Signal Transduction I Flashcards
Exam 2 Content
Describe how cell-cell communication works in signal transduction.
What is cell-cell communication?
* The various mechanisms through which cells interact and exchange information.
Different Types (5 types)
* Autocrine Signaling–> Cells respond to signals they themselves secrete
* Paracrine Signaling–> Signals are released and affect nearby target cells.
* Endocrine Signaling–> Hormones are secreted into the bloodstream and affect distant cells.
* Synaptic Signaling–> Neurotransmitters are released at synapses, affecting adjacent neurons.
* Juxtacrine Signaling–> Direct cell-to-cell contact mediates communication
In-depth description
* Juxtacrine–> cell-cell contact, two surface proteins bind
* Endocrine–> hormones secreted into bloodstream, no cell-cell contact, low concentration (10^-12-10^-9 M), high affinity receptor; response minutes to hours
* Paracrine–> Secreted ligands target nearby cells, relatively high local concentration (10^-9-10^-6 M) , lower affinity receptor; rapid, transient response (secs to minutes)
Mode of cell-cell communication
* Synaptic or neuronal signaling–> synapse between neuron and target is short distance, very high local concentration (10^-6-10^-3), very low affinity receptor; dissociates rapidly (ms)
* Autocrine signaling–> sender and target are the same cell, response time similar to paracrine signaling, target receptors on same cell
What is a signal transduction cascade?
What is signal transduction?
* Signal transduction is when cells receive external signals through receptor molecules.
* “tranduced” = converted into another form
* Transduction is through stepwise regulation of interactions of intracellular signaling proteins, and often amplified.
* A cellular response is elicitated involving processes like gene expression, membrane transport, metabolism, cell growth/death
Bottom line
* When information from the environment is transmitted inside a cell, which generates a cellular response.
Characterize a signal transduction cascade.
Description of signal transduction cascade:
* Sequentional biochemical events to transfer a signal through a series of reactions that activate intermediate molecules to find a final target (e.g. regulatory molecule or transcription factor)
Steps:
* 1) Reception–> signaling molecule binds to the receptor (typically the cell surface receptors)
* 2) Transduction–> Relay molecules in a signal transduction pathway
* 3) Response–> Activation of a cellular response
Impact of signal transduction cascade
* Signaling cascades often amlify the message by producing multiple intracellular activated molecules for every one receptor that is bound.
What are first messengers?
- Secreted molecules are first-messenger ligands for receptors
Ligands/first messengers are these types of molecules:
* Can be big: proteins, polypeptides
* Small: amino acids, lipids, nucleotides
* And other chemical types: steroids, vitamins, histamine, modified amino acids
Receptors for most first messengers are either intracellular proteins or integral membrane proteins.
What are second messengers?
- Second messengers are crucial for amplifying the signal inside the cell.
- They allow for a rapid and widespread response.
Common Second Messengers:
* Cyclic AMP (cAMP): Generated from ATP by the enzyme adenylate cyclase, it activates protein kinase A (PKA), which phosphorylates larger proteins.
* Ca2+ Ions: Released from the endoplasmic reticulum or enters through ion channels, calcium acts as a versatile second messenger, regulating various cellular processes.
* Inositol Triphosphate (IP3) and Diacylglycerol (DAG): These are generated from phosphatidulinositol and are involved in activating protein kinase C (PKC) and releasing calcium from endoplasmic reticulum.
What are receptors?
Differentiate between second and first messengers
- They are specialized proteins that respond to specific stimuli (sensors of cells).
*First Messenger (secreted, hydrophobic ligand molecules): *
1. Intracellular Receptors (inside cell)
* Lipid soluble hormones diffuse through the plasma membrane and bind to the intracellular receptor.
* Signal is propagated by changes in receptor upon binding. Changes lead to altered gene expression.
* Endocrine signaling= steroid hormones, thyroid hormone, vitamins
* ONLY the cells with the specific receptor for a given hormone respond even though nearly all cells in the body are exposed to the hormone
* Ex. Hormonal nuclear receptor- HRE is highly specific to given hormone/NR
* Ex. Steroid nuclear receptor for steroid hormone signaling- changes in gene expression over hours to days- can be a transcription factor- direct interaction with DNA and control of gene expression- receptor binds to steroid, receptor binds to specific site on DNA, associates with coactivaters, and transcription gets activated.
* Ex. Heterodimer nuclear receptor- Retinoid X receptor LXR-beta (light blue) and liver X receptor RXR-alpha bound to DNA response element- DBD, hinge, LBD- Ligands are antagonist, agonists, or partial agonist.
* Ex. Thyroid nuclear receptor- The thyroid hormone, which is lipid soluble, diffuses through the plasma membrane. Inside the cell, thyroid hormones bind receptor and promotes dimerization of receptor (green+purple in one polypeptide chain). Binding recrutis coregulatory proteins, which promote DNA binding and specific recognition of thyroid response element. Signaling outcome is to turno on or off transcription.
2. Other Type of FM receptor: Integral Membrane proteins (inside cell membrane)
* General Process: First messenger (hydrophobic ligand) binds to the receptor, which leads to the activation of effector proteins and other intracellular enzymes. Sometimes there are coupling proteins. Sometimes the ligand binding alters receptor/enzyme activity. Sometimes ligand binding leads to the opening of ion channels, which changes the membrane potential.
Second Messenger Relationship to Receptors
* Small, intracellular molecules that transmit and amplify the initial signal from the extracellular first messenger binding to receptors. 1st messenger–> 2nd messenger–> Intracellular response
* Inorganic ions or organic products of enzyme catalyzed reaction (Ions: Ca2+; Water-Soluble: cAMP, cGMP, IP3; Lipid: diacyclyglycerol (DAG), Phosphatidylinositol 3,4,5-triphosphate (PIP3) )
Estrogen Receptor Alpha- over expressed in 70% breast cancer. Tamoxifen is ER antagonist to treat breasts.
Describe the difference between transduction and protein phosphorylation.
Signal Transduction: 1st messenger binds to the receptor, which activates effector proteins and other intracellular enzymes. This activates 2nd messengers, which stimulate the intracellular response.
Protein Phosphorylation: Modification by phosphorylation controls protein-protein interactions and ezymatic activity. Phosphorylation of a protein can induce conformational changes that result in increased or decreased enzyme activity (Protein Kinase + ATP).
* Mechanism to control protein-protein interactions and enzymatic activity.
* Promotes or disrupts
* Promote: binding site with a phosphorylated residue is recognized by the binding partner, but the unphosphorylated one is not.
* Disrupt: binding site with a phosphorylated residue is NOT recognized by the binding partner, but the unphosporylated one is recognized by the binding partner.
* Under the control of phosphorylation, large assemblies of proteins (scaffold, adapter, or anchoring proteins) form. (Phospho-Y, phospholipid).
Describe the difference between transduction and GTP-binding regulatory proteins.
Signal Transduction: 1st messenger binds to the receptor, which activates effector proteins and other intracellular enzymes. This activates 2nd messengers, which stimulate the intracellular response.
GTP-binding regulatory proteins:
* G proteins bind and hydrolyze GTP, and are therefore GTPases.
* G proteins constitute a molecular switch between OFF/ON states of a signal.
* The GDP-bound form of the G-protein is a different conformation from the GTP-bound form.
* The exhange of GDP for GTP is catalyzed by proteins called guanine nucleotide exchange factors, GEFs (more to come).
* GEF binding to the G-protein/GDP complex promotes release of GDP, followed by binding of GTP, which activates the G-protein, Activates G protein to signal
* GTP hydrolysis turns off the signal.
Explain the process of signal termination.
Rapidly reducing the level of message, or agonist availability, in the extracellular vincity of a target cell. Common mechanism for synaptic signaling.
* Rapid re-uptake of neurotransmitters by transporters, e.g. serotonin, dopamine (remember SERT)
* Breakdown by enzymes. Example: acetylcholine esterase
Receptor loss or desensitization (lower response to same agonist concentration)
* Reduced receptor availability by internalization and. in some cases, degradation of the agonist-bound receptor complex
* Functionally adapted by modifying receptors (e.g. phosphorylation or dephosphorylation) to be less sensitive.
What does signaling allow you to do?
Signaling is inter-cellular communication mediated by secreted molecules/ligands that bind receptors and trigger intracellular cascades in a regulated fashion to generate a specific cellular response.
* Serves to coordinate numerous processes needed for multicellular organisms
* Signals are amplified
* Differs from metabolic pathways
* 5 modes of cell-cell communication differ in response time, receptor affinity, local ligand concentration
Describe the receptor learning objective.
- Signaling is initiated by receptors binding the secreted molecules/ligands, which are 1st messengers of varying molecular types
- Cell surface receptor proteins bind hydrophilic or large ligands
- Intracellular receptor proteins bind hydrophobic ligands such as steroid hormones.
What are the different ways that cell surface receptors initiate signaling?
- 2nd messenger production
- Change in membrane potental
- Effector or receptor enzyme activation
What are the four classes of cell surface receptors?
- Ion channel-linked receptors
- G-protein-linked receptors
- Enzyme-linked receptors
- Cytokine-linked receptors
What control mechanisms do we have for signaling?
- the control mechanisms switch proteins between a down-regulated or inactive form and an active form.
Two major control mechanisms:
1. Protein phosphorylation contols enzyme activity and protein-protein interactions
2. G proteins and GTPase activity control protein-protein interactions
