Topics and Speakers Richard Ambron, PhD
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Synopsis
In this lecture, Dr Richard Ambron explains the complex process of gene regulation in neurons, focusing specifically on how a neuron reacts to external events relatively close to the nucleus and later, on how a neuron reacts to external events far from it. A firm grasp of signal transduction, transcription, translation, kinases, and growth factors is essential to understanding the fascinating manner in which a neuron interacts with its environment. Dr Ambron first outlines how a message is transcripted, then moves on to gene regulation, and concludes by explaining the phenomenon of neuropathic pain as a direct consequence of neuronal injury.
It is necessary to first understand that a common misconception among students is that the nucleus is somehow the "brain" of the cell when in fact it is a responsive structure to events that occur in the periphery. Its goal is to produce proteins for the environment. Other than that, the nucleus does very little on its own. Where the "action" really lies is on the nucleus's external membrane, where the first step toward the transcription of a message occurs. It is here that the binding of some factor starts signal transduction and activates a kinase (some of the most researched kinases include protein kinase A (PKA), protein kinase G (PKG), and MAP kinase). The active kinase then enters the nucleus and activates a transcription factor, which then binds to an enhancer site on the DNA, which in turn can now be expressed and produce a message.
The type of signal transduction that is used in gene regulation involves growth factors, which end in the activation of a kinase. The greater the amount of gene regulation required, the greater the complexity (i.e., the number of steps) in that pathway, each of which serves as a "fail-safe monitor" in case the production of the protein needs to be halted.
Dr Ambron uses the ERC kinase to illustrate a gene regulation pathway. When the ERC undergoes a conformational change after the phosphorylation events caused by signal transduction, its nuclear localization signal (NLS) becomes exposed. The NLS is required to enter the nucleus since the DNA is highly guarded. When the ERC enters the nucleus, transcription begins, the DNA folds and activates enzymes that create openings in the DNA which allow polymerase to synthesize the message.
It used to be believed that one message (i.e., one gene) produced one protein. While this is true in prokaryotic cells, it is has been found not to be true in eukaryotic cells. Hence, one gene can produce more than one protein and this depends on where the gene is spliced or "cut." Once the message is spliced, it undergoes translation in the ribosomal machinery, where the protein is produced and then folds. It is discussed in detail that it is possible to intervene in the synthesis of a protein in many ways: silencing RNAs, short interfering RNAs (siRNAs), RNAi (RNA interference), microRNAs, or using antisense technology.
Dr Ambron concludes the lecture with neuropathic pain. When a neuron is injured, the injury must be communicated to the cell body, especially if it occurred relatively far from the nucleus. This can happen in two ways: there is either an action potential discharge or proteins in the axon communicate from the periphery back to the cell body by exposing their NLS. Sensory neurons that are damaged develop long-term hyperexcitability (LTH), which means they have a greater propensity to fire. LTH is directly related to neuropathic pain. The molecular pathway for LTH involves the activation of the PKG pathway and the MAP kinase pathway in an abnormal manner, which ends in the activation of a transcription factor that results in LTH. The details of this pathway are discussed. Dr Ambron believes that current research should be focused on blocking the PKG pathway at different points in order to ameliorate pain.
