Lecture 9: Cell Signaling Part 1

Big Questions of Cell Signaling

• How do cells communicate?

• How are signals sensed?

• How is the information in a signal translated into action?

Signal Transduction

• The process by which one type of signal is converted into another

Cell Communication

• Cells use extracellular signal molecules to communicate with one another in various ways

• Types

  • Endocrine Signaling

  • Paracrine Signaling

  • Neuronal Signaling

  • Contact-Dependent Signaling

Endocrine Signaling

• Long distance signaling that is widely broadcast

  • Therefore, the most public type of signaling

• Hormones

  • Extracellular signal that is secreted and transported via the bloodstream to target tissues on which it exerts a specific effect

Paracrine Signaling

• Local signaling

  • Occurring between cells that are close to one another

• A central cell releases signaling molecules

• Signaling molecules act as chemical messengers that diffuse locally through the extracellular fluid to nearby cells rather than traveling through the bloodstream over long distances

• Nearby cells have specific receptors that bind to these local mediators to receive the signal and trigger a biological response

• Autocrine signaling (related)

  • When a cell responds to a signal it produces by having the molecules bind to receptors on its own cell surface

Neuronal signaling

• Long distance BUT not widely broadcast

  • The message can travel across long distances across the body through extended cell structures, but unlike hormones, this travel is specific to the nervous system

• Structure of the neuron

  • Cell Body: The main body of the nerve cell

  • Axon: The long extension that conducts electrical impulses over distance

  • Nerve Terminal: The end of the axon where chemical signaling molecules are stored and released

  • Synapse: The narrow gap junction between the nerve terminal and the specific target cell

• How the signal travels

  • An electrical impulse travels down the neuron’s axon toward the nerve terminal

  • At the nerve terminal, the electrical signal is converted into a chemical signal

  • Chemical messengers called neurotransmitters are released into the synapse

  • The neurotransmitters cross the synapse and bind to specific receptors on the target cell to deliver the message

Contact-dependent Signaling

• The most intimate, short range signaling method

  • Requires two cells to physically touch each other

• Membrane-bound signal molecules

  • Unlike other types of signaling where molecules are released or secreted, the signaling molecule remains anchored directly to the membrane of the signaling cell

• The signaling molecule binds directly to a receptor protein on the surface of the neighboring target cell

Signal Molecules

• Signal molecules can be proteins, peptides, amino acids, nucleotides, steroids, fatty acid derivatives, or even dissolved gases

• Big takeaway: Signal molecules exist in all shapes and sizes

Cell-Surface Receptors

• Often, signals are too large or hydrophilic to cross the plasma membrane of the target cell

• Cell-Surface Receptors

  • Because the signals can’t cross the membrane directly, they bind to cell-surface receptor proteins embedded in the plasma membrane

• Internal Relay

  • When the extracellular signal molecules bind to the outside of the receptors, it triggers a change that activates intracellular signaling molecules inside the cell

  • This helps carry the message forward to produce a response

Intracellular Receptors

• Occasionally, some receptor proteins can be found inside the cell

  • Which are often located inside the nucleus or just the cytosol

• Intracellular receptors can bind small, hydrophobic signal molecules

Same Signal Effect

• The same signal can induce different responses in different target cells

• Example: Neurotransmitter Acetylcholine

  • Heart Pacemaker Cell

    • Acetylcholine will bind to receptor proteins located on the plasma membrane of target cells that then trigger decreased rate of firing

  • Salivary Gland Cell

    • Acetylcholine will bind to receptor proteins located on the plasma membrane of target cells that then trigger secretion

  • Skeletal Muscle Cell

    • Acetylcholine will bind to receptor proteins located on the plasma membrane of target cells that then trigger contraction

Combinations of Signal Molecules

• Signals often bind to receptors in complex combinations that can alter

  • Cell Shape

  • Movement

  • Metabolism

  • Gene Expression

  • Proliferation

  • Survival

  • Differentiation

Response Time

• The length of time it takes a cell to respond to a signal depends on what needs to happen once the message is received

• Fast Response (seconds to minutes)

  • When only protein function needs to be altered

• Slow Response (minutes to hours)

  • When altered protein synthesis needs to occur

A “Simple” Cell Signaling Pathway (and slightly more complicated pathway)

• “Simple” Cell Signaling Pathway

  • Like a molecular relay race

  • A receptor recognizes an extracellular signal and binding of that molecule generates an intracellular signal

  • The message is passed downstream from one intracellular signaling molecule to another

  • Response to signal is performed by target cells

    • Effector proteins execute specific actions at the end of the pathway

• Slightly More Complicated Pathway

  • Can involve amplification and transduction by intracellular molecules

  • Can involve feedback loops

Positive Feedback and Negative Feedback Loops

• Positive Feedback Loop

  • A component that lies downstream in the pathway acts on an earlier (upstream) component in the same pathway

  • Enhances the response to the overall signal

• Negative Feedback Loop

  • A component that lies downstream in the pathway acts to inhibit an earlier (upstream) component in the same pathway

  • Diminishes the response to the overall signal

Molecular Switches (Intracellular Signaling Proteins)

• In more complicated signal pathways, many intracellular signaling proteins can act as molecular switches

• Intracellular signaling cascades use a combination of mechanisms to transmit the signal

  • A mix of phosphorylation and GTP binding

• Signaling by GTP Binding

  • GTPases are proteins that can bind and hydrolyze GTP

  • OFF State: When GTPase is bound to GDP, the switch is turned off and is inactive

  • Turning ON: When a signal comes into the cell, the GTPase can exchange its GDP for a GTP molecule, which flips the switch to the ON state

    • GEFs

  • Active State: GTPase can bind with downstream proteins (effector proteins) and activate them, creating a signaling cascade

  • GTP hydrolysis can be performed by GTPase to return the protein to its OFF state

    • GAPs

• Signaling by Phosphorylation

  • Phosphorylation can turn some proteins on and others off

    • There’s no guarantee that attaching a phosphate group will turn the protein on and no guarantee that removing a phosphate group will turn the protein off

  • Kinase: A protein that covalently attaches a phosphate group to a protein

  • Phosphatase: A protein that removes the phosphate from a protein