Thursday, February 21, 2013

All About Signaling Molecules

As we have seen in the previous post regarding some of the signaling molecules that transmit information. In this post, I will clear out the different types of signaling molecules. Lets classify the different signaling molecules in five different categories as below:

1. Steroid Hormones and Nuclear Receptor Superfamily:
As we have seen in the previous post that the signaling molecules bind to receptors which are present on the surface of the target cell. However, there are certain molecules that are intracellular and are present in the cytosol and the nucleus. It is interesting to know that these intracellular molecules respond to various small hydrophobic signaling molecules which diffuse the cell membrane. Let me make this more clear to you by taking the examples of steroid hormones.  All the steroids hormones including testosterone, estrogen, progesterone, corticosteroids and ecdysone are included under this sub-heading of steroid signaling molecules. The former three are sex steroids which are produced by gonads and are synthesized from cholesterol (structures can be seen in the adjacent figure). The corticosteroids are produced by adrenal gland. These include glucocorticoids and mineralocorticoids (representative structure in the above figure). The glucocorticoids act on variety of cells to stimulate the production of glucose whereas the mineralocorticoids act  on kidney to regulate water and salt balance. Ecdysone is an insect hormone and it plays a key role in the metamorphosis from larvae to insect. The brassinosteroids are plant-specific steroids that help in a number of processes like plant differentiation, cell growth etc.
These steroid hormones are hydrophobic in nature and hence they can cross the plasma membrane by diffusion. When they enter inside the cell, they bind to intracellular receptors. Now, what are these intracellular receptors? These receptors are nothing but the receptors which are expressed by the target cells which are responsive to the hormones. These receptors are the members of nuclear receptor superfamily and are transcription factors which includes domains for ligand binding. This ligand binding can act as activators or repressors thereby regulating the function. Hence, the steroid hormones directly regulates the gene expression.
Lets take an example of estrogen receptor and understand how the ligand binding has distinct effect. When the hormone estrogen is not present, the estrogen receptor is bound to chaperone, Hsp90 (as can be seen in the adjacent figure). In the presence of estrogen, there is conformational change, as a result of which Hsp90 is displaced and it leads to the formation of receptor dimers which then further binds to regulatory DNA sequence and hence regulates gene expression.
Just similar to these steroid hormone functions the thyroid hormone, vitamin D3 and retinoic acid (structure of these molecules in the adjacent figure).

2. Nitric Oxide and Carbon Monoxide:
Nitric oxide (NO) and Carbon Monoxide (CO) both are simple gases and functions as signaling molecules. NO is a paracrine signaling molecule in nervous, immune and circulatory systems. Being a small molecule it can easily diffuse the plasma membrane. However, a point to note is that it doesn't behave like steroid hormones (recall that, steroid hormones bind to a receptor that regulates transcription), NO rather alters the activity of intracellular target enzymes. Points to remember:
i. NO is synthesized inside the cell from the ariginine. Once produced, it then diffuses out of the cell and can act locally on nearby cells. This is so because NO is extremely unstable as half life of NO is only for a few seconds.
ii. The major intracellular target of NO is guanylyl cyclase. NO binds at the enzyme's heme group and stimulates the synthesis of cyclic GMP.
iii. NO directly modifies some target proteins by nitrosylation of cysteine residues. 
iv. NO also signals the dilation of blood vessels.

CO functions as signaling molecule in nervous system. It is closely related to NO and acts similar to that of a neurotransmitter and helps is blood vessel dilation.

3. Neurotransmitters:
Neurotransmitters are a group of small molecules that are hydrophilic in nature (hence unable to cross the plasma membrane of the target cell). These include acetylcholine, dopamine, adrenaline, serotonin, histamine, glutamate, glycine and GABA (structures of all these are given in the adjacent figure).
The neurotransmitters, as the name suggests, transmits or carries the signals between neurons or from one neuron to other parts of the cell. When there is action potential at the terminus of the neuron, the neurotransmitters are released. They diffuse through the synaptic cleft and binds to the receptor on the target cell.
Note: Unlike steroid hormones, NO and CO, the neurotransmitters act by binding to the receptor at the cell surface.

4. Peptide Hormones and Growth Factors:
The maximum number of signaling molecules fall under this group of peptides which ranges from a few amino acids to more than a hundred amino acids. The peptide hormones includes neuropeptides and a variety of growth factors. Neuropeptides are the small peptides which are released by neurons instead of  neurotransmitters. The peptides include enkephalins and endorphins which acts as neurotransmitters as well as neurohormones i.e.; not only they function at synapses but also at distant cells. The enkephalins and endorphins act as natural analgesics that decreases pain.
The various polypeptide growth factors include:
i. Nerve Growth Factor (NGF) - Regulate the survival and regulation of neurons.
ii. Epidermal Growth Factor (EGF) - Stimulates cell proliferation
iii. Platelet derived growth factor (PDGF) - Helps in wound healing.
iv. Cytokines - Regulates the development of blood cells and control activity of lymphocytes
v. Membrane-anchored growth factors - Remains associated with plasma membrane.
All these hormones and growth factors are unable to cross the plasma membrane and hence they act by binding to the receptor at the cell surface. 

5. Eicosanoids:
Eicosanoids is a class of lipids that serves a signaling molecules. This group includes prostaglandins, prostacyclins, thrombaxanes and leukotrienes. They affect the target cells in various ways like blood platelet aggregation, inflammation and smooth muscle contraction. These eicosanoids are broken down rapidly and they act locally in paracrine or autocrine signaling.