Cell Signaling Notes

General Principles of Cell Signaling

• Signals Can Act over a Long or Short Range
  • Animal cells use extracellular signal molecules to communicate with one another in various ways.
    • Endocrine: Hormones produced in endocrine glands are secreted into the bloodstream and are distributed widely throughout the body.
    • Paracrine: Paracrine signals are released by cells into the extracellular fluid in their neighborhood and act locally.
    • Neuronal: Neuronal signals are transmitted electrically along a nerve cell axon. When this electrical signal reaches the nerve terminal, it causes the release of neurotransmitters onto adjacent target cells.
    • Contact-Dependent: Cell-surface-bound signal molecule binds to a receptor protein on an adjacent cell.
  • Many of the same types of signal molecules are used for endocrine, paracrine, and neuronal signaling. The crucial differences lie in the speed and selectivity with which the signals are delivered to their targets—and the distance they must travel.
• Extracellular Signals Act Through Specific Receptors to Change Cell Behaviors
  • Every cell type displays a set of receptor proteins that enables it to respond to a specific set of extracellular signal molecules produced by other cells
  • Signal molecules work in combinations to regulate the behavior of the cell.
  • Cells may require multiple signals to survive, additional signals to grow and divide, and still other signals to differentiate.
  • If deprived of the necessary survival signals, most cells undergo a form of cell suicide known as apoptosis. An animal cell depends on multiple extracellular signals.
• A Cell’s Response to a Signal Can Be Fast or Slow
  • Fast response: altered protein function (seconds to minutes)
  • Slow response: altered protein synthesis (minutes to hours)
• Cell-Surface Receptors Relay Extracellular Signals via Intracellular Signaling Pathways
  • Intracellular signaling proteins can relay, amplify, integrate, distribute, and modulate via feedback an incoming signal.
• Some Intracellular Signaling Proteins Act as Molecular Switches
  • Signaling by phosphorylation: Protein kinase adds a phosphate (P) from ATP to the protein, switching it ON. Protein phosphatase removes the phosphate, switching the protein OFF.
  • Signaling by GTP binding: GTP-binding protein is induced to exchange GDP for GTP, switching the protein ON. The protein then hydrolyzes its bound GTP to GDP, switching itself OFF.
  • The activity of monomeric GTPases is controlled by two types of regulatory proteins.
    • Guanine nucleotide exchange factors (GEFs) promote the exchange of GDP for GTP, thereby switching the protein on.
    • GTPase-activating proteins (GAPs) stimulate the hydrolysis of GTP to GDP, thereby switching the protein off.
• Cell-Surface Receptors Fall into Three Main Classes
  • Ion-Channel-Coupled Receptors: Convert chemical signals into electrical ones. Also called transmitter-gated ion channels.
  • G-Protein-Coupled Receptors
  • Enzyme-Coupled Receptors

G-Protein-Coupled Receptors

• Stimulation of GPCRs Activates G-Protein Subunits
  • An activated GPCR activates G proteins by encouraging the α subunit to release its GDP and pick up GTP.
  • The G protein α subunit switches itself off by hydrolyzing its bound GTP to GDP
• Some Bacterial Toxins Cause Disease by Altering the Activity of G Proteins
• Some G Proteins Directly Regulate Ion Channels
• Many G Proteins Activate Membrane-bound Enzymes That Produce Small Messenger Molecules
• The Cyclic AMP Signaling Pathway Can Activate Enzymes and Turn On Genes
  • Cyclic AMP is synthesized by adenylyl cyclase and degraded by cyclic AMP phosphodiesterase.
  • ATP \rightarrow cyclic \, AMP + PP (catalyzed by adenylyl cyclase)
  • cyclic \, AMP + H_2O \rightarrow AMP (catalyzed by cyclic AMP phosphodiesterase)
  • In the resting cell, the cyclic AMP concentration is about 5 \times 10^{-8} M. Intracellular concentration of cyclic AMP has risen more than twentyfold (to >10^{-6} M) in the parts of the cell where the serotonin receptors are concentrated.
• The Inositol Phospholipid Pathway Triggers a Rise in Intracellular Ca^{2+}
• A Ca^{2+} Signal Triggers Many Biological Processes
  • Fertilization of an egg by a sperm triggers an increase in cytosolic Ca^{2+} in the egg
  • Calcium binding changes the shape of the calmodulin protein.
• Some GPCR Signaling Pathways Generate a Dissolved Gas That Carries a Signal to Adjacent Cells
  • Nitric oxide (NO) triggers smooth muscle relaxation in a blood-vessel wall.
• GPCR-triggered Intracellular Signaling Pathways Can Achieve Astonishing Speed, Sensitivity, and Adaptability
  • A rod photoreceptor cell from the retina is exquisitely sensitive to light
  • When the rod cell is stimulated by light, a signal is relayed from the rhodopsin molecules to cation channels in the plasma membrane.
  • These cation channels close in response to the cytosolic signal, producing a change in the membrane potential of the rod cell.
  • The change in membrane potential alters the rate of neurotransmitter release from the synaptic region of the cell.
  • Released neurotransmitters act on retinal nerve cells that pass the signal on to the brain.

Enzyme-Coupled Receptors

• Activated RTKs Recruit a Complex of Intracellular Signaling Proteins
  • Activation of an RTK stimulates the assembly of an intracellular signaling complex
  • Intracellular signaling proteins interact to form a cross-linked, gel-like matrix at the plasma membrane
• Most RTKs Activate the Monomeric GTPase Ras
• RTKs Activate Phosphoinositide 3-Kinase to Produce Lipid Docking Sites in the Plasma Membrane
  • Some RTKs activate the PI-3-kinase-Akt signaling pathway
  • Activation of Akt promotes cell survival
• Some Receptors Activate a Fast Track to the Nucleus
  • The Notch receptor itself is a transcription regulator
• Some Extracellular Signal Molecules Cross the Plasma Membrane and Bind to Intracellular Receptors
• Plants Make Use of Receptors and Signaling Strategies That Differ from Those Used by Animals
• Protein Kinase Networks Integrate Information to Control Complex Cell Behaviors