Cell Signaling

Why Do Cells Need Signals?

• To respond to a changing environment
  • A cellular response to the environment can be critical for survival
  • Example: Glucose signals yeast cells to increase glucose transporters and enzymes allowing efficient uptake and use of glucose

Cell Signaling Requirements

• Signaling Molecule
  • Large hydrophilic molecules
  • Small hydrophobic molecules
  • Hormones
• Receptor
  • Transmembrane
  • Cytosolic
  • Nucleoplasm

Signals Relayed Between Cells

• Direct intercellular signaling:  Cell junctions allow signaling molecules to pass from one cell 

  to another.

• Contact-dependent signaling:  Molecules bound to the surface of cells serve as signals to 

  cells coming in contact with them.

• Autocrine signaling:  Cells secrete signaling molecules that bind to their own cell surface or similar neighboring cells.

• Paracrine signaling: signal does not affect originating cell, but does influence nearby cells

• Endocrine signaling: signals called hormones travel long distances and are usually longer lasting in effect

Three Stages of Cell Signaling

• Receptor activation: signaling molecule binds to receptor
• Signal transduction: activated receptor stimulates a sequence of changes
  • a signal transduction pathway
• Cellular response
  • Different responses possible
  • Change enzyme activity
  • Change function of structural proteins 
  • Change gene expression

Cell Signaling: Responding to the Outside World

• Interpreting extracellular signals via proteins that span their plasma membrane called receptors
• Receptors are comprised of extracellular and intracellular domains
• The extracellular domain relays information about the outside world to the intracellular domain
• The intracellular domain then interacts with other intracellular signaling proteins
• These intracellular signaling proteins further relay the message to one or more effector proteins
• Effector proteins mediate the appropriate response
• Same receptor molecule can interact with many intracellular relay systems at the same time so same signal and same receptor => different effects in different cells 
  • Same relay system many act on many different intracellular targets
• By changing the conformation of a receptor, signals lead to a response inside the cell.

Reception

• A receptor
  • Has to have an endogenous ligand
  • Has to bind it with high affinity (strength)
  • Has to recognize the biologically active ligand from other similar molecules (specificity)
  • Has to produce the biological response
• All the conditions have to be met

Signal Transduction Pathway

• First messenger: signals binding to the cell surface
• Many signal transduction pathways lead to production of second messengers
  • Second messengers: relay signals inside cells
  • Examples:
  • cAMP
  • Ca²⁺
  • Diacylglycerol (DAG) and inositol triphosphate (IP₃)

Signal Transduction via cAMP

• Cyclic adenosine monophosphate 
• Signal binding to GPCR activates G protein to bind GTP, causing dissociation, freeing α subunit 
• α subunit binds to adenylyl cyclase enzyme, stimulating synthesis of cAMP
• cAMP then activates protein kinase A (PKA)
• Activated catalytic PKA subunits phosphorylate specific cellular proteins
• PKA targets include
  • enzymes
  • structural proteins
  • transcription factors
• When signaling molecules no longer produced, eventually effects of PKA are reversed
• cAMP has two advantages
  • Signal amplification: binding of signal to one receptor can cause the synthesis of many cAMP molecules that activate PKA, and each PKA can phosphorylate many proteins
  • Speed: in one experiment a substantial amount of cAMP was made within 20 seconds after addition of signal

Signal transduction via DAG and IP3

• Another way for an activated G protein to activate a signal transduction pathway
• α subunit activates phospholipase c
• Phospholipase C cleaves plasma membrane phospholipid PIP₂ producing diacylglycerol (DAG) and inositol triphosphate (IP3) 
• Ca2+ channels in ER open, causing Ca²⁺ influx
• Ca2+ exerts a variety of effects on cell behavior

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