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