Cells perform numerous tasks at the same time throughout their life, and many of these functions depend on the external environment of not only the cell but also the organism. However, many times, different cells need to perform different tasks at the same time and communication is necessary. Cells can signal each other using certain molecules, and they can decipher these messages through receptors on the plasma membrane and some second messenger molecules present in cells. Cell communication is crucial to the survival of an organism. In fact, if a cell receives no signals, it signals apoptosis. The three steps to cell signaling are reception, transduction, and response. In reception, a cell signaling molecule binds to a receptor protein on the cell membrane or inside the cell if the signaling molecule is hydrophobic and can pass through the membrane. In transduction, the binding of the molecule to the receptor induces a conformational change, and the signal is converted into a form to which the cell can respond. Usually, this requires a sequence of changes within the cell, and this is called a signal transduction pathway. The final stage is the response, and this can manifest in countless ways. It could be anything from the catalysis by an enzyme to the rearrangement of the cytoskeleton to reproduction.
G-Protein Coupled Receptors Structure
The largest family of human cell surface receptors are the G-protein coupled receptors (GPCR). They are also called seven-pass transmembrane proteins because they cross the membrane seven times. The parts of the receptor that pass through the membrane are alpha helices. As would be expected, this transmembrane protein contains both hydrophobic and hydrophilic amino acids. The N-terminus is located on the extracellular side and the C-terminus of the protein is located on the cytosolic side of the membrane. Another feature that is common to most GPCRs is palmitoylation, which is the modification of cysteine residues with an acyl group. This modification targets GPCRs for cholesterol and sphingolipid-rich domains of the plasma membrane. These regions are known as lipid rafts.
As they are the most common surface receptors, it is understandable that they are involved in a wide variety of physiological roles. GPCRs are involved in sight, taste, smell, behavioral, and mood regulation, and regulation of the immune system. Even though the signaling molecules, types of GPCR, and mechanisms of action may be different for all these roles, all of them involve certain extracellular signals that are converted into a cellular response. For example, mood regulation is affected by GPCRs because these receptors in the mammalian brain can bind to different neurotransmitters and create different physiological responses. Some of the molecules that can bind to GPCRs in the brain and lead to different moods are dopamine, serotonin, and GABA.
Our current understanding of the mechanisms of signal transduction pathways stems from the work of Earl W. Sutherland, a professor at Vanderbilt University. His research led to a Nobel Prize in 1971. The general mechanism involved in cellular communication has been described. However, two, main signal transduction pathways involve GPCRs that can be discussed in more detail. These two pathways are the cAMP signal pathway and the phosphatidylinositol signal pathway.
An example of the cAMP pathway can be illustrated in the mechanism of glycogen breakdown. In skeletal muscles, adrenaline acts as a stimulator molecule and binds to a GPCR. This activated receptor, in turn, activates a G-protein and the alpha subunit of this protein activates adenylate cyclase. This enzyme boosts the production of cAMP from ATP, and this leads to an enormous amplification of the original signal. The cAMP is a second messenger, a small intracellular signaling molecule amplified or generated in response to an extracellular signal. The cAMP activates Protein Kinase A (PKA), which phosphorylates and activates another enzyme called phosphorylase kinase. This kinase, in turn, activates the glycogen phosphorylase and glycogen can be broken down. It is apparent that the activation of many enzymes is involved in this signal transduction pathway. Since changes in gene expression and protein synthesis do not occur, the pathway occurs very rapidly.
The phosphatidylinositol signal pathway begins in a similar way to the cAMP pathway. A signaling molecule binds to a GPCR and activates it, which in turn activates a G-protein. This activated G-protein, however, activates Phospholipase C. The function of this phospholipase is to cleave a plasma membrane phospholipid PIP into DAG and IP. Both DAG and IP become second messengers in different pathways. IP rapidly diffuses through the cytoplasm and binds to a gated calcium channel on the endoplasmic reticulum, causing it to open. Calcium ion flow down their concentration gradient from the endoplasmic reticulum to the cytosol. The calcium ions activate further pathways. In this pathway, calcium ions can be thought of as third messengers because IP was the second messenger. However, the term second messenger is used for all small, non-protein components in a signal transduction pathway.
G-protein coupled receptors and G-proteins are prevalent throughout the human body and are involved in a wide range of physiological functions. Mutations in these proteins can lead to a variety of diseases including retinitis pigmentosa and cholera. Retinitis pigmentosa, caused by a mutation in a GPCR, is an eye disease in which the retina is damaged. People with this disease have blurred vision and.or difficulty seeing in low light conditions. This eye disease is an inherited disorder, and there is no treatment. Wearing sunglasses can protect the vision that remains. There are over one thousand different GPCRs in the human body. Mutations in different GPCR’s would cause different conditions. Along with retinitis pigmentosa, recent studies have shown that mutations in these critical surface receptors can play a role in hypothyroidism, hyperthyroidism, nephrogenic diabetes insipidus, and fertility issues.
The G-protein itself can also be affected, and it need not be genetic. Cholera is caused by a bacteria that multiplies within the human intestine and secretes a protein called cholera toxin. This toxin penetrates the cells that line the intestine and modifies the G protein. The alpha subunit, which stimulates adenylyl cyclase, is the subunit modified. This modification prevents GTP hydrolysis and locks the G-protein in the active state. The constant stimulation of adenylyl cyclase results in a prolonged and excessive outflow of chloride ions and water into the gut. This leads to severe diarrhea and dehydration. This can quickly lead to death, so water and ions should be replenished as fast as possible. Treatment consists of rehydration and antibiotics.
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