Cell Signaling 1

Chapter 16 , pages 531-552

Up to this point in the term, we have looked at various aspects of a single cell, from its chemical constituents to its organelles, their functions and the maintenance of the cell's architecture by its cytoskeleton. We move now to a consideration of how cells receive signals from their environment and how they communicate among themselves. It is intuitively obvious that even bacterial cells must be able to sense features of their environment, such as the presence of nutrients or toxins, if they are to survive. In addition to being able to receive information from the environment, multicellular organisms must find ways by which their cells can communicate among themselves. Since different cells take on specialized functions in a multicellular organism, they must be able to coordinate activities perfectly like the musicians in an orchestra performing a complicated piece of music. Because of the great complexity of multicellular organisms, a variety of mechanisms have arisen to ensure that cell-cell communication is not only possible but astonishingly swift, accurate and reliable. Get ready for a whole new level of complexity.

How are signals sent between cells?
The basic principle of cell-cell signaling is simple. A particular kind of molecule, made by the signaling cell, is recognized and bound by a receptor protein in the target cell. The binding of the signal molecule to the receptor sets off a chain of events in the target cell.



What kinds of molecules are used by cells for signaling?
Signal molecules can be of many kinds: they can be proteins, short peptides, hormones, nucleotides, even gases.

See Table 16.1








What determines whether a cell will respond to a signal?
The average cell in a multicellular organism is assaulted by hundreds of signals of varying kinds. Which of these signals it responds to depends primarily on what receptors the cell possesses. If a cell lacks a receptor for a particular signal, it cannot respond to it (in the same way that if someone sends you a sheet of written instructions you can't follow them if you are blind). Different cells make different sets of receptors, so they can "see" only some signals and not others.






Does having some kinds of receptors but not others work against a cell's ability to respond to signals?
Not really. The number of signals is so vast, and the types of things that different cells do so varied, that it makes sense to limit each cell type to certain kinds of receptors. Even with a limited set of receptors, cells can respond to a stunning range of signals with a great variety of responses. This is because:
a. A single signal can bring about a variety of responses in a target cell
b. Each signal is passed on from the receptor, through the cell's messenger system, to bring about the cell's response. Since these messengers that relay the signal can vary depending upon cell type, different cells may respond differently to the same signal. See Fig. 16.5
c. Since a given cell has dozens of different receptors, it is capable of receiving dozens of signals at once. The presence of one signal can affect the response to another signal. This means the cell can have different responses depending on the combinations of signals received. See Fig. 16.6






What do receptors do when they receive a signal?
A given receptor (generally a protein) is specific for a particular signal. If that signal shows up at the cell, the receptor will bind it and this binding causes the receptor, in turn, to generate a new signal within the cell. This is called the first step in signal transduction.






What does "signal transduction" mean?
The transformation of the information in the signal from one form to another is called signal transduction. An everyday analogy is the conversion of the electronic signal in phones (one kind of signal) into sounds (another kind of signal). The phone receiver acts as a receptor for the electrical signal and transduces or converts the signal into sound. See Fig.16.2






What happens after the receptor transduces the signal?
The new signal is relayed through a series of messengers that can both amplify and distribute the message to various parts of the cell, causing the cell to respond to the message.






How do signals cause changes in cells?
Signals may cause the cell to change what it is doing in a variety of ways. Depending upon the signal, conditions inside a cell may change, for example, by:

• a change in intracellular conditions like ion concentrations
• metabolic changes, like the activation of enzymes that were previously inactive
• gene expression changes, like activation of transcription of previously unexpressed genes

How do signals get into cells?
That depends on the kinds of signals they are. If the signal molecule is large and/or hydrophilic, it cannot easily cross the plasma membrane. For such signals, there are receptors located on the cell surface.

Other signals, like steroid hormones, are relatively small and hydrophobic, so they can diffuse through the plasma membrane into the cell. The receptors for such molecules are within the cell.

See Fig. 16.8 




Let us first consider some signals that can cross the plasma membrane.  One such example is steroid hormones.

What happens when a steroid hormone binds its receptor?
The receptors for steroid hormones are proteins with a double life: they are actually dormant transcriptional activators that sit around the cell till a steroid hormone binds and causes a conformational change in them. When this happens they become capable of binding to enhancer sequences (remember them from transcription?) and functioning as transcriptional activators that can stimulate the transcription of target genes.

 See Fig. 16.10






Now we will shift our attention to signals that cannot cross the plasma membrane. 

What kinds of signal molecules do not cross the plasma membrane?
In contrast to steroid hormones that can diffuse across the plasma membrane, many other classes of signal molecules are unable to cross the membrane. These include important groups of signaling molecules like neurotransmitters (acetylcholine, dopamine, serotonin, etc.) and peptide hormones (like insulin, glucagon, growth hormone, etc.,).



What kinds of receptors do these signals have?
All signals that can't easily cross the plasma membrane have cell-surface receptors. These receptors are proteins that span the plasma membrane. The major kinds of cell-surface receptors we will examine are:

1. Gated ion channels
2. G-protein linked receptors
3. Receptor tyrosine kinases (enzyme linked receptors). 



Cell surface Receptors 1: Gated Ion Channels

Gated Ion channels are often the receptors for neurotransmitters like acetylcholine.

What do neurotransmitters do?
Neurotransmitters carry signals between neurons or from neurons to target cells, e.g., they are involved in relaying signals from nerves to muscle.






How do neurotransmitters work?
The cell surface receptors for neurotransmitters are often gated ion channels. The protein(s) making up the channel can bind the neurotransmitter and the opening or closing of the gate occurs when the neurotransmitter signal binds. See Fig.16.15






Cell surface Receptors 2: G-protein coupled receptors (GPCRs)

G-protein coupled receptors receive a variety of different kinds of signals. A classic signal that is bound by a G-protein coupled receptor is epinephrine.

What are G-protein coupled (a.k. a G-protein linked) receptors?
G-protein linked receptors are cell surface receptors that pass on the signals that they receive with the help of guanine nucleotide binding proteins (a.k.a. G-proteins). There are hundreds of G-protein linked receptors known for mammalian cells.






What does a G-protein linked receptor look like?
Though there are hundreds of different G-protein linked receptors, they all have the same basic structure:
-They all consist of a single polypeptide chain that threads back and forth seven times through the lipid bilayer of the plasma membrane.
-For this reason, they are sometimes called seven-pass transmembrane receptor proteins.
- One end of the polypeptide forms the extracellular domain that binds the signal. The other end is in the cytosol of the cell.
See Figure 16.16 





What is a G-protein?
A G-protein is a protein that can interact with a G-protein linked receptor. The name G-protein comes from the fact that it is a protein that can bind a guanine nucleotide (either GTP or GDP). There are various sorts of G-proteins, all of which have a characteristic structure (please note that not all proteins that can bind guanine nucleotides are G-proteins, only those that have the classic three-part structure described below, and that interact with the G-protein linked receptors).






What is the structure of a G-protein?
All G-proteins have a similar structure- they are composed of three subunits called alpha, beta and gamma. Because of this, they are sometimes called heterotrimeric G proteins (hetero=different, trimeric= having three parts). The alpha subunit of such proteins can bind GDP or GTP.

In the unstimulated state of the cell, the G-proteins are found in the trimeric form (alpha-beta-gamma bound together) and the alpha subunit has a GDP molecule bound to it.

See Fig. 16.17a






What happens when a G-protein linked receptor binds a signal?
The binding of a signal molecule by the extracellular part of the G-protein linked receptor causes the receptor to interact with, and alter the conformation of, a G-protein that is associated with the cytosolic side of the plasma membrane.
When the G-protein's conformation is altered:
1. The alpha subunit of the G-protein loses its GDP and binds a GTP instead.
2. The G-protein breaks up into the GTP-bound alpha part and the beta-gamma part.
These two parts can diffuse freely along the membrane and act upon their targets, which in turn may relay the signal to yet another part of the cell.
See Fig. 16.17






Does the signal bound by the receptor permanently activate the signal transduction pathway?
No, it is a transient effect. There are a couple of factors at play here:
1. How long the alpha and the beta-gamma subunits bind to their respective targets
2. How long the alpha subunit is associated with a GTP molecule. The alpha subunit has the ability to hydrolyze GTP to GDP. Once the alpha subunit has a GDP bound to it instead of GTP, it then reassociates with the beta-gamma part and becomes inactive again, and is ready for another round of receptor binding.

See Figure 16.18






What happens when G-proteins bind to their target proteins?
G-proteins generally bind to one of two kinds of target proteins:
1. Ion channels
We have earlier seen that some gated ion channels can be opened or closed by the binding of neurotransmitters directly to the ion-channel protein. In other cases, ion channels are regulated by the binding of G-proteins. The change in the distribution of ions across the plasma membrane causes a change in the membrane potential, and therefore in the electrical properties of the cell. These are extremely swift responses, completed in a matter of milliseconds. See Fig.16.19.
2. Enzymes
The interaction of G-proteins with their target enzymes can regulate the activity of the enzyme, either increasing or decreasing its activity. Often the target enzyme will pass the signal on in another form to another part of the cell. As you might imagine, this kind of response takes a little longer than the kind where an ion channel is opened instantaneously. See Fig.16.20






What are some examples of enzymes whose activity is regulated by binding of a G protein?
Two well known examples of enzymes whose activity is regulated by binding of a G protein are adenylate cyclase and phospholipase C.

When adenylate cyclase is activated, the molecule cAMP is produced in large amounts.

When phospholipase C is activated, the molecules inositol trisphosphate (IP3) and diacylglycerol (DAG) are made.

Click here to see a flow chart of events upto this point. 




What is the purpose of making cAMP, IP3 and DAG? 
cAMP, IP3 and DAG are called second messengers.
Second messengers are small, diffusible molecules that can spread the message (i.e., signal) to other parts of the cell.





We will first trace the effects of activating adenylate cyclase and the resulting increase in cAMP.

What happens to the cAMP after it has done its job?
We just noted that cAMP levels increase when adenylate cyclase is activated. When its job is done, cAMP is broken down by an enzyme called phosphodiesterase.

See Fig.16.21





How does cAMP pass on signals?
Many of the effects of elevated cAMP levels are mediated by an enzyme called Protein Kinase A (PKA). High levels of cAMP activate PKA.

See Figure 16.23 





How is PKA involved in passing on the signal from cAMP?
We encountered PKA when we discussed allosteric regulation: the enzyme is composed of two catalytic and two regulatory subunits which are bound tightly together. Upon binding of cAMP the catalytic subunits are released from the regulatory subunits, allowing the enzyme to carry out its function, namely phosphorylating other proteins.

Thus, cAMP can regulate the activity of PKA, which in turn, by phosphorylating other enzymes can change their activity. This response is quite fast, though not as swift as the opening and closing of ion channels, and occurs on the order of seconds.

 See Fig 16.23





Does PKA phosphorylate only enzymes?
No, PKA can phosphorylate proteins besides enzymes, such as transcriptional activator proteins. The phosphorylation of a transcriptional activator can cause the activator to bind to its enhancer sequence and to increase the transcription of the gene it controls. See Figure 16.24

This sort of response, that depends on changes in gene expression will naturally take longer than those that depend on activating an enzyme.





Let us now look at the second messengers IP3 and DAG, which are produced by activation of Phospholipase C. 

What do IP3 and DAG do?
IP3 and DAG produced by activated phospholipase C each has a function:
IP3 diffuses to the ER membrane where it binds to gated calcium ion channels. This causes calcium channels in the ER membrane to open and release large amounts of calcium into the cytoplasm from the ER lumen.

The increase in intracellular calcium ion concentration has various effects, one of which is to activate a protein kinase called protein kinase C (C for calcium). DAG remains associated with the plasma membrane and together with calcium, is involved in activating protein kinase C (PKC).

See Fig.16.25 





What does PKC do?
Like PKA, PKC phosphorylates a variety of proteins in the cell, altering their activity and thus changing the state of the cell.

Click here to see a flow chart summarizing various events following the binding of a signal to a G-protein linked receptor.



Copyright © 2011 Indira Rajagopal