormone
Receptors are very specific
Testosterone
Responsible for development of secondary sexual characteristics
Lack of the testosterone receptors, as a result of a mutation, leads to a development of outward female characteristics
More to come on this genetic disorder

39. Steroid Hormones

40. Specificity of Receptor Molecules

41. Hormones & Gene Transcription

42. Nitric Oxide & Intracellular Receptors
Signal : -Nitric Oxide
Dissolved gas made from arginine
Operates as a local mediator in many tissues
Released by endothelial cells that line every blood vessel
Released in response to stimulation by nerve endings

43. Nitric Oxide & Intracellular Receptors
Causes blood vessel to dialate and relax
Causing blood to flow more freely
Used to activate an intracellular enzyme guananyate cyclase
Catalyzes the formation of cyclic GMP from GTP
Cyclic GMP activates a short intracellular signaling pathway

44. Nitric Oxide III
Drug nitroglycerine is used to treat patients with angina
Pain due to inadequate blood flow to the heart muscle
Converted to NO in the body
Released by nerve terminals in the penis hence resulting in an erection for males
But what about the clitoris in females?
Works locally and quickly because of a short half-life

45. Cell Surface Receptors

46. Mechanisms via Surface Receptors
Initiated by ligand binding to receptors located in the plasma membrane
Does not directly regulate gene expression
Done indirectly
Ligand triggers conformational change, in the receptor protein, that triggers a trans-membrane signal
3 classes of cell-surface receptors

47. Classes of Cell-Surface Receptors
Three classes
Ion-channel linked receptor
G-protein linked receptor
Enzyme-linked receptor

48. Ion Channel Receptors

49. Ion-Channel-Linked Receptors
Also known as transmitter-gated ion channels
Found in muscle and nervous tissue
Convert chemical signals into electrical signals
Receptors serve for rapid transmission across synapses in the nervous system
Chemical signal arrives as a neurotransmitter
Delivered to the outside of the target cell
Chemical signal changes to an electrical signal in the form of a change in voltage across the plasma membrane

50. Ion-Channel-Linked Receptors II
Neurotransmitter binds
Receptor alters its conformation
Causes channel to open (or close)
Allows the flow of specific ions across membrane
Na+ K+
Ca2+
Cl-
Driven by electrochemical gradient, ions rush in or out of the cell
Depends on the concentration gradient
Results in a change in the membrane potential of the post-synaptic cell
Change promotes, or inhibits, neurotransmission

51. Ion-Channel-Linked Receptors III
Examples of Neurotransmitters
Nicotinic acetylcholine
Nerve and muscle
GABA
Γ-aminobutyric acid
CNS
Glycine
Special Note
Many ion channels are not directly coupled to their receptors but are coupled by G-proteins

52. Ion Channel Receptors

53. G-Protein linked Receptors

54. Introduction
G-protein-linked receptors and enzyme-linked receptors are used by practically every cell type of the body
G-protein linked receptors form the largest family of cell-surface receptors
G-protein-linked receptors are not found in bacteria
Signals received by G-protein-linked, or enzyme-linked receptors are transmitted to elaborate relay systems formed from cascades (a series) of intracellular signaling molecules

55. Introduction II G-protein-linked receptors
Mediate responses to an enormous diversity of extracellular signal molecules
Hormones
Local mediators
Neurotransmitters

56. G-Protein-Linked Receptors
Bound ligand initiates a series of reactions that ultimately result in a specific intracellular response
Ligand
Molecule, such as a hormone or a neurotransmitter, that binds to a specific site on a protein.
Intracellular messenger systems, using cell receptors, function as signal amplification
Active receptor can activate many effector molecules

57. G Protein Linked Receptors

58. Second Messenger Molecules
G Proteins activate second messengers
Are small, nonprotein, water-soluble molecules or ions
Intervene between original message and the ultimate effect of the cell
Part of the cascade of events that translate binding hormone, or neurotransmitter, into a cellular response
Two mostly recognized second messenger systems
Adenylate cyclase system
Calcium/phosphatidylinositol system

59. cAMP Second Messenger

60. Cyclic Adenosine Monophosphate

61. Calcium ions and Inositol Triphosphate (IP3)
Calcium, when released into the cytosol of a cell
Acts as a second messenger in many different pathways
Calcium is an important second messenger
Because cells are able to regulate its concentration in the cytosol

62. Calcium ions and Inositol Triphosphate (IP3) II

63. Calcium ions and Inositol Triphosphate (IP3) III

65. Enzyme-linked receptors

66. Catalytic Receptors Enzyme-Linked Receptors
Recall that active proteins are called enzymes
Most catalytic receptors are in the form of a tyrosine-specific protein kinase
Protein Kinase
Enzyme that transfer a phosphate group from ATP to a specific amino acid or target protein.
Tyrosine is the amino acid

67. Example
Binding of ligand, insulin for example, activates the intrinsic tyrosine kinase activity
Enzyme transfers the terminal phosphate group from ATP to the hydroxyl group of specific tyrosine residues of target proteins and of the receptor itself

68. Catalytic Receptors

69. Transduction Pathways

70. Introduction
Enzymatic reactions can be organized into multistep sequences
Pathways
The product of one reaction serves as the substrate of a subsequent reaction
Different pathways integrate to create a network of chemical reactions
This networking is collectively called metabolism
A Bigger Picture
Known as a metabolic map

71. Pathways Two classifications Catabolic pathway Anabolic
Degradable pathway
Reactions serve to capture chemical energy {ATP} from the degradation of energy-rich fuel molecules
Reactions that break down complex molecules, such as proteins, polysaccharides, and lipids, to a few simple molecules
Anabolic
Synthetic pathway
Combine small molecules, such as amino acids to form complex molecules such as proteins
Require energy
ATP is broken down to ADP + P

72. Introduction of Pathways
Multistep Pathways
Can amplify a signal
Provide more opportunities for coordination and regulation
At each step in a pathway
The signal is transduced into a different form, commonly a conformational change in a protein
Many signal pathways
Include phosphorylation cascades
In this process
A series of protein kinases add a phosphate to the next one in line, activating it
Phosphatase enzymes then remove the phosphates

73. Phosphorylation Cascades

74. Cascade Utilizing G-proteins

75. Regulation of Pathways
How does the organism regulate metabolism?
Regulatory signals inform individual cells of the metabolic state of the body as a whole
Hormones
Nervous system
Availability of nutrients
These influence signals that are generated within the cell itself

76. Signals Within the Cell
Regulatory signals
Substrates
Allosteric activators
Allosteric inhibitors
Product
Cause a rapid response

77. Cell Surface Receptors
There are two classes of receptors
Cell Surface Receptors
Largest class of receptors
Used for signals that are too large or too hydrophillic to cross the plasma membrane
Lie in the plasma membrane of the cell
Relays message across the membrane

78. Signaling Cascades The relay chain during transduction
Physically transfer the point of reception to the end point where the cell machinery will make the response
Transform the signal into a form that stimulates the response
Amplify the signal received
Distribute the signal so that many processes are influenced
Each step is open to interference from other factors so that the signal of the cell can me modulated according to conditions prevailing inside or outside the cell

79. Special Case
Signal Molecules Crossing the Plasma Membrane

80. Response
The cell’s behavior after officially receiving the signal