Cell communication

Cells make contact with other cells through the cell surface, by means of specific glycolipids and glycoproteins embedded in the membrane. This mechanism is important in cell recognition (tissue formation) but also in immune recognition In addition to these contact interactions cells have to communicate with each other to relate the need for metabolites, fuel molecules, growth and cell division. These interactions are based on the release of chemical substances ( from special glands) which travel to target cells. These chemical substances are known as hormones, or neurotransmitters in case of nerve cell stimulation . At the target cell these messenger molecules attach themselves via a highly specific interaction to membrane bound receptors. This in turn leads to the activation of certain enzymes inside the cell initiating a particular cellular response. The entire process is called cell signaling
There are three forms of signaling

• Paracrine signaling: A signal (hormone) is released into a neighboring cell, where after a short while it is removed by hydrolytic enzymes. Paracrine signaling plays an important part in early development. Examples of paracrine hormones are histamines which are released as local responses to stress and injury. Prostaglandins fulfill a similar function.
• Endocrine system: the endocrine system are tissues or organs which are functionally related to the nervous system. Cells of the endocrine system produce and release hormones into the blood. These hormones travel to target cells where they may stimulate metabolism, growth or cause other specific responses. Major physiological functions of the human body are regulated by such hormones and include sex hormones (androgens and estrogens exerting reproductive control, thyroxin which regulates the metabolism, or the regulation of the heart rate by epinephrine (adrenaline).
• Neurotransmitters: Long range signaling is accomplished by the nervous system. An electrical signal can travel along the a nerve cell (neuron) and may stimulate the release of neurotransmitter molecules at the terminal region of the neuron. The neurotransmitter will travel to the target cell which is in close proximity to the nerve ending and after binding to its receptor will cause a specific response by the target cell.

Chemical signals such as hormones and neurotransmitters attach to receptor molecules on the surface of the target cell. This attachment is the first step in a cascade of events which brings about the specific response by the target cells. There are several different types of cell receptors:

• ion channel receptors
  a neurotransmitter binds to a specific site on an ion channel causing it to open and allow specific ions to pass. Nerve cell
• G-protein linked receptors
  a ligand binds to a receptor protein, which activated a G-protein, which in turn will activate a series of enzymes
• Receptor tyrosine kinases (RTK)
  a ligand binds to the RTK which functions as receptor protein and has kinase activity on its own.

G-protein linked receptors image

Protein kinases are enzymes which catalyze phosphorylation reactions. We have seen earlier that phosphorylation can cause conformational changes for example in transporter molecules enabling them to transport substances across the membrane. Phosphorylation can also be important for enzymes which catalyze metabolic reactions. Such enzymes can be activated or deactivated by enzymes ( called kinases) which catalyze the posphorylation reaction. G-protein linked receptors will activate such kinases.
An example for a G-protein linked receptor pathway is the control of blood glucose levels by the hormone glucagon. When the blood glucose levels are low glucagon is released into the blood from the pancreas (the alpha cells of the ilets of Langerhans). Glucagon will attach itself to a receptor protein on a liver cell. After binding, the receptor changes its configuration and activates a trimeric GTP-binding protein called G-protein. The G(alpha)/GTP subunit of the G-protein in turn can activate a membrane bound enzyme called adenylate cyclase which then will catalyze the cyclization of ATP to cAMP. cAMP is called a second messenger since it can activate a number of different enzymes. In our case cAMP activates protein kinase A. Protein kinase A is an enzyme which catalyses phosphorylation reactions with ATP as participant. Protein kinase A phosphorylates and thus activates other enzymes which finally leads to the activation of glycogen phosphorylase. This last enzyme in this cascade catalyzes the hydrolysis of glycogen (storage form of glucose) to glucose 1-phosphate, which then in turn is released as glucose into the blood.

Besides releasing cAMP, the G-protein pathway can also activate another second messenger, called inositol triphosphate (IP₃). In this pathway the G-protein attaches to a membrane bound phospholipase, which can release the IP₃. It will migrate to the SER where it attaches to Ca⁺⁺ ion gate, which will then release Ca⁺⁺ into the cytoplasm. Ca⁺⁺is required to activate protein kinase C. The activated protein kinase C can now activate other enzymes to cause a specific cellular response. The scheme below shows the activation pathway for PKC

Here are some examples for hormones which use the G-protein - cAMP pathway :
- the hormone epinephrine activates many different signaling pathways
- the adrenocorticotropic hormone stimulates the growth of the adrenal cortex ,
-heart rate and blood pressure are controlled by epinephrine which is targeting cardiovascular cells.

Examples for hormones which use the G-protein - IP₃/Ca⁺⁺ pathway are:
Peptide growth factor initiating DNA synthesis and cell division,
Acetylcholine attaching to the beta cells of the islets of Langerhans in the pancreas, causing the secretion of insulin,
Thrombin , which causes platelet activation in the process of blood clotting
The release of histamine by mast cells is initiated by protein kinase C , this response is trigerred by the G-protein pathway which is activated through the binding of foreign agents.

The chlorea toxin is a protein which can activate the G-protein pathway. The interaction with the receptor is such that the G-protein is continuously active, resulting in high levels of cAMP. This rise in cAMP activates certain membrane transporters permitting massive salt and water flows into the intestinal lumen causing the severe dehydration symptoms of cholera.

Receptor tyrosine kinases (RTK) image

RTKs are receptor proteins that have kinase activity, i.e. the receptor itself can catalyze phosphorylation reactions. The receptor is inactive in its monomeric state, however, after attachment of the hormone (epidermal growth factor, EGF, in the above example) the receptor can act as a kinase and it phosphorylates itself. This changes the configuration of the receptor and it can attach to a so called Grb2 protein via SH2 domains and a guanosine exchange factor (sos). This association will activate a membrane bound protein called ras-GDP. Upon binding ras-GDP is converted into ras-GTP which then will activate so called MAP kinases. Ras-GTP is deactivated (hydrolyzed) by GTPase Activating Proteins, terminatiing the receptor response. The MAP kinases activate cellular enzymes.

The RTK pathway is very important in cell proliferation and cell cycles. The pathway controls transcription of DNA into RNA through the activation of transcription factors.

An other example for the RTK pathway is the insulin receptor. the hormone insulin is released into the blood stream when the blood glucose levels are high. This release is initiated by attachment of acetylcholine to a receptor on the beta cells of the islets of Langerhans. Insulin will travel to its target cells (liver, muscle) and after binding to its RTK receptor, ras-GTP will be formed and will activate a MAP kinase which in turn leads to the activation of glycogen synthase. This last enzyme catalyzes glycogen synthesis from glucose. In addition MAP kinases activates a process by which glucose transporter containing vesicles fuse with the plasma membrane, causing an increase in glucose uptake.

Diabetics Type I have high glucose levels because of inadequate insulin secretion, whereas Type II diabetics have normal insulin levels, but their insulin receptors do not work or they have to few of them.

Neutrotransmitters

There are over 60 different neutrotransmitters are used by the cells of the nervous sytem. The neurotransmitter acetylcholine , released from a motor nerve cell travels a short distance to a muscle cell , where it attaches to a cell surface receptor, Nicotinic Acetylcholine Receptor which is an excitatory receptor ( mechanism of muscle contraction , simplified diagram ) . This process causes an increase in cytoplasmic Ca++ concentration, which initiates skeletal muscle contraction. Electronmicrograph of a skeletal muscle cell and ajacent nerve cell .
The Muscarinic Acetylcholine Receptor (inhibitory receptor) is also activated be acetylcholine, however, the cellular reponse is opposite. For example the activation of a the Muscarinic Acetylcholine Receptor on heart muscle cells has the effect of lowering the heart rate.

Agonists : either mimic the hormone or inhibit the removal of the hormone
Antagonists : bind to receptor but do not activate it.

The neurotransmitter serotonin is involved in emotional behavior as well as sleep control. A lack of serotonin may cause clinical depressions. The drug Prozac, which is commonly used against depression, slows down the reuptake of serotonin, thus enhancing its activity. Glutamate and aspartate are the most common neurotransmitter in brain cells. They are activating cation channels causing influx of e.g. Na⁺ ions, which in turn changes the membrane potential causing excitation of the cell. Gamma aminobutyric acid (GABA) is an inhibitory neurotransmitter which oposes the action of glutamate. A lack of GABA is responsible for certain depressions. It can be treated with the drug Valium, which causes an increase in GABA levels.

Human mood disorders (depressions) are effectively treated with drugs which specifically block the reuptake of serotonin into the presynaptic axon terminal, for example fluoxetine (Prozac). Hunger or appetite is reduced by drugs which elevate serotonin levels in the brain (e.g. fenfluramine/Pondimin or dexfenfluramine/Redux), which made these drugs popular in the treatment of obesity. Because of severe side effects these drugs have been taken off the market. Drugs which have the opposite effect, that is they reduce serotonin levels, produce an increase in carbohydrate craving and intake.
Delay of sleep onset is reduced with tryptophan, an amino acid necessary for the biosynthesis of serotonin, suggesting that serotonin may play a role in sleep induction. Grandmother's suggestion to drink a glass of warm milk before sleep may be sound, since milk is a good source of tryptophan.

Proto-Oncogenes
Mutations of the genes which code for proteins and enzymes involved in the regulation of the cell cycle can result in uncontrolled growth and cause the cell to become cangerous. In their unaltered form these genes are called proto-oncogenes. After mutation, these genes could become oncogenes ( = genes that produce a cancerous cells) because the transcribed proteins may have lost their function as regulators of the cell division, resulting in uncontrolled growth. Oncogenes may not only affect cell division but also promote metastasis There are several different types of oncogenes: Oncogenes coding for:

• protein kinases
• growth factors such as peptide hormones EPG and PDGF
• cell surface receptors for hormones
• G-protein
• ras protein

Growth factor oncogenes:
Normal pathway: Hormone (PDGF, platelet derived growth factor) - RTK - ras - MAP kinases . MAP kinases can induce cell division. A faulty PDGF could cause a continued activation of RTK, which in turn would activate ras. PDGF receptors are found on fibroplast tissue, nerve cells and smooth muscle cells, making those tissues receptible to cancer.
Mutations in ras gene can also cause continued activation of the rasGTP, leading to continued activation of MAP kinases. A ras mutation is for example the cause for cervical cancer.