Lec 28: Cell Signaling

Class 28: Cell Signaling (Wednesday, November 5th)

Guiding Questions

  • How are external signals converted into responses within the cell?

  • How can we classify different types of signaling receptors?

  • What can the classification of a signaling receptor tell us about how it functions?

Clicker Question 1

  • Scenario: Low pH of partially digested foods entering the duodenum.

  • Response:

    • S cells of the duodenum secrete secretin in response to a drop in pH.

    • Secretin circulates in the blood and stimulates pancreatic cells to release bicarbonate.

    • Bicarbonate release leads to an increase in pH, neutralizing stomach acid.

  • Question: What is the sensor in this homeostatic system?

    • Options:
      a) Secretin
      b) Bicarbonate
      c) S cells
      d) Digested food

Clicker Question 2

  • Homeostasis refers to the relative constancy of the external environment.

    • D) True

    • E) False

Homeostasis and Feedback Loops

  • When a response moves the variable in the opposite direction as the initial stimulus, this is termed a negative feedback loop.

Key Concepts in Cell Communication

  • Cell communication involves converting one signal into another.

    • Example: Radio signal in, sound out.

Signaling Molecules and Receptors

  • Signaling molecules (ligands): Molecules that bind to usually a larger molecule (the receptor).

  • Receptors: Chemical structures made of proteins that receive and transduce signals.

  • The ligand-receptor interaction initiates cell signaling.

General Diagram of Cell Signaling

  1. Signal Reception: A chemical signal is detected when a signaling molecule binds to a receptor.

  2. Signal Transduction: The conformational change in the receptor protein initiates signal transduction within the cell.

  3. Cellular Response: The transduced signal is converted into a response.

Types of Signaling Based on Distance

  • Signaling can be defined by the distance from the source to the receptor:

    • Direct communication: Molecules on the plasma membrane of one cell can be recognized by receptors on the plasma membrane of a neighboring cell.

    • Synaptic signaling: Neurotransmitters released from a neuron travel across a synapse to a neighboring neuron.

    • Paracrine signaling: A specific cell secretes signaling molecules that affect nearby cells.

    • Endocrine signaling: Hormones travel via the circulatory system to affect distant target cells.

Clicker Question 3

  • In Bio1AL lab, we performed complementation analyses by crossing yeast strains of opposite mating types. How would you categorize the cell signaling in yeast mating?

    • Options:
      a) Synaptic signaling
      b) Paracrine signaling
      c) Endocrine signaling
      d) Direct contact signaling

Types of Membrane Receptors

  • Membrane receptors can be defined by location:

    • Cell surface receptors:

    • G-protein-coupled receptors (GPCRs)

    • Channel-linked receptors

    • Enzyme-linked receptors

    • Intracellular receptors

G Protein-Coupled Receptors (GPCRs)

  • Largest family of cell surface receptors.

  • Characterized by:

    • 7-transmembrane domains

    • They rely on G proteins:

    • Active State: When bound to GTP.

    • Inactive State: When bound to GDP.

    • Composed of α, β, and γ subunits.

  • When a ligand binds to a GPCR, it activates a G protein, which promotes cellular response.

Generalized Diagram of G-Protein Signaling

  1. A signaling molecule binds to a GPCR, causing it to bind to a G protein.

  2. The G protein exchanges GDP for GTP, dissociating from the receptor into an active α subunit and a β/γ dimer. The activated subunits promote cellular responses.

  3. The signaling molecule eventually dissociates from the receptor, and the α subunit hydrolyzes GTP into GDP + Pi, reassociating with the β/γ dimer.

Example of GPCR Signaling: Taste Bud

  • In taste signal transduction on the tongue:

    • Afferent sensory fibers interact with taste cells and receptors (Ga-gus, GB, Gy) which involve ion channels.

    • Increased intracellular Ca²⁺ triggers neurotransmitter release into the CNS.

Generalized Diagram of Channel-Linked Receptor Signaling

  • Two extracellular signaling molecules (ligands) bind to open the ion channel, permitting ion passage through the membrane.

  • Example in nervous system: Neurotransmitters bind to ligand-gated ion channels, allowing ions to cross the membrane.

Generalized Diagram of Enzyme-Linked Receptor Signaling

  • Structure of enzyme-linked receptors:

    • Extracellular signal-binding domain

    • Intracellular catalytic domain

  • When a signaling molecule binds, the receptor activates its catalytic domain.

  • Phosphorylated protein: The receptor catalyzes the transfer of a phosphate group from ATP to an intracellular protein.

Example of Enzyme-Linked Receptor Signaling

  • Insulin binds to the insulin receptor, leading to the phosphorylation of the insulin response protein.

Generalized Diagram of Intracellular Receptor Signaling

  1. Hormones cross the plasma membrane and bind to cytoplasmic receptors.

  2. Hormone binding alters receptor conformation so it no longer binds inhibitor, exposing the DNA-binding site.

  3. Hormone-receptor complex translocates to the nucleus, binds to DNA, altering gene transcription and cellular response.

Example of Intracellular Receptor Signaling

  • Estrogen receptor in mammalian cells:

    • Estrogen enters nucleus, binds to estrogen receptor subunits which form a dimer and activate transcription of specific genes affecting the cell structure and function.

Summary of Signaling Types

  1. Direct Contact: Adjacent plasma membranes communicate directly.

  2. Paracrine Signaling: Local signaling (secretory cell to neighboring cells).

  3. Endocrine Signaling: Hormone secretion into the blood by endocrine glands to distant target cells.

  4. Synaptic Signaling: Neurotransmitter release by nerve cells into synaptic gaps.

Summary of Different Types of Receptors

  • Types of receptors:

    • Enzyme-linked receptor: Plasma membrane, leads to phosphorylation of an intracellular protein.

    • G-protein-coupled receptor (GPCR): Plasma membrane, binds to a G protein.

    • Ligand-gated ion channel: Plasma membrane, opens ion channels.

    • Intracellular receptor: Cytosol or nucleus, involved in transcription regulation.

Clicker Question 4

  • After eating a meal, a rise in blood glucose triggers the pancreas to release insulin. Insulin binds to receptors on adipose and skeletal muscle cells, leading to increased glucose uptake. What type of signaling does this represent?

    • Options:
      A. Autocrine signaling
      B. Paracrine signaling
      C. Endocrine signaling
      D. Direct intercellular signaling
      E. Contact-dependent signaling

Phosphorylation in Protein Function Control

  • Phosphorylation involves adding phosphate groups; dephosphorylation involves their removal.

  • Protein Kinases: Add phosphate groups from ATP to proteins.

  • Phosphatases: Remove phosphate groups from proteins.

  • Protein kinases categorized based on modified amino acids:

    • Serine-Threonine kinase

    • Tyrosine kinase

Role of Relay Proteins and Second Messengers

  • Many signal transduction pathways utilize relay proteins that are protein kinases.

  • Phosphorylation and dephosphorylation function as molecular switches, regulating activity levels.

  • Second messengers: Small molecules/ions that relay signals from cell-surface receptors to effector proteins, commonly include cyclic AMP (cAMP) and calcium ions.

Second Messengers in Detail

  • cAMP and Inositol Triphosphate (IP3):

    • Diacylglycerol (DAG) activates protein kinase C (PKC).

    • Adenylyl cyclase converts ATP to cAMP.

    • Phospholipase C converts PIP2 to DAG and IP3.

  • Calcium as a Second Messenger:

    • Calmodulin is a cytoplasmic protein that binds Ca²⁺, forming a complex that activates other proteins.

GPCRs and Second Messengers

  • Inositol triphosphate binds to Ca²⁺ channels on the endoplasmic reticulum, releasing Ca²⁺ into the cytoplasm.

  • GTP-bound G protein activates adenylyl cyclase converting ATP into cAMP.

Receptor Tyrosine Kinases (RTKs)

  • RTKs are a type of enzyme receptor characterized by their transmembrane protein structure.

  • Activation Steps:

    1. Ligand binds, causing dimerization and autophosphorylation.

    2. Phosphorylation of response proteins occurs, leading to cellular responses.

  • Insulin receptor is an example of a tyrosine kinase that phosphorylates insulin response proteins.

Why Use Second Messengers and Relay Proteins?

  • Enzyme cascades amplify the cell's response to signals, resulting in a greater number of activated products at each step in the pathway.

Cellular Responses from Signaling

  • Cellular responses lead to:

    • Regulation of transcription or cytoplasmic activities.

    • Nuclear response: Activation of transcription factors that stimulate specific gene transcription.

    • Cytoplasmic response includes metabolic changes.

Review of Guiding Questions

  • How are external signals converted into responses within the cell?

  • How can we classify different types of signaling receptors?

  • What can the classification of a signaling receptor tell us about how it functions?

Next Time

  • Topic: How does the nervous system transmit information?

  • Homework: Week 11 Self-Assessment DUE SUNDAY, 11/9 before 11:59pm.