Lecture notes
Calcium signalling
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- Aston University, Birmingham (Aston)
In depth cell signalling and physiology notes, created using synchronous and asynchronous material.
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Calcium signalling.Intracellular signalling.
There are two main ways of initiating intracellular signalling.
1. Ion channels- once they have bound to an agonist, they will open a pore, which
allows ion to flood into the cells. This is a direct method. There is one receptor, there
is a ligand and once the agonist or ligand binds to the receptor, there is a
conformational change which then allows the ions to flood into the cells.
2. GPCRS- use an indirect approach, the receptor binds to a ligand, an agonist, and
undergoes a conformational change. But in an indirect approach this relies on
several intracellular proteins which recognize the activation of the receptor, which
can then initiate this intracellular signal.
We have a receptor, this can be GPCR or it can be an ion channel or a transporter.
We have a ligand, if the ligand is an agonist and it binds to our receptor then there is
a conformational change.
We have signal transduction.
Then we have a response inside the cell. The response inside the cell is the
intracellular signal.
This response can be widespread. It can be anything from influencing transcription,
influencing mitosis and meiosis, influencing which receptors are trafficked and
transported to the cell surface.
Intracellular signals, intracellular signaling pathways and the cooperation of different
cell types, not only in the same location but amongst different tissues, this
cooperativity allows us to function as a multicellular organism.
Which means ligands can be secreted from different parts of the body, they can be
secreted near their particular target.
Its all about getting the body to work in a cooperative manner and intracellular
signaling is the final stage of this pathway.
A ligand can be secreted from somewhere, it can go to the bloodstream and the
lymph.
It goes from one cell to the next, it influences membrane proteins on the cell surface.
And then the final stage is the intracellular signaling aspect.
cAMP.
cAMP is one of the major intracellular signaling pathways.
It controls a whole multitude of intracellular signaling responses.
For example, it controls cardiac tissue, there is loads of beta-2-andronergic receptors
on the exterior surface of the heart and various vessels throughout the body.
Increases in cAMP specifically in heart tissue:
Increase contractility (ionotropy), increase heart rate (chronotropy), and also
increase conduction velocity (dromotrophy).
This is all from an intracellular signaling messenger.
The roles of cAMP are varied, an example of how cAMP can influence cell
proliferation to the maximum (cancer), is when there is links between beta-2
receptor activation and the progression of various types of cancer.
cAMP can perform various functions within the cell.
, When signaling messengers are not regulated, things like cancer can occur.
So it is important that intracellular signaling pathways need to be regulated.
In GPCRs there are lots of ways to initiate or to change intracellular signalling levels.
Tyrosine kinase receptors, nuclear hormone receptors, enzymes on the cell surface.
There are many different routes that can be used to modulate intracellular signals.
We have the inactive form of the receptor and the active form of the receptor.
Once an agonist has bound to the binding pocket, we have a conformational change.
cAMP generation.
Second messenger cAMP is generated in several steps.
These steps add to the control of the system.
If you had a single step system, which is either on or off, it would be really hard to
control that because a system is either on or off.
If you have a system of many steps, and at its simplest level each one of its steps can
either be on or off, or each one of those steps can be graded between on or off (50%
on, 60% on, 70% on) all of these steps give you control within a system.
For a cell, control over its generation of intracellular signals is very important.
Initial state of the system- we have our receptor, our g protein (g-alpha s), and our
ligand.
Ligand is floating around in pre solution.
Once our ligand (an agonist) is bound to our receptor, the receptor undergoes a
conformational change.
This is then recognized by the G protein.
And it dissociates away from the receptor.
There is a difference in step 1 and step 2.
In step 1 there is a molecule called GDP whereas in step 2 there is a molecule called
GTP.
This is part of the biological clock, which is important in regulating the activation of a
particular G protein.
Once the receptor is activated the G protein can then recognize the activated state
of the receptor.
And then the G protein also undergoes a conformational change.
This conformational change leads to the dissociation of the alpha and the beta-
gamma subunits.
The 3rd step
The G-alpha-S subunit interacts with the membrane enzyme, called adenyl cyclase.
Whilst it is a membrane bound enzyme, once it is activated, it converts ATP into our
signaling molecule, cAMP.
Each one of the previous steps leads to the activation of adenyl cyclase.
RECAP:
Our receptor is activated.
This leads to the dissociation of our G protein.
The G- protein transverses across the membrane and interacts with adenyl cyclase.
This interaction then activates adenyl cyclase, which converts ATP into cyclic AMP.
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