NURS 6630 Foundational Neuroscience Discussion

Foundational Neuroscience

Question 1

Agonists are drugs that imitate the endogenous molecule (hormone or neurotransmitter) molecule that causes the same neuronal response. Dopamine agonists are used to treat the motor systems of Parkinson’s disease (PD), such as Requip. The exogenous dopamine agonists have the same effect as the endogenous dopamine molecule itself and help correct the dopamine starved motor state of the patient with PD. There are other agonists that stimulate the serotonin system. Examples of serotonin agonists include 5-HT agonists like buspirone and sumatriptan (Kowalski et al., 2017) NURS 6630 Foundational Neuroscience Discussion.

Antagonists attach to a receptor so that an endogenous agonist like dopamine or serotonin cannot attach. This either blocks a biologic response or reduces the response of the neuron to the endogenous molecule. Medications that fall under this category include antipsychotics, anticholinergics, antihistaminergic, beta-blockers, calcium channel blockers, and neuromuscular blockers (Kowalski et al., 2017).

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Partial agonists elicit a response that is less than the response of an agonist. A partial agonist can increase endogenous activity in some areas of the brain and slow it down in another area. Aripiprazole increases neuronal activity in the underactive mesocortical dopaminergic tract while decreasing the neuronal activity in the overactive mesolimbic tract. Aripiprazole has a higher affinity for the dopamine receptor than dopamine itself (Kowalski et al., 2017).

Inverse agonists have an opposite effect to that of an agonist. An inverse agonist is dependent on the receptor having some level of basal activity. Many neurons continue to fire even in the absence of an agonist. If an agonist opens an ion channel, the inverse agonist will close the channel. Examples of some inverse agonists are naloxone and naltrexone (Kowalski et al., 2017).

Question 2

G protein-coupled receptors (GPCRs) are integral cell membrane proteins responsible for translating the molecular signals encoded in the chemical structure of hormones and neurotransmitters from outside to inside the cell. The binding of endogenous or synthetic agonists causes the activation of the receptor, which results in conformational changes that allow the allosteric coupling of accessory proteins such as G-protein at the intracellular part of the receptor. Activation of these accessory proteins triggers the series of steps that constitute the signal transduction mechanism which, eventually lead to the observed physiological responses (Cruz- Barbosa et al., 2018).

Ligand-gated ion channels are multimeric proteins constructed from large glycoprotein subunits. They are activated by a chemical (agonist) binding to a distinct site or sites within the channel complex. In most cases, neurotransmitters released from the presynaptic neurons serve as the primary agonists, acting as part of a complex integrated process required for rapid neuronal communication. Binding of the neurotransmitter to the protein induces a conformational change, resulting in the opening of the integral ion channel. The charge and the direction of ion flux through the activated channel determine its effect on cellular function (Weir, 2020).

In pharmacology, a receptor is a protein that recognizes an endogenous chemical mediator such as a neurotransmitter, hormone, or inflammatory mediator. When the mediator (agonist) binds to the receptor, a series of reactions takes place, ultimately leading to a change of function of the host cell (Weir, 2020). GPCRs are at the center of current drug discovery programs. As of November 2017, approximately 35% of approved drugs in the United States or European Union targets GPCRs (Cruz- Barbosa et al., 2018). There are different criteria for different drug designs. One is selectivity, as it seems appropriate that drugs act selectively through specific receptors. Another is the concept of receptor polypharmacology in which a drug exerts a combination of positive effects by binding to different receptors (Cruz- Barbosa et al., 2018).

The voltage-gated ion channel (VGIC) is a large number of membrane-bound proteins that are structurally similar. These proteins can be activated by a change in the transmembrane voltage. The proteins are divided into voltage-gated calcium, potassium, and sodium channels. VGICs can be opened according to the changes in the membrane potential, so the ion can flow down the electrochemical gradient across the cell membrane. Because of the importance of the VGICs, these proteins are the molecular targets for a variety of biological toxins from many organisms. These VGIC toxins provide valuable tools for exploring the function of ion channels. Moreover, these VGIC toxins can be used as pharmacological tools for exploring a variety of physiological processes and understanding potential therapeutic targets. Some VGIC toxins have been proved to have therapeutic value and are currently being investigated as drugs (Weir, 2020).

Question 3

Epigenetics studies heritable changes in gene expression that are not caused by alteration in DNA sequences. Epigenetic regulation may lead to relatively stable changes that are affected by other factors such as age, diet, lifestyle, disease, and environment. Some mechanisms of epigenetics that have been studied extensively include DNA methylation, histone modifications, and non-coding RNAs. Each of these can change gene expression without altering the underlying DNA sequences (Boks et al., n.d.). Evidence suggests that epigenetic regulation of brain functions is important in the etiology of psychiatric disorders. The recent interest in the role of epigenetics in the brain has led researchers to explore the possibility that drugs can modify epigenetic processes involved in psychiatric disorders. So far, several psychiatric drugs have been found to influence epigenetic mechanisms, suggesting that this may partially explain their mechanism of action (Boks et al., n.d.).

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With recent improvements in understanding of the actual function of the entire genome, there needs to be some modification in pharmacology to tackle disease not only in the drug-receptor sense but in a more global-response sense. Drugs may have to act broadly over a range of epigenetic events. The regulatory mechanisms of these events may regulate a large group of genes. The advantage of this approach is that epigenetic variations can often be the underlying cause of a particular disease, and simply targeting one protein of the multiple pathways involved may be futile (Stefanska & MacEwan, 2015).

Question 4

As providers, nurse practitioners (NPs) should be cautious about the epigenetic properties of drugs which may affect drug-metabolizing gene expression and drug disposition. Some clinically used drugs may also have the property to alter epigenetic signatures of drug-metabolizing genes, and lead to unexpected changes in drug metabolism and toxicity (Boks et al., n.d.). Evidence shows that valproic acid has been discovered as a histone deacetylase inhibitor with potent antitumor activity. When this kind of epigenetic drug is administered, the prescriber needs to consider potential changes in drug-metabolizing genes under epigenetic regulation (Boks et al., n.d.). Also, risperidone, an atypical antipsychotic antagonizes D2 receptors and binds to 5HT2 receptors. This induces global phosphor-acetylation of H3 in the striatum, mediated by the NMDA receptor, suggesting that dopamine, serotonin, and glutamate act in synchrony to influence chromatin regulation (Boks et al., n.d.).

References

Boks, M. P., de Jong, N. M., Kas, M. J. H., Vinkers, C. H., Fernandes, C., Kahn, R. S., Mill, J., & Ophoff, R. A. (n.d.). Current status and future prospects for epigenetic psychopharmacology. EPIGENETICS, 7(1), 20–28. https://doi-org.ezp.waldenulibrary.org/10.4161/epi.7.1.18688

Cruz-Barbosa, R., Ramos-Pérez, E.-G., & Giraldo, J. (2018). Representation Learning for Class C G Protein-Coupled Receptors Classification. Molecules, 23(3), 690. https://doi-org.ezp.waldenulibrary.org/10.3390/molecules23030690

Kowalski, P. C., Dowben, J. S., & Keltner, N. L. (2017). My Dad Can Beat Your Dad: Agonists, Antagonists, Partial Agonists, and Inverse Agonists. Perspectives in Psychiatric Care, 53(2), 76–79. https://doi-org.ezp.waldenulibrary.org/10.1111/ppc.12208

Stefanska, B., & MacEwan, D. J. (2015) Epigenetics and pharmacology. Br J Pharmacol,

172(11):2701-4. doi:10.1111/bph.13136. PMID: 25966315; PMCID: PMC4439868.

Weir, C. J. (2020). Ion channels, receptors, agonists and antagonists. Anaesthesia & Intensive Care Medicine, 21(1), 62–68. https://doi-org.ezp.waldenulibrary.org/10.1016/j.mpaic.2019.10.022

An agonist generates a structural change in the G-protein-linked receptor that activates the synthesis of the second messenger to the fullest extent possible (Stahl, 2013). At times, the action of full agonists can cause too much stimulation of neurotransmitters; in this situation, impeding the activity of the natural neurotransmitter may be advantageous (Stahl, 2013). The antagonists’ role is to simply hinder the activity of the agonist, but produces no result itself (Stahl, 2013). Partial agonists are often referred to as “stabilizers” because they create stability between the conditions of extreme agonist action and the absence of agonist action (Stahl, 2013). Since partial agonists are considered “stabilizers”, if a patient is experiencing the extreme action of a full agonist, a partial agonist would be appropriate to downgrade, or stabilize, the signals. The role of the inverse agonist is to generate a structural change in the G-linked-protein receptor that changes it to a completely inactive state; they bind to the receptor and create an opposite effect from the agonist, decreasing the signal transmission level to below baseline (Stahl, 2013). NURS 6630 Foundational Neuroscience Discussion

G coupled protein receptors (GPCR) stimulate various pathways in the cell, and specific GCPR ligands have the ability to preferably activate specific pathways (Wingler & Lefkowitz, 2020). Ion-gated channels are trans membrane proteins that contain an opening to allow the flow of particular ions through the plasma membrane (Alexander et al., 2017). Once open, ions such as potassium and sodium can move through the channel, changing the electrical signal in the cell. GPCRs and ion channels are similar in that they conclusively result in alterations in neuronal activity, often linked to variations in gene expression (Stern et al., 2016). GPCRs and ion-gated channels are structurally different. GPCRs have seven helices and possess the ability to change shape after binding occurs to alter the protein (Latorraca et al., 2017). In contrast, ion-gated channels are direct trans membrane pathways. Additionally, the movement of ions through the ion channels rapidly transform the membrane potential and neuronal action; GPCRs operate slower in the second messenger systems (Stern et al., 2016).

Lockwood and Youssef (2017) describes epigenetics as the examination of any possibly stable and inborn changes in gene expression or cell phenotype that takes place without changes in DNA sequence. Epigenetic modifications are the primary mechanism underlying numerous diseases, particularly growth and developmental conditions (Furtado et al., 2019). Understanding the epigenetics of different diseases and conditions can aid healthcare providers in developing individualized pharmacologic treatment plans that will lead to improved responses to drug therapy (Wachman & Farrer, 2019).

Studies show there is an association between abnormal epigenetic mechanisms of gene expression and schizophrenia, bipolar disorder, and major depressive disorder (Peedicayil & Grayson, 2018). Furthermore, evidence suggests that abnormalities in the DNA methylation throughout the genomes are present in patients with schizophrenia (Peedicayil & Grayson, 2018).  A patient with this particular epigenetic abnormality may benefit from a DNA methyltransferase (DNMT) inhibitor that acts on DNA methylation, such as 5-azacytidine (Kular & Kular, 2018). Understanding what the abnormality is in the gene will help the provider chose the appropriate pharmacotherapy for the best patient outcomes.

References