Fast hormonal Signal Transduction Processes Flashcards
What is signal transduction?
A process wherby the extracelluar agents alter the cell function and metabolism
Describe a generalised process of signal transduction.
1) Hormone release
2) Hormone binding to the receptor on the cell surface causing a some kind of change of the intracellular part of the receptor
3) Change in concentration of second messenger, that can amplify the effect of the hormone
4) Second messenger decrease or increase the activity of the effectors
5) Signal is shut down by removing receptor/braking down the hormones/reversing the effects of the intracellular cascade
What mechanisms and structural features allow for signal specificity?
o The effects/targets of hormones are defined – specificity for them is needed
o Hormones are often released only into a specific location
- E.g. neurotransmitters
o Each cell expresses a specific group of receptors responds to a restricted number of hormones
- Different receptors can bind the same hormone stimulating production of different second messengers and therefore different responses
o Each 2nd messenger has specific effects in the cell
- Activated by specific receptor and thus also specific hormone
o Cells express different isoforms of effectors, which can differ in their effects on the cell or their regulatory pathways
- Enzymes - effect of a 2nd messenger on different tissues can have different effects
What mechanisms and structural features contribute to cells sensitivity to a signal?
- For some hormones, the concentrations reaching the target cells are very low
E.g. insulin is active at only 〖10〗^(-10)M - Cells responding to these hormones need to be very sensitive
- High sensitivity is achieved by high affinity of the ligand for the receptor
- Signal is amplified on the stage of 2nd messenger relatively few signals are needed to produce a large intracellular response
- Second messengers often stimulate some effectors and inhibit others achieving their effect through different, opposing mechanisms amplification of the effect
Do all signalling types have a desensitization mechanism? How do cells desensitize to a signal?
o Not all pathways have desensitisation mechanism
o Initiation of the signal (hormone binding) often also stimulates the enzymes, that will shut it down, when the hormone is no longer present
o Desensitisation can occur even if the hormone is still present
- E.g. Insulin sensitivity is decreased in type II diabetes – despite/because high insulin blood levels
How do cells integrate signals and how can different signals interact with each other?
o Most cells can respond to a variety of hormones and sometimes these pathways can interact with each other
1) Synergistic or antagonistic action
o Some different receptors may modulate the concentrations of the same second messenger
o Different signaling pathways may alter the same effectors fine tuning of the cell’s response
What are the allosteric effects of the hormonal signal binding?
Signal binds to the receptor changing it confirmation and having an effect on it as long as it is bound
Hormones & hormone receptors – conformational change in the cytosolic domain
GPCRs & G-Proteins – subunit α dissociates from the βγ subunit
Ca^(2+) & Calmodulin –hydrophobic areas are exposed, which allows the calmodulin to interact with other proteins
cAMP & PKA – regulatory subunits dissociate, activating the catalytic subunits
do not amplify the signal
ratio 1:1 or worse
What protein domains have affinity for:
- phosphorylated tyrosines
- proline rich regions
- phosphoinostitolines
- Ca2+
Domains with high affinity for phosphorylated tyrosines
PTB – Phosphotyrosine binding domain
SH2 – Src homology 2
Domain with high affinity for proline-rich regions
SH2 – Src homology 3
Domain with high affinity for phosphoinostitolines (phospholipids + phosphorylated Inositol)
Pleckstrin homology
Domain with high affinity for Ca^(2+)
EF-Hand
What are Endocrine, Paracrine and Autocrine hormones? What are the examples of such hormones?
o Endocrine – act on cells far from the site of release
1) E.g. insulin & adrenaline
o Paracrine – act on nearby cells
1) E.g. in immune responses
o Autocrine – act on the cell that released the hormone
1) E.g. T-cells & interleukin-2
What chemical compounds can hormones be? What are the examples of a hormone of each type?
o Polypeptides - E.g. insulin
o AA derivatives - Adrenaline, thyroxine
o Eicosanoids - Prostaglandins, leukotrienes
o Purines - Adenosine
What is the difference in typical action between hydrophobic and hydrophylic hormones
- Hydrophobic hormones tend to have long-term effects on the cell behavior, as they often act on gene transcription
o E.g. estrogen - Hydrophobic hormones tend to produce effect quicker response
o Can’t diffuse into the cell need to have a receptor on cell membrane
What are the 4 basic GPCR divisions (α-subunits)?
Gs – activate adenylate cyclase, increase [cAMP]
Gi – inhibit adenylate cyclase, reduce [cAMP]
Gq – activates phospholipase C, increasing [DAG], [IP3] and [Ca^(2+)]
Gt – activates retinal cGMP phosphodiesterase
Describe the process of beta-adrenoceptor activation.
1) Adrenaline binds to the receptor
2) Receptor changes shape
3) G-protein binds to the receptor and changes conformation, releasing GDP and allowing for GTP binding
4) G-protein subunits dissociate
5) Gs α-subunit activates the Adenylate cyclase
6) Adenylate cyclase converts ATP into cAMP
7) cAMP binds to the regulatory subunits of PKA, releasing the catalytic subunits
8) Catalytic subunits phosphorylate their target proteins:
• Hormone-sensitive lipase (+)
• Acetyl CoA carboxylase (-)
• Glycogen synthase (-)
• Transcription factor CREB (+)
What are the points of amplification in beta-adrenoceptor activation pathway?
1) Adrenaline-receptor complex can catalyse GDP exchange on multiple G-proteins
• Each G-α can bind to a single adenylate cyclase
2) Active adenylyl cyclase can catalyse the formation of many cAMP molecules
• It takes only 4 to activate 2 PKA subunits
3) Active PKA subunit can phosphorylate many proteins
How is beta-adrenoceptor pathway shut down?
1) Each point of amplification needs to be turned off to stop signaling
2) Adrenaline removed from the receptor site
3) α-subunit self-dephosphorylates uncovering the binding site for β and γ subunits and G-protein re-associates stopping the activation of adenylate cyclase
4) Cyclic Nucleotide Phosphodiesterase continuously converts cAMP to AMP, so when the adenylate cyclase is inactivated [cAMP] decreases
5) Decreased [cAMP] causes re-association of regulatory subunits of PKA with the catalytic subunits
6) Phosphorylated target proteins are dephosphorylated by phosphatases, which are continuously active in the cell
