Neurobiology For Dummies. Frank Amthor

histone acetyltransferase enzymes (HATs) dissociate the histone complex from a section of DNA. The presence of histones blocks expression, so by removing histones, transcription can proceed. Methylation and histone deacetylation may act simultaneously to control DNA expression.

      Introns and exons

      The discovery that many genes were interrupted by introns (intervening sequences) that were not expressed came as quite a shock to much of the scientific world. Depending on the species, introns may be the majority of the total DNA sequence of the organism. RNA splicing (refer to the earlier section “Protein synthesis”) removes introns to produce a final mRNA molecule ready for translation. The term intron refers to both the non-expressed DNA sequence and its corresponding sequence in the unspliced mRNA. After the introns are spliced out of the mRNA, the result is called an exon.

      

The origin of introns is still unclear. Introns were initially viewed as accidental DNA sequences, possibly leftovers from evolution or even parasitic “selfish” DNA. One conjecture has been that introns provide places for the DNA sequence to break during crossover in meiosis, making it less likely that a break will occur in the middle of a needed gene.

      Regardless of their origin, introns allow the protein sequences generated from a single gene to vary greatly. This is because the same DNA sequence can generate different proteins by varying how the mRNA is spliced. Environmental factors that get taken up by a cell can modify the control of alternative RNA splicing.

      Protein synthesis versus regulation

      The classic picture of DNA being transcribed to RNA, and RNA being translated into proteins, was typically thought of as a one-way process. However, this description is not complete. The products of DNA expression, as well as external substances that get taken up by a cell, can also regulate protein production.

One example of the backward flow of information (or backward synthesis) is reverse transcription, which is the transfer of information from RNA to make new DNA. Reverse transcription occurs in retroviruses such as HIV and is a common feature of the replication cycle for many viruses. The main function of many proteins synthesized from DNA is to regulate DNA expression, typically by modulating methylation and histone acetylation (refer to “Gene regulation,” earlier in this chapter). The expression of DNA can even be regulated by sequences within the DNA itself. For example, some introns enhance the expression of the gene in which they dwell through a process called intron-mediated enhancement. More generally, introns may have short sequences that are important for efficient splicing by spliceosomes.

      Post-translational processing

      When proteins are created by ribosomes that translate the mRNA into polypeptide chains, the amino acid polypeptide chains may undergo folding and/or cutting before becoming the final protein. The processes of folding and cutting often occur in the endoplasmic reticulum and may include structural changes based on the formation of disulfide bridges.

      Also after translation happens, other biochemical functional groups may be attached to the amino acid sequence of the protein, such as carbohydrates, lipids, and phosphates. Adding phosphate groups is called phosphorylation. This is a common mechanism for activating or inactivating an enzyme protein.

      Some of the amino acids on a polypeptide can be modified. For example, the amino acid arginine can enzymatically converted to citrulline in a process called citrullination. The presence of citrulline residues can alter the protein’s structure and thereby change its function. Vesicles containing secretory proteins and some neurotransmitters then pass through the Golgi apparatus, where additional post-translational modifications can occur.

      Various enzymes may cut the peptide chain or remove amino acids from the amino end of the protein. Also, most polypeptides initially start with the amino acid methionine because the “start” codon on mRNA codes for it. Methionine is usually taken off during post-translational modification.

      Epigenetics

      Epigenetics is the change in gene expression (and thus, cell phenotype, which we discuss earlier in this chapter) due to mechanisms other than changes in the underlying DNA sequence. The most important epigenetic mechanisms are DNA methylation and histone modification. Other mechanisms include X chromosome inactivation, transvection, and paramutation. Teratogens (environmental agents that cause cancer) often act through epigenetic mechanisms.

Epigenetic changes may persist through all cell divisions of a cell and be passed to offspring. If this sounds “Lamarckian” to you, you’re partly right. In the original development of the theory of evolution, an alternative theory advanced by French biologist Jean-Baptiste Lamarck was that acquired characteristics could be inherited. Giraffes, for example, by stretching their necks to reach leaves on higher branches would give birth to offspring with longer necks.

      

However, we know that Lamarck’s hypothesis is not the main way that evolution works. An important difference exists between epigenetic and Lamarckian inheritance. The Lamarck hypothesis offers no specific mechanism by which a trait acquired or developed through practice can be inherited. In epigenetics, however, the change in DNA expression may or may not be linked to any behavior, and may or may not actually be selected for in terms of that behavior. Epigenetic changes work according to standard Darwinian evolution.

      Epigenetic changes are crucial in the process of cellular differentiation during development, where totipotent stem cells (cells that can develop into any cell type) differentiate into hundreds of different cell types such as neurons, muscle cells, or liver cells. This happens because of epigenetic activation and inhibition of relevant genes preserved in subsequent cell divisions of that cell line.

Meeting Cell Molecules: Important Ions and Proteins

      What distinguishes neurons from other cells in the body is that they are excellent communicators. Their membranes contain receptors and ion channels that allow them to do the following:

       Sense energy and substances from the environment

       Communicate between distant parts of the same cell

       Communicate with other neurons

       Activate muscles and secretory cells

      Most cells in the body have the DNA required to produce the hundreds of ion channel and receptor proteins found in neurons. But the genes that code for many of these neuronal proteins are expressed only in specific types of neurons, and not other cells. Many neuron-specific proteins form receptors or ion channels that either directly or indirectly control the flow of four major ions through the membrane: sodium, potassium, chloride, and calcium. The next section explores these ions in more detail.

Eyeing important ions

      The most important ions that flow through neuronal membrane channels are sodium, potassium, chloride, and calcium. A fifth ion, magnesium, is also important because it controls conduction through the NMDA receptor, a glutamate receptor. The following list tells you more about the roles of these ions inside neurons:

       Sodium: The concentration of sodium is much higher outside the cell than inside the cell. Sodium entering into cells can trigger action potentials and lead to synaptic release, two crucial neural functions.

       Potassium: This ion has a high concentration inside cells compared to fluid outside cells. So, opening potassium channels tends to hyperpolarize cells (make the inside more negative) by the exit of the positively charged potassium ions.