Physio. Ch5 Chemical Messenger and Cell Signaling

Direct Communication

• Least common method of cell to cell communication

• Done between tight junctions

• Very fast way of communication

- Used in heart cells to allow them to contract as one unit

Indirect communication

• Most common method of cell to cell communication

• Done with chemical messengers

• Slower communication of messages from cell to cell

• Multi-step process

- 1: Secretory cell secrets a chemical messenger

- 2: Chemical messenger enters the intracellular fluid

- 3: Chemical messenger binds to receptor on target cell

- 4: Receptor cell caries out a response

Signal transduction

• Process where an extracellular signal molecule activates a receptor that then activates a intracellular signal molecule to create a cellular response

• Facilitated by membrane proteins

• Multi-step process

- 1: Chemical messenger binds to receptor

- 2: Receptor activates

- 3: Receptor sends signal to activate intracellular signal molecule, alter activity of target protein, inhibit synthesis of target protein

- 4: Response

Functional classifications of Messengers

• Paracrines or autocrines

• Neurotransmitters

• Hormones (endocrines)

Paracrines or autocrines

• Travel short distances to target cells via diffusion in interstitial fluid

• Chemically classified

- Eicosanoids

- Amines

- Peptides/proteins

Neurotransmitters

• Travel short distances to target cell via a synapse

• Chemical classifications

- Amino acids

- Amines

- Peptides/proteins

Hormones (endocrines)

• Travel long distances through the blood stream

• Chemical classifications

- Steroids

- Amines

- Peptides/proteins

Chemical classification

• Amino Acids

• Amines

• Peptides

• Steroids

• Eicosanoid

Amino Acids

• Four in existence

- Glutamate

- aspartate

- glycine

- gamma-aminobutyric acid (GABA)

• Only used in CNS and produced by neurons

• Hydrophilic / lipophobic

• Receptors: Plasma membrane

• Stored: Secretory vesicles

• Secretion: Exocytosis

• Transport in blood: Disolved

• Signal mechanism

- Open-close ion channels

- Activate membrane-bound enzyme

- G proteins to secondary mesangers

• Distance: Short

Amines

• Derived from amino acids

• Hydrophilic / lipophobic

• Receptors: Plasma membrane

• Stored: Secretory vesicles

• Secretion: Exocytosis

• Transport in blood: Disolved

• Signal mechanism

- Open-close ion channels

- Activate membrane-bound enzyme

- G proteins to secondary mesangers

• Distance: Short

Peptides and Protein

• Most abondent

• Hydrophilic / lipophobic

• Receptors: Plasma membrane

• Stored: Secretory vesicles

• Secretion: Exocytosis

• Transport in blood: Disolved

• Signal mechanism

- Open-close ion channels

- Activate membrane-bound enzyme

- G proteins to secondary mesangers

• Distance: Short

Steroids

• Made from cholesterol

• All function as hormones

• Hydrophobic / lipophilic

• Receptors: Cytosol

• Storage: None

• Secretion: Simple diffusion

• Transport in blood: Bound to protein

• Signal transduction mechanism: Gene activation/inhibition: Alter transcription of mRNA → alter protein synthesis

• Distance: Long

Eicosanoid

• Made from arachidonic acid

• Paracrine messanger

• Hydrophobic / lipophilic

• Receptors: Cytosol

• Storage: None

• Secretion: Simple diffusion

• Transport in blood: Bound to protein

• Signal transduction mechanism: Gene activation/inhibition: Alter transcription of mRNA → alter protein synthesis

• Distance: Long

Hydrophobic

• Does not like to be around water

• Does not dissolve in water

• Lipophilic

Hydrophilic

• Likes to be around water

• Dissolve in water

• Lipophobic

Lipophobic

• Does not like to be around lipids

• Does not dissolve in lipids

• Hydrophilic

Lipophilic

• Likes to be around lipids

• Dissolves in lipids

• Hydrophobic

Half-life

• The time it takes for a molecule to have it’s concentration decreased by half

• Hormone bound to protein is about 90min.

• Hormone dissolved in interstitial fluid is about 10min

Interactions between messengers and receptors

• Locations: Plama membrane, cytoplasm, nucleus

• Messengers can bind to more than one receptor type

- Respecters can hold more than one messenger type

• Target cell response depends on

- Concentration of messengers

- Number of receptors

- Affinity of receptors for the message

Changes in receptor concentration

• Up-regulate

- More receptors are present

- Less messengers are present

- Receptor is more sensitive to the messenger

• Down-regulate

- The inverse of up-regulating

Agonist

• A compound that binds to and activated a receptor to cause the normal biological response

Antagonist

• A compound that binds to and activated a receptor to cause the opposite of a normal biological response

Receptor activation

• A messanger binds to a receptor

Signal Transduction Mechanisms: Intracellular Receptors

• A messenger uses simple diffusion to get through the plasma membrane and join up with a receptor

• This method works through altering mRNA production

• Step 1: Lipophilic messenger penetrates the plasma membrane

• Step 2: Messenger mets up with receptor, forms a hormone-receptor complex

• Step 3: Hormone receptor complex acts as a transcription factor

• Step 4: mRNA production is altered

• Step 5: Altered mRNA leaves to the ribosomes where it undergoes normal protein folding procedure

Fast ligand-gated channels

• The messenger binds directly to the ion gate that it is trying to affect

• The ion gate is both the receptor and ion gate in this case

• Step 1: Messenger connects to membrane protein

• Step 2: The membrane protein opens up the channel and ions flow

Enzyme-linked receptors

• Same transmembrane protein acts as the receptor and the enzyme

• Can change metabolism of cell or regulate protein synthesis

Membrane-bound receptors: Enzyme-linked receptors (Tyrosine kinase receptor)

• A long chain of reactions that phosphorylate protein is used to trigger cause a response in part of the cell

• Step 1: Tyrosine kinase messenger binds to Tyrosine kinase receptor

• Step 2: Receptor causes the kinase, protein, ATP to interact to make a phosphorylated protein and ADP

• Step 3: Earlier reaction continues until it meats something that isn’t another protein

• Step 4: Passing off of a phosphate causes a change in the cell

Membrane-bound receptors: G protein coupled receptors (GPCRs) Slow ligand-gated ion channel

• A messenger activates a receptor that then disassembles a protein to cause another reaction

• Step1: Messanger binds to receptor

• Step 2: Receptor causes “a” of the G protein to no longer like “GDP”

• Step 3: “GDP” is removed and replaced with “GTP”

• Step 4: The other components of the G protein break off and leave “GTP” and “a” alone

• Step 5: “GTP” and “a” go off an stimulate an ion channel

Membrane-bound receptors: G protein coupled receptors (GPCRs) Adenylate cyclase-cAMP mechanism

• The same as the Slow ligand-gated ion channel but instead of “a” and “GDP” binding to the ion channel they bind to Adenylate enzyme

• Step 1: The Adenylate enzyme makes cAMP from ATP

• Step 2: cAMP stimulates protein kinase A

Membrane-bound receptors: G protein coupled receptors (GPCRs) Phospholipase C-DAG-IP3 mechanism

• The same as the Slow ligand-gated ion channel but instead of “a” and “GDP” binding to the ion channel they bind to the phospholipase C enzyme

• Step 1: The phospholipase C enzyme procures PIP2

• Step 2: PIP2 is broken down into IP3 and DAG

• Step 3a: IP3 is hydrophilic and diffuses to the rough ER

• Step 4a: The rough ER releases calmodulin

• Step 5a: Calmodulin stimulates a protein kinase to trigger a cellular response

• Step 3b: DAG activates protein kinase C to trigger a cellular response

Signal Amplification

• A primary signal setting off a cascade of secondary signaling

G-protein

• Protein made of alpha (a) beta (B) and gamma (Y)

• Used to carry out all G-protein based messaging

cAMP

• Activation of Protein kinase A and binds to ion channels

cGMP

• Activation of Protein kinase G and binds to ion channels

cAMP phosphodiesterase

• Break down cAMP into AMP

- Non-functional after broken down

Inhibitory G proteins

• Regulates cAMP production

Signal amplification

• The ability for small changes in chemical messenger concentration to elicit large responses in target cells

• Only possible because of secondary messengers