What are cell surface receptors and second messenger systems?
Cell surface receptors.
Most types of hormone are not fat-soluble. This means that they cannot dissolve in the cell membrane to gain entry into the cell. Instead they are transported around the blood, normally on transport proteins (such as albumin), to the target tissue where they bind to receptors on cell surfaces.
Cell surface receptors - click to enlarge
The two main types of cell surface receptor are:
G protein linked receptors
These are protein receptors that sit in the cell membrane, with an extracellular domain and an intracellular domain. The peptide chain that forms the protein always spans the membrane. When the hormone binds to the extracellular domain, this causes a change in shape of the receptor (a conformational change). This causes the intracellular domain to activate G proteins. G proteins have 3 main parts: an a subunit, a b subunit and a g subunit. When activated, firstly the a subunit substitutes a GDP molecule for a GTP molecule. This results in the activation of the G proteins. They can be either stimulatory or inhibitory i.e. they can cause an increased level of enzyme activity or a decreased level of activity in the second messenger systems.
Diagram to illustrate G proteins - click to enlarge
'Non-G protein coupled' receptors
These are receptors with an intracellular domain that is activated when the hormone binds to the extracellular domain. The intracellular portion either
- has intrinsic enzyme activity itself
or
- activates other enzymes inside the cell
These enzymes are generally involved in the phosphorylation of proteins (so-called kinase activity).
An example of one type of these is the tyrosine-kinase receptor for insulin. Here, once insulin binds, the intracellular domain is activated resulting in the dimerisation of (the fusion together of) two receptors. A kinase enzyme on one of the two receptors phosphorylates the tyrosine amino acids of the other receptor, a process called transautophosphorylation. Other intracellular proteins that recognise the phosphorylated dimerised receptors bind to them. These proteins activate second messenger systems.
Diagram of insulin binding - click to enlarge
Second Messenger systems
These are systems within the cell that are activated upon stimulation of the receptor. They act to amplify the signal. Although only one hormone molecule can stimulate one receptor (at any one time), the stimulated receptor can produce multiple second messengers, each of which can stimulate other molecules within the cell. One hormone molecule can therefore cause a large effect. This accounts for the fact that concentrations of hormone in the blood are so low.
The main types of second messengers are:
- cAMP (cylcic adenosine monophosphate)
- IP3 (inositol 1,4,5-triphosphate) and DAG (diacylglycerol)
- Calcium
cAMP
cAMP is produced from ATP (adenosine triphosphate) by the enzyme adenylate cyclase. Adenylate cyclase can be stimulated by several mechanisms. The enzyme is activated by stimulatory subunits of G proteins and other proteins activated by phosphorylated enzyme-linked receptors. It is inhibited by other inhibitory G proteins. cAMP goes on to activate other enzymes which affect the expression of certain genes in the cell.
cAMP linked receptors - click to enlarge
IP3 and DAG
IP3 and DAG are produced from another molecule PIP2 (phosphatidylinositol 4,5 -bisphosphate) by the enzyme phospholipase C. Phospholipase C is activated again by stimulatory G proteins and other proteins activated by phosphorylated enzyme-linked receptors. IP3 goes on to release calcium from intracellular stores. Calcium together with DAG can then go on to activate other enzymes (such as protein kinase C, PKC) which in turn activate proteins that alter cell activity.
Phospholipase C pathways - click to enlarge
Calcium
As mentioned calcium is released from intracellular stores by IP3. It can then go on to activate enzymes such as protein kinase C with DAG. It can also bind to a molecule called calmodulin. This molecule can activate many other proteins producing a wide range of effects that ultimately alter cell activity and function