Physiology 3140A Lecture Notes - Lecture 7: Adenylyl Cyclase, Phosphodiesterase, Cell Signaling
22 May 2018
School
Department
Course
Professor
Physiology 3140
Dr. Rylett
Lecture 7
Cyclic AMP (cAMP)
- Synthesized from ATP by plasma membrane-bound adenylate cyclase
o 3 high energy phosphate molecules
- adenylate cyclase (membrane bound enzyme) can chop off a few of those phosphates, leaving a
monophosphate
o this becomes cyclized – becomes a ring structure
o the rings stores a lot of energy and is a signalling molecule
- cAMP is degraded to 5'-AMP by cyclic AMP-specific phosphodiesterase
o cycle AMP specific phosphodiesterase is able to look at this molecule and open the ring
o so it leaves the phosphate on the molecule, but opens the ring (when the ring is open,
the molecule doesn’t have the same type of energy)
- ATP is not considered to be a cell signalling molecule
- Althought ATP and other analogues can serve as a ligand for some receptors but is not
considered to be a signalling molecule in the cell – it serves other purposes (generation of
energy, substrate for cAMP creation)
- 5’AMP doesn’t have any biological activity in terms of a signalling molecules
- once the ring structure is broken, you get a molecule htat doesn’t have biological activity
- cAMP is a ligand that can signal into the cell
cAMP as a signaling molecule
- for something to serve as a signalling molecule in a cell, it has to be present in a resting cell
either at 0 concentration or at very low concentration
- To function as an intracellular messenger, cAMP concentration (normally < 10-7 M) must be able
to change its concentratoin up or down rapidly in response to extracellular signals
- Example - upon hormonal stimulation, cAMP levels can change 5-fold within a few seconds
find more resources at oneclass.com
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o Ex: adrenaline binding to beta adgrenic receptors – the cAMP levels changes within
seconds
o This change doesn’t have to be huge – it can be 5 fold or 10 fold
o Lets say you have 10^7 in the resting cell and it goes to 10^6M then it can mediate an
effect and that will start falling back as the phosphodiesterase breaks it down to go back
to resting level
- In normal resting cells, the basal cAMP concentration is very low
o [cAMP] is below a level that can mediate any biological effects in the cell
o the cell then receives info (ex: ligand binding to a receptor)
o activation of adenyl cycles and you get activation of cAMP
o the concentration remains high for a certain period of time and then the
phosphodiesterase will start degrading it and the concentration starts to go back to the
basal level
o this is like a step function
- its this step function that really signals to the cell to be able to mediate some type of biological
effect
- when the concentration of cAMP increases, the immediate effect is that the probability that
there can be a biological effect increases
o the initial step is that bc there is an increase in concentration of 2nd messenger, now the
probability that there can be a biological effect has increased
o this relates to the ability of the 2nd messenger to bind to its targets
o 2nd messenger is more likely to bind to its target – PKA (affinity has increased)
o the probability has increased bc now youre in the range where the binding affinity is
appropriate for this to happen
Primary physiological function of cAMP
- cAMP can either
o serve as a ligand that binds to PKA to mediate an effect
o serve as a ligand to bind to a specific group of cation channel (which detect certain
odors in olfactory neurons)
- serve as an intracellular second messenger to bind to and activate protein kinase A (PK-A)
- act as a ligand for a specific class of odorant cation channels in olfactory neurons
o Sensory organs, olfactory system, retinal rod cells: cAMP can serve as a ligand
o Ligand-operated ion channel (the ligand is cAMP) on the inner surface of the plasma
membrane
o cAMP causes a change in the gating properties of the ion channel upon binding
- in sensory organs (sensory neurons), cAMP can be a ligand to bind to PKA to mediate an affect, it
can also be a ligand to bind to a specific group of cation channels
Adenylate cyclase
- consists of two alternating hydrophobic and hydrophilic domains
- hydrophobic domains each contain 6 membrane-spanning domains
- hydrophilic regions having two catalytic domains
- multiple isoforms of adenylate cyclase - stimulated by Gs and inhibited by Gi
- membrane bound enzyme found at plasma membrane
- this is a family of enzymes
- its kind of like a duplicated molecule (6 transmembrane
segments repeated and separated by catalytic domains)
- lets say you have a GPCR which couples a G protein
o if the G protein is Gs, that’s going to lead to stimulation of
the adenylate cyclase
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Atp is not considered to be a cell signalling molecule. Althought atp and other analogues can serve as a ligand for some receptors but is not considered to be a signalling molecule in the cell it serves other purposes (generation of. To function as an intracellular messenger, camp concentration (normally < 10-7 m) must be able to change its concentratoin up or down rapidly in response to extracellular signals. In normal resting cells, the basal camp concentration is very low. Adenylate cyclase consists of two alternating hydrophobic and hydrophilic domains hydrophobic domains each contain 6 membrane-spanning domains hydrophilic regions having two catalytic domains. Multiple isoforms of adenylate cyclase - stimulated by gs and inhibited by gi. So, in one conformational state, proteins may have more or less binding affinity for another protein and if that conformation changes, the binding affinity may change. If conformation changes, affinity may increase or decrease for protein partners (can be regulatory proteins)
