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Questions and Answers

What is the primary role of adenylyl cyclase in signal transduction?

  • To synthesize G-proteins
  • To trigger the release of pyrophosphate
  • To hydrolyze ATP into ADP
  • To convert ATP into cyclic AMP (correct)

Which molecule is formed when cyclic AMP is hydrolyzed?

  • Adenosine triphosphate
  • Cyclic diphosphate
  • 5'-adenosine monophosphate (correct)
  • Cyclic guanosine monophosphate

Who conducted seminal research that identified cyclic AMP as a key molecule in signal transduction?

  • Mendel
  • Watson and Crick
  • Koshland
  • Sutherland (correct)

What is the significance of the particulate fraction in Sutherland's experiments?

<p>It released cyclic AMP when activated by hormones (D)</p> Signup and view all the answers

How many different Gα subunits are encoded by the genes discussed?

<p>21 different subunits (A)</p> Signup and view all the answers

What is the first step in the cell signaling process?

<p>Synthesis of the signaling molecule (D)</p> Signup and view all the answers

Which type of signaling involves messenger molecules reaching target cells via the bloodstream?

<p>Endocrine signaling (C)</p> Signup and view all the answers

What is the role of the ligand once it binds to its receptor?

<p>It causes a conformational change in the receptor (A)</p> Signup and view all the answers

What type of receptor is primarily involved in signaling molecules that cannot cross the plasma membrane?

<p>Cell-surface receptors (C)</p> Signup and view all the answers

What occurs after the binding of a ligand to a receptor?

<p>Initiation of one or more intracellular pathways (B)</p> Signup and view all the answers

Which type of signaling involves cells that have receptors on their surface responding to the same messenger they produce?

<p>Autocrine signaling (D)</p> Signup and view all the answers

Which of the following is NOT a type of cell-surface receptor?

<p>Intracellular receptors (B)</p> Signup and view all the answers

What is a characteristic of juxtacrine signaling?

<p>Requires physical contact between sending and receiving cells (C)</p> Signup and view all the answers

What role do second messengers play in cellular signaling?

<p>They enhance or reduce concentrations in response to first messengers. (B)</p> Signup and view all the answers

What is the primary function of protein kinase A (PKA)?

<p>To phosphorylate target proteins on specific amino acids. (A)</p> Signup and view all the answers

How does PKA recognize which substrates to phosphorylate?

<p>By the specific cell type and the corresponding stimulus. (B)</p> Signup and view all the answers

What is the purpose of kinase anchoring proteins (AKAPs)?

<p>To confine PKA signaling to specific cellular locations. (C)</p> Signup and view all the answers

Which substrates does PKA primarily phosphorylate?

<p>Serine and threonine residues on target proteins. (C)</p> Signup and view all the answers

What is one function of AKAP5 as described in the content?

<p>It functions as a scaffold protein in signaling hubs. (D)</p> Signup and view all the answers

Why is the confinement of the PKA signaling process important?

<p>To allow relevant substrates to be phosphorylated first. (B)</p> Signup and view all the answers

How many different AKAPs have been discovered according to the information provided?

<p>At least 50 (A)</p> Signup and view all the answers

What role do AKAPs play in the context of PKA signaling?

<p>They help localize PKA to specific substrates. (D)</p> Signup and view all the answers

What type of mutations can lead to disorders associated with G protein-coupled receptors?

<p>Both loss and gain of function mutations. (B)</p> Signup and view all the answers

How do gain of function mutations in G proteins affect cellular signaling?

<p>They create a constitutively activated G protein. (C)</p> Signup and view all the answers

What is the role of adenylyl cyclase in relation to cAMP?

<p>It generates cAMP from ATP. (D)</p> Signup and view all the answers

What relationship exists between cAMP and PKA?

<p>cAMP activates PKA by binding to it. (C)</p> Signup and view all the answers

Which statement correctly describes first and second messengers in signaling pathways?

<p>First messengers activate receptors on the cell surface; second messengers transmit signals intracellularly. (B)</p> Signup and view all the answers

What is the primary function of GRK in the context of GPCR signaling?

<p>To phosphorylate activated GPCRs for desensitization. (A)</p> Signup and view all the answers

How can certain polymorphisms in G protein-related genes affect health?

<p>They may increase susceptibility to some conditions while decreasing it for others. (A)</p> Signup and view all the answers

What is the role of second messengers in cell signaling pathways?

<p>They amplify the initial signal received by receptors. (C)</p> Signup and view all the answers

What molecular change does phosphorylation typically induce in a protein?

<p>It alters the protein's charge and conformation. (B)</p> Signup and view all the answers

Which component activates an effector protein in G protein-coupled receptor signaling?

<p>GTP binding to the alpha subunit. (B)</p> Signup and view all the answers

What characterizes the conformational change in G protein-coupled receptors upon ligand binding?

<p>The affinity for G proteins increases significantly. (C)</p> Signup and view all the answers

What happens during the desensitization of G protein-coupled receptors?

<p>Active receptors are inhibited from activating G proteins. (A)</p> Signup and view all the answers

What distinguishes triple-negative breast cancer cells from other cancer cells?

<p>Higher levels of tyrosine phosphorylation. (B)</p> Signup and view all the answers

How is GTP involved in the regulation of GTP-binding proteins?

<p>It hydrolyzes to GDP to deactivate the protein. (D)</p> Signup and view all the answers

Which proteins are classified as GEFs in G protein signaling?

<p>Guanine nucleotide exchange factors. (A)</p> Signup and view all the answers

Which is a characteristic feature of protein kinases?

<p>They add phosphate groups to hydroxyl groups. (C)</p> Signup and view all the answers

In which form do G proteins exist when they are inactive?

<p>Bound GDP in the alpha subunit. (A)</p> Signup and view all the answers

What common feature is found in most signaling pathways?

<p>Incorporate the process of phosphorylation. (A)</p> Signup and view all the answers

What is the function of arrestins in receptor signaling?

<p>They block active receptors from activating G proteins. (B)</p> Signup and view all the answers

What type of messengers can act as first messengers in cell signaling?

<p>Various types including proteins, peptides, and fatty acids. (B)</p> Signup and view all the answers

What is the primary outcome of signal integration in a cell?

<p>Triggering different cellular responses. (B)</p> Signup and view all the answers

Flashcards

Cell Signaling

Process where cells communicate with each other to coordinate their activities.

Signal Transduction

The process of converting a signal from one form to another within a cell.

Extracellular Signal

Communication signal originating outside of a cell.

Cell-Surface Receptors

Proteins embedded in the cell membrane that bind to hydrophilic signaling molecules.

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Endocrine Signaling

Long-distance signaling via the bloodstream.

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Paracrine Signaling

Short-distance signaling between nearby cells.

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Autocrine Signaling

A cell signals to itself.

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Juxtacrine Signaling

Requires direct contact between cells for signaling.

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G protein subunits

There are 21 different Gα subunits, 6 different Gβ subunits, and 12 different Gγ subunits. These subunits combine to form heterotrimeric G proteins, which are involved in signal transduction pathways.

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G protein activation of adenylyl cyclase

G proteins can activate adenylyl cyclase, an enzyme that converts ATP into cyclic AMP (cAMP). This is a key step in many signaling pathways.

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Adenylyl cyclase reaction

Adenylyl cyclase removes two phosphates from ATP as pyrophosphate to create cAMP. The hydrolysis of pyrophosphate drives this reaction forward.

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cAMP hydrolysis

cAMP is a relatively short-lived molecule that is quickly hydrolyzed to 5'-AMP by phosphodiesterase.

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Sutherland's discovery of cAMP

Earl Sutherland discovered cAMP as the second messenger responsible for activating glycogen phosphorylase in response to glucagon or epinephrine. This landmark discovery marked the beginning of the field of signal transduction.

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Second Messenger

A small molecule inside a cell whose concentration changes in response to a signal (first messenger). It helps relay the signal further within the cell.

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cAMP

A cyclic nucleotide that acts as a second messenger, often activated by G protein-coupled receptors.

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Protein Kinase A (PKA)

An enzyme activated by cAMP. It adds phosphate groups (phosphorylates) to target proteins, altering their activity.

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Phosphorylation

The addition of a phosphate group to a molecule, often to a protein. It can switch a protein 'on' or 'off'.

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AKAP

A kinase anchoring protein that binds PKA, confining it to a specific location within the cell.

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Scaffold Protein

A protein that brings together other proteins into a functional unit. It helps organize signaling complexes.

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Signaling Hub

A region in the cell where multiple signaling pathways converge, allowing for the integration of different signals.

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How are different signals mediated by PKA?

AKAPs confine PKA to specific locations within the cell, ensuring that the appropriate substrates are phosphorylated in response to a particular stimulus. This allows for cell-specific responses and efficient signal transduction.

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Intracellular Receptors

Proteins located inside the cell, typically in the cytoplasm or nucleus, that bind small, hydrophobic signaling molecules.

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First Messenger

The signaling molecule (ligand) that initially triggers a signaling cascade.

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Protein Kinases

Enzymes that add phosphate groups to specific amino acids in proteins, modulating their function.

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Protein Phosphatases

Enzymes that remove phosphate groups from proteins, reversing the effect of kinases.

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GTP-binding Proteins

Proteins that switch between active (GTP-bound) and inactive (GDP-bound) states, often acting as molecular switches in signaling.

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GTPase

Enzymes that hydrolyze GTP to GDP, turning off the signaling pathway.

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G Protein-coupled Receptors (GPCRs)

Cell surface receptors that bind signaling molecules and activate a G protein.

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Heterotrimeric G protein

A type of G protein comprised of three subunits (α, β, and γ), which is common in signal transductions.

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Effector Proteins

Proteins that respond to activation by a G protein, initiating a downstream effect.

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Signal Amplification

A small signal triggering a large cellular response.

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Signal Integration

Cells integrating many signals to generate appropriate cellular responses.

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Tyrosine Phosphorylation

Adding phosphate groups to tyrosine amino acids in proteins, frequently involved in signaling.

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Downregulation

A process where cell reduces the activity or quantity of surface receptors to limit response to a signaling molecule.

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GRK in GPCR regulation

G protein-coupled receptor kinases (GRKs) are a family of serine/threonine kinases that phosphorylate the cytoplasmic tail of activated GPCRs.

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Arrestin in GPCR regulation

Arrestins are proteins that bind to phosphorylated GPCRs, preventing further G protein activation and promoting receptor internalization.

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cAMP generation

Adenylyl cyclase, an enzyme activated by G proteins, catalyzes the conversion of ATP into cyclic AMP (cAMP).

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cAMP and PKA

cAMP acts as a second messenger, binding to and activating protein kinase A (PKA).

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Loss of Function Mutation

A genetic change that results in the loss or reduction of normal protein function, leading to a nonfunctional signaling pathway.

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Gain of Function Mutation

A genetic change that causes a protein to become more active than normal, leading to constitutive activation of a signaling pathway.

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Study Notes

Cell Signaling and Signal Transduction

  • Cell signaling is the process of communication between cells.
  • Extracellular signals elicit a cellular response.
  • Signaling molecules are synthesized, released, travel to a target cell, and bind to a receptor.
  • Receptor binding triggers a response.
  • Receptors initiate one or more intracellular pathways.
  • Cellular function, metabolism, gene expression, shape, and movement can all change as a result of such processes.
  • Receptor deactivation and ligand removal conclude the process.

Types of Intercellular Signaling

  • Endocrine signaling: Signaling molecules (e.g., insulin) travel through the bloodstream to distant target cells.
  • Paracrine signaling: Signaling molecules travel short distances through extracellular space (e.g., neurotransmitters) to nearby target cells.
  • Autocrine signaling: Cells have receptors that respond to signaling molecules they themselves secrete (e.g., T-cells).
  • Juxtacrine signaling: Signaling molecules remain at the surface of cells, requiring physical contact between sending and receiving cells (e.g., antigen presentation).

Receptor Location

  • Cell-surface receptors: Hydrophilic signaling molecules bind to receptors on the cell surface.
    • Three major classes: G-protein coupled receptors (GPCRs), enzyme-linked, and ion channel-linked.
  • Intracellular receptors: Small hydrophobic signaling molecules can diffuse across the plasma membrane to bind to intracellular receptors.

Signaling Pathways

  • Two types:
    • Receptors on or in target cells receive the message.
    • Some cell surface receptors generate soluble, diffusible intracellular second messengers.
    • Second messengers activate or inactivate proteins.
    • Other surface receptors recruit proteins.
  • Many signal transduction pathways combine these mechanisms.

Second Messengers

  • Small molecules that increase or decrease in concentration in response to a first messenger.
    • Bind to proteins to modify their activity.
  • Examples: Cyclic AMP (cAMP), cyclic GMP (cGMP), 1,2-diacylglycerol (DAG), inositol 1,4,5-trisphosphate (IP3).

Protein Kinases and Phosphatases

  • Kinases phosphorylate target proteins.
  • Phosphatases dephosphorylate them.
  • Phosphorylation changes a protein’s charge and generally leads to a conformation change.
  • This can increase or decrease ligand binding or other features, altering activity.

GTP-Binding Proteins

  • GTPase superfamily hydrolyzes GTP to GDP.
  • Two conformations (on and off).
    • on = bound GTP
    • off = bound GDP.
    • GTPase-activating proteins (GAPS), regulators of G protein signaling (RGSs), or guanine nucleotide dissociation inhibitors (GDIs), can influence signal transduction.
  • Guanine nucleotide exchange factors (GEFs) facilitate the exchange between GDP and GTP.

Molecular Switches

  • Phosphorylation
    • Addition of phosphate groups to hydroxyl groups on serine, threonine, and tyrosine, commonly.
    • Kinases phosphorylate.
    • Phosphatases dephosphorylate
  • GTP-binding proteins
    • Hydrolysis of GTP to GDP can change protein activity.

Signal Amplification

  • A small amount of ligand can elicit a large cellular response via amplification.
    • Epinephrine can illicit a large cellular response.

Signal Integration

  • Cells receive many signals.
  • Combinations of signals generate specific responses.

Survey of Extracellular Messengers and Receptors

  • Receptor location varies:
    • On or in the target cell
  • Ligands vary in the type of molecule.
  • Ligands include ions, enzymes, second messengers, etc.

Signal Transduction by GPCRs

  • GPCRs have 7 membrane-spanning a-helices.
  • Ligand binding changes receptor conformation which changes the G protein's activity.
  • Different G protein types exist, leading to different responses.

Termination of Response

  • Desensitization: Blocking receptors from turning on additional proteins (GRK-phosphorylates GPCR).
  • Arrestins: Competing with G proteins for binding to GPCRs.
  • Receptor recycling/internalization: Recycling GPCRs back to the cell surface for continued responsiveness.

cAMP

  • Second messenger generated by adenyl cyclase.
  • Adenyl cyclase catalyzes the conversion of ATP to cAMP.
  • Protein kinase A (PKA) gets activated by cAMP.

Discovery of cAMP

  • Sutherland identified a substance released from cell membranes: cAMP.
  • cAMP activates glycogen phosphorylase, involved in glucose mobilization.

cAMP activates PKA

  • Protein Kinase A (PKA) is known to have many substrates
  • PKA phosphorylates proteins, resulting in phosphorylation of serine, threonine which affects a variety of cellular activities.

AKAPs

  • Anchoring proteins confine signaling processes, leading to localized effects on target proteins.
  • PKA is confined and is only activated by kinases at specific locations.

The Human Perspective

  • Many G protein-coupled receptors (GPCRs) are associated with human diseases stemming from mutations, both gain and loss of function type.
  • Ligands that bind to GPCRs are over 1/3rd of the prescription drugs.

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