REB 2. Cellular Mechanisms of Hormone Action Flashcards
What are the 2 systems that coordinate communication throughout the body?
[1] Endocrine System
[2] Nervous System
What are characteristics of the endocrine system?
- slower, but long-acting responses
- include reproduction, development, energy metabolism, growth and behaviour
- uses hormones
What are characteristics of the nervous system?
- conveys high-speed electricla signals along neurons
- these signals regulate other cells
- uses electrical signals
What is the difference between endocrine and exocrine glands?
Endocrine - release chemical substances directly into the bloodstream
Exocrine - the chemical substances are secreted into ducts (e.g. for enzymes)
What are hormones?
- biochemical messengers
- released into endocrine glands
- has an impact on gene expression/protein state
- they complement neurotransmitters
What is the difference between neurotransmitters and hormones?
Neurotransmitters - work through adjacent cell contact
Hormones - work by broadcasting a message
What is the main regulation mechanism for regulation within the endocrine system?
Regulated by Feedback
- in particular, Negative Feedback
- Positive Feedback has an opposite effect
What are the 3 main types of hormonal signalling that acts upon cells?
[1] Endocrine Signalling - enters the blood stream to act on cells (usually acts on distant sites, but may also act locally)
[2] Paracrine Signalling - the target cells lie near the secreting cells
[3] Autocrine Signalling - the target cell is also the secreting cell
How are hormones specific and potent?
- although concentration of hormones are low, they only bind onto specific receptors
- the specificity and potency is delivered through receptors
Describe the basic principle/mechanism of how a hormone works after a stimulus is received.
- stimulus is received + processed by endocrine gland
- hormones released into blood
- hormones carried to target tissues where they bind (with high specificity) to receptors
What actions/changes may hormones produce in tissues/cells?
[1] altering plasma membrane permeability [by closing/opening protein channels]
[2] regulating expression of functional proteins [via gene activation or suppression]
[3] moderating enzyme activity [via activation or deactivation]
[4] inducing or suppressing release of secretory products
[5] stimulating mitosis and cell division
What are the 2 main factors influencing the degree of cellular response? (and some examples)
[1] Delivery of Hormone
- rate of synthesis + secretion of hormone
- proximity of target cell to hormone source
- the rate at which hormones dissociate from carrier proteins
- rate of conversion from inactive to active forms
- rate of clearance by liver/kidney
[2] Receptor/Tissue Status
- Density and state of occupancy of receptors
- Affinity of receptors for hormone
- Desensitization of receptor
What are the 4 main categories that we use to classify hormones?
[1] Chemical Nature/Hormone Structure
- Steroids, Peptides, Glycoproteins
[2] Solubility
- Lipophilic vs. Hydrophilic
- In other words, hydrophobic vs. hydrophilic
- Lipophilic = Hydrophobic
- Lipophobic = Hydrophilic
[3] Cellular Binding Site/Receptor Location
- Intracellular vs. Cell Surface
[4] Receptor Basis
- G-Protein Receptors
- Secondary Messengers
- Kinase Receptors
What are the 4 main hormone structures and some characteristics of each?
[1] Steroid Hormones
- derived from cholesterol (e.g. testosterone and estrogen)
- hydrophobic + travel bound to transport protein in blood
[2] Peptide Hormones
- short chain amino acids (e.g. oxytocin or insulin)
[3] Protein Hormones
- long chain amino acids/complex proteins (e.g. TSH)
[4] Amine Hormones
- amino acid derivatives (e.g. epinephrine, thryoxine)
- derived from modification of amino acids
- mainly synthesized from tryptophan and tyrosine
- can be both hydrophobic or hydrophilic
What are the 2 main classes of hormones based on solubility?
[1] Hydrophilic
- soluble and readily diffuses into the blood
[2] Hydrophobic
- poorly water soluble
- binds to tranporter proteins/plasma proteins within the blood circulation
What are the 2 main classes of hormones based on its cellular binding site? Give a general overview of how these processes work.
[1] Water-Soluble Hormones
- unable to diffuse through cell membrane
- their receptors are located at the extracellular surface
- this initiates a signalling cascade that is carried out by second messengers
- “rapid” metabolic effects
[2] Lipid-Soluble Hormones
- readily diffuse through cell membrane
- they can reach the intracellular receptor within the cytosol or nucleus
- the hormone-receptor complex binds to a segment of DNA triggering transcription of target gene to mRNA
- “slow” developmental effects
What are the steps in hydrophobic intracellular signalling?
- Diffusion
- hydrophobic hormones can readily diffuse through the lipid bilayer of the cell membrane to reach the intracellular receptor - Binding
- encounters specific receptors within cell - Translocation
- activated receptor translocates to the nucleus - Hormone Response Elements
- Once in nucleus, activated receptor binds to the hormone response elements (HREs) of DNA - [DELTA] Expression/Change in Expression
- this binding drives changes in mRNA and resulting protein expression
What are Hormone Response Elements (HRE)?
- they are regions of DNA that the (hydrophobic) hormone-receptor complex binds to
- they are normally upstream of the 5’ transcription initiation site
- nuclear receptor proteins/transcription factors can also bind to them (providing further layer of complexity/control)
What are the steps in hydrophilic signalling?
- Binding
- encounters specific receptors on cell membrane
- typically G-protein coupled receptors (GPCRs)
- receptors carry signal across membrane - Intracellular Signalling
- activated G protein activates adenylate cyclase - this converts ATP to cAMP which propagates the signal through the cell - Activation of Protein Kinase A (PKA)
- cAMP targets and activates PKA in the cytosol - Phosphorylation
- PKA triggers selective phosphorylation of cellular proteins (phosphorylation cascade)
- e.g. metabolic enzymes, nuclear transcription factors
What are some functions of Protein Kinase A (PKA)?
[1] Inhibition of Glycogen Synthesis
[2] Promotion of Glycogen Breakdown
In extracellular/hydrophilic hormone signalling, how is the phosphorylation cascade shut off?
PKA activated Phosphodiesterase (PDE) within the cytosol which deactivates cAMP - turns off the signal until next stimulus
Explain a bit about the process of another secondary messenger, Calcium, starting from how the whole process is activated and what intermediates are created.
- G-proteins activate the Phospholipase C enzyme
- Phospholipase C cleaves membrane-bound phospholipid (PIP2) into:
- Diacylglycerol (DAG)
- Inositol Triphosphate (IP3)
Functions of DAG:
- activates protein kinases that initiate phosphorylation cascade
Functions of IP3:
- causes calcium ions to be released from storage sites in cytosol
- (1) calcium influences enzymatic and other cellular activities
- (2) binds to calcium-binding protein, calmodulin, which is able to modulate protein kinase within the cell
What are the 2 main functions of calcium as a second messenger?
[1] calcium influences enzymatic and other cellular activities
[2] calcium binds to calcium-binding proteins, calmodulin, which is able to modulate protein kinase within the cell
What is cGMP and how is it created? What is an example of the use of cGMP?
- it is a secondary messenger
- GTP is converted to cGMP through the membrane-bound receptor Guanylate Cyclase
- Example: Atrial Natriuretic Peptide
-Increased B.P induces ANP release from the cardiac
atria- The binding of ANP to its receptor causes the
conversion of GTP to cGMP - cGMP activates a Protein Kinase G (PKG) and also
directly regulates ion channels - ANP induces reduction in ECF volume by increasing
renal sodium excretion
- The binding of ANP to its receptor causes the
Explain the process by which insulin receptors work and how the signal is transmitted to lead to glucose uptake and glycogen synthesis (insulin release during high glucose levels).
- insulin receptor is a Tyrosine-Specific Protein Kinase (NO second messengers!)
- after ligand binding, the receptors dimerize
- they both undergo autophosphorylation
- the Insulin Receptor Substrate (IRS-1) binds to phosphate groups and get phosphorylated
- this further propagates signal transduction
- leads to (a) glucose uptake
(b) glycogen synthesis
What are the 2 main diseases that may arise due to a defect in a hromone receptor.
[1] Type II Diabetes (insulin resistance)
- reduction/insensitive to insulin receptor results in downstream signalling deficits and increased blood glucose levels
- not reactive to receptor so signal isn’t transmitted
[2] Graves’ Disease (TSH receptor)
- autoantibodies against Thyroid Stimulating Hormone (TSH)
- the autoantibodies bind to TSH receptor resulting in increased thyroid hormone production
- leads to hyperthyroidism
