L4. Cellular Communication Pt. 2 Flashcards
Signal amplification?
One hormone molecule (first messenger) binding to its cell receptor
- Triggers a cascade of second messengers
- Each second messenger may cause the activation or production of many other second messenger molecules
- So 1 hormone molecule binding can end up producing 1 million molecules of the final product
Signal transduction?
Converting a signal into a cellular response
Signal transduction in water soluble hormones?
- Change in membrane potential e.g. neurons, skeletal muscle cells, cardiac muscle cells
Second messenger pathways:
2. Increase in calcium concentration
3. Phosphorylation of proteins
4. Increase in gene transcription
Second messenger - increase in Ca2+ concentration?
Ca2+ is the most common second messenger:
- Normally Ca2+ levels in the cytoplasm are very low
- Ca2+ levels are increased by activation and opening of membrane calcium channels AND endoplasmic reticulum calcium channels
- Ca2+ binds to proteins and changed their conformation and function: calmodulin (troponin)
- Activates kinases
- Another example of calcium being used as a second messenger is during the release of neurotransmitter from the axon terminals of a neuron
Second messenger - activation of protein kinases?
Kinases phosphorylate other molecules which can increase or decrease activity like transcription factors, channels and transporters, enzymes etc.
Second messenger - activation of transcription factors?
Hormone binds to cell surface which activates a metabotropic receptor and then activates other proteins via phosphorylation
Signal transduction of water soluble different receptors?
Ionotropic receptors (open ion channels) = an ion channel in the cell membrane that opens in response to a neurotransmitter or hormone binding
- Ligand-gated ion channels
- Metabotropic receptors (change cellular metabolism) = a receptor on the cell membrane that initiates a number of metabolic steps to regulate cell function
- Receptor tyrosine kinases
- Tyrosine kinase associated
receptors
- G-coupled protein receptors (GPCRs)
Receptor tyrosine kinases?
- Part of the receptor is a tyrosine kinase
- The hormone (first messenger) binds to receptor
- Induces a conformational change so that the tyrosine kinase portion of the receptor is activated, causing it to phosphorylate its OWN tyrosine residues (autophosphorylation)
- The phosphorylated tyrosine’s act as docking sites for other proteins
- Proteins can dock and be phosphorylated
- Or docking may bring them into proximity with other membrane bound proteins which they can interact with
e.g. Insulin receptor
Tyrosine kinase associated receptor?
- A tyrosine kinase is associated with the receptor
- The hormone binds to the receptor to induce a conformational change in the receptor
- This leads to activation of the JAK kinase (just another kinase)
- The activated kinase then phosphorylates tyrosine residues on other proteins, changing their cellular function
e.g. prolactin and GH receptors
G-protein coupled receptors (GPCR)?
- A G-protein is coupled to the receptor
- The receptor is a transmembrane protein
- It is associated with a G-protein, which has three subunits –> alpha, beta, and gamma
- Alpha subunit can bind GTP, GDP, and can act as a GTPase (hydrolysing GTP to GDP + Pi)
- Beta and gamma help to anchor the G-protein to the receptor
Types of G-protein coupled receptors:
- Gs-protein
- Gi-protein
- G-q protein
GPCR activation?
- When the receptor is activated, there is a conformational change which changes the affinity of the alpha subunit such that it is more likely to bind GTP
- Once bound to GTP, the alpha subunit dissociates from beta/gamma and can then interact with effector proteins in the membrane: ion channels and enzymes
- After the alpha subunit has interacted with its effector proteins the alpha subunit acts as a GTPase, hydrolysing GTP –> GDP + Pi
- This inactivates the alpha subunit
- It leaves the effector proteins and recombines with the other two subunits
- Ready to receive another signal
Gs-protein coupled receptors?
- Hormone binds to the receptor
- GTP can bind to the alpha subunit of the Gs protein, causing it to unbind from the rest of the G-protein
- Then it will interact with the enzyme adenylyl cyclase and ACTIVATE IT
Gs protein - Stimulates adenylyl cyclase
- Activated adenylate cyclase converts ATP –> cAMP
- cAMP activates cAMP-dependent protein kinases
e.g. protein kinase A (PKA) - Phosphorylation of proteins causes the cellular response
- Remember phosphorylation can activate or inhibit
Examples of Gs-protein coupled receptors = beta adrenergic receptors in the heart and ADH receptors in the kidney
Gi-protein coupled receptors?
- Same process as the Gs-protein coupled receptor but instead of activating adenylyl cyclase, Gi INHIBITS it
- Inhibition of adenylyl cyclase causes: decrease cAMP, decreased activation of PKA, and decreased protein phosphorylation
Examples of Gi-protein coupled receptors = muscarinic acetylcholine receptors in the heart and alpha-2 adrenergenic receptors
Gq-protein coupled receptors?
- Same process as the others except in interacts with the enzyme phospholipase C (PLC) (as the effector protein) and ACTIVATES it
- PLC catalyses the breakdown of PIP2 –> IP3 + DAG
- DAG activates protein kinase C
- Protein kinase C (PKC) phosphorylates other proteins causing part of the cellular response
-IP3 binds to ligand-gated Ca2+ channels on the endoplasmic reticulum
- Increase in Ca2+ in the cytoplasm causing part of the cellular response
- Plus it increases activation of PKC
Steroid hormone signal transduction?
- Lipid soluble hormones diffuse out of the blood into the cell
- Receptor is in the cytoplasm or nucleus
- One hormone can regulate multiple different genes
- Can increase or decrease the rate of gene transcription into mRNA, and therefore protein synthesis
- Response takes hours to days
Example = Aldosterone and increases sodium reabsorption
Thyroid hormone signal transduction?
- Thyroid hormones are lipophilic, so they can cross cell membrane by free diffusion as well as being transported
- T4 (inactive prohormone) converted to bioactive T3 via deiodinase enzyme
- The thyroid hormone receptor (TR) and the RXR protein are bound to the thyroid response element (TRE) on DNA
- When there is NO thyroid hormone present, compressors are bound and transcription is blocked
- When T3 binds, conformational change in receptor complex allowing for binding of coactivators, promoting transcription of genes
Synergy?
The power that results from the combination of two hormones which is greater than the maximum individual response
Permissive effect?
One hormone is required for another hormone to be able to exert its full effect (needs permission from another hormone to work)
True or False?
GTP binding to the alpha subunits of a G-protein coupled receptor triggers it to dissociate from the other subunits
True
Gq-protein coupled receptors:
A. Activate ligand-gated calcium channels
B. Decrease protein kinase activity
C. Are in the cell nucleus
D. Increase production of cAMP
A
