Lecture 5: Cellular Endocrine 2 Flashcards
What is signal amplification?
- 1 hormone molecule 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
1 hormone molecule binding can end up producing 1 million molecules of the final product
What is signal transduction?
The process of converting a signal into a cellular response
What are the 4 mechanisms of signal transduction for peptide and catecholamine hormones?
- Change in the membrane potential e.g. neurons, skeletal muscle cells, cardiac muscle cells
Second messenger pathways:
- Increase in calcium concentration
- Phosphorylation of proteins
- Increase in gene transcription
Describe the mechanism for the increase in Ca2+ concentration:
- Activation and opening of membrane and/or ER calcium channels
- Calcium binds to proteins and changes their conformation and function: calmodulin (troponin)
- Activates kinases - kinases phosphorylate other molecules
Describe the mechanism of phosphorylating proteins:
Kinases phosphorylate other molecules:
* Phosphorylation can increase or decrease activity
Kinase + ATP -> Protein-P + ADP
What can be phosphorylated?
- Transcription factors
- Channels and transporters
- Enzymes
Describe the mechanism of increasing gene transcription:
- Hormone binds to metabotropic receptor
- Activation of proteins that function as transcription factors via phosphorylation or other means
- Primary gene responses in the nucleus -> mRNA -> synthesis of different transcription factors outside nucleus
- Responses of other genes in the nucleus -> mRNA -> synthesis of proteins that mediate the cell’s response to the 1st messenger e.g. proliferation and differentiation
How can gene transcription be regulated?
- Metabotropic receptors for peptide and catecholamine hormones (cell membrane)
- Steroid receptors (cytoplasmic/nuclear)
- Thyroid hormone receptors (nuclear)
What are ionotropic receptors?
An ion channel in the cell membrane that opens in response to a neurotransmitter or hormone binding
What are metabotropic receptors?
A receptor on the cell membrane that initiates a number of metabolic steps to regulate cell function
What are the 4 types of receptors for peptide and catecholamine hormones?
Ionotropic receptors (open ion channels):
- Ligand-gated ion channels
Metabotropic receptors (change cellular metabolism):
- Receptor tyrosine kinases
- Tyrosine kinase associated receptors
- G-coupled protein receptors (GPCRs)
What are the 3 steps in the signal transduction pathway for ionotropic receptors?
- When the hormone isn’t bound, the channel in the receptor is closed
- When the hormone (first messenger) binds the ion channel opens
- Causes a response in the cell via:
- Change in membrane potential
- Ca2+ influx
Give 2 examples of ionotropic receptors:
- Neuromuscular junction: nicotinic acetylcholine receptors
- Chemical synapses between neurons
What are the 4 steps in the signal transduction pathway for receptor tyrosine kinase?
- The hormone binds to metabotropic 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
Give an example of a receptor tyrosine kinase:
Insulin receptor
What are the 3 steps in the signal transduction pathway for tyrosine kinase associated receptor?
- The hormone binds to the receptor and induces a conformational change
- This leads to activation of the JAK kinase
- Janus Kinase
- Just Another Kinase - The activated kinase then phosphorylates tyrosine residues on other proteins, changing their cellular function.
Give 2 examples of a tyrosine kinase associated receptor:
- Prolactin
- GH receptors
What is a G-protein coupled receptor and what are it’s subunits?
- The receptor is a transmembrane protein
- It is associated with a G-protein, which has 3 subunits - alpha, beta & gamma
- Alpha subunit can bind GTP, GDP and can act as a GTPase; hydrolysing GTP to GDP + Pi
- Beta & gamma help to anchor the G-protein to the receptor
What are the 6 steps in the signal transduction pathway for G-protein coupled receptors?
- Receptor is activated, causing conformational change which changes the affinity of the alpha subunit so that it’s more likely to bind GTP
- Once bound to GTP, the alpha subunit dissociates from beta/gamma and can interact with effector proteins in the membrane:
* ion channels
* enzymes - After the alpha subunit has interacted with its effector proteins the alpha subunit acts as a GTPase; 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
What are the 3 types of G-protein coupled receptors?
- Gs-protein
- Gi-protein
- Gq-protein
What are the 6 steps in the signal transduction pathway for Gs-protein coupled receptors?
- A hormone binds to the receptor, activating it
- GTP binds to alpha subunit of the Gs-protein, causing it to unbind from the rest of the Gs-protein
- GTP and aplha interacts with adenylyl cyclase and ACTIVATES IT
- Activated adenylate cyclase; ATP -> cAMP
- cAMP activates cAMP-dependent protein kinases e.g. Protein kinase A (PKA)
- Phosphorylation of proteins causes a cellular response; activate or inhibit
Give 2 examples of Gs-protein coupled receptors:
- Beta adrenergic receptors in the heart
- ADH (vasopressin) receptors in the kidney
What are the 4 steps in the signal transduction pathway for Gi-protein coupled receptors?
- A hormone binds to the receptor, activating it
- GTP binds to alpha subunit of the Gi-protein, causing it to unbind from the rest of the G-protein
- GTP and alpha interacts with adenylyl cyclase and INHIBITS IT
- Inhibition of adenylate cyclase causes:
↓ cAMP
↓ activation of PKA
↓ protein phosphorylation
Give 2 examples of Gi-protein coupled receptors:
- Muscarinic acetylcholine receptors in the heart
- Alpha-2 adrenergic receptors
What are the 4 steps in the signal transduction pathway for Gq-protein coupled receptors?
- A hormone binds to the receptor, activating it
- GTP binds to alpha subunit of the Gq-protein, causing it to unbind from the rest of the G-protein
- GTP and alpha interacts with Phospholipase C (PLC) and ACTIVATES IT
- PLC catalyses the breakdown of: PIP2 → IP3 + DAG
What is the role of DAG in the signal transduction pathway for Gq-protein coupled receptors?
- DAG activates Protein Kinase C
- Protein Kinase C (PKC) phosphorylates other proteins - causing part of the cellular response
What is the role of IP3 in the signal transduction pathway for Gq-protein coupled receptors?
- IP3 binds to ligand gated Ca2+ channels on the endoplasmic reticulum
- ↑ Ca2+ in the cytoplasm - causing part of the cellular response + ↑ activation of PKC
Give an example of a Gq-protein coupled receptor:
Alpha 1 adrenergic receptors
Describe the signal transduction pathway for steroid hormones:
- 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
Describe how thyroid hormones get from the blood into the cell in the signal transduction pathway:
- Thyroid hormones are lipophilic, they can cross cell membrane by free diffusion as well as being transported
- T4 converted to active T3 via deiodinase enzymes
Describe the reception of thyroid hormones in the signal transduction pathway:
- The thyroid hormone receptor and the RXR protein are bound to the thyroid response element on DNA
- When there is NO thyroid hormone present corepressors are bound and transcription is blocked
- When T3 binds, conformational change in receptor complex allowing for binding of coactivators, promoting transcription of genes
- Thyroid hormone receptors are in the nuclei of most cells in the body, which is why they can have such widespread effects
What is the permissive effect?
One hormone is required for another hormone to be able to exert its full effect
What is synergy?
The maximum combined response of two hormones is bigger than addition of maximum individual responses
