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Chemokine Receptors in the Brain: Hierarchical Expression by Subsets of Neurons
Published in Richard Horuk, Chemoattractant Ligands and Their Receptors, 2020
Stephen C. Peiper, Richard Horuk
The association of IL-8RB with the neuritic component of Alzheimer’s disease provides further rationale to postulate that IL-8 and/or MGSA may promote regenerative responses in neurons. It is evident that Alzheimer’s disease is a complex disorder which involves multiple reparative mechanisms (see References 56 and 57 for reviews) and may be associated with genetic mutations in the gene encoding the amyloid precursor polypeptide on chromosome 21 and genes encoding polypeptides predicted to contain seven transmembrane spanning helices on chromosomes 1 and 14. Alzheimer’s plaques have been found to contain multiple protein kinases and phosphoproteins, as well as hyperphosphorylated intermediate filaments, perhaps representing ongoing signal transduction involved in neuritic outgrowth. The induction of IL-8RB expression may indicate the involvement of the cognate chemokines in regenerative and reparative mechanisms in the central nervous system.
Drugs of Abuse and Addiction
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Shalini Mani, Chahat Kubba, Aarushi Singh
Opioids belong to the first class of mechanistic classification of drugs that is they act by activating GPCRs (Luscher et al., 2006). G-proteins, cAMP second messenger, and protein phosphorylation pathway mediate important aspects of opioids. Opioids increase dopamine concentration by acting on MORs which is manifested on GABA neurons of the VTA region. These MORs act with a dual action on these GABA neurons, first by hyperpolarising the GABA neurons this way the plasma membrane potential becomes more negative and action potential is never reached. Secondly, it decreases the release of GABA (Pickel et al., 2002; Luscher et al., 1997). Mediation of post-hyperpolarization is done by G-protein coupled inwardly rectifying K+ channels (GIRK). MORs inhibit Ca2+ channels and activate voltage-gated K+ channels (Pickel et al., 2002; Luscher et al., 1997; Vaughan et al., 1997; Johnson and North, 1992). Opioids also act on the locus coeruleus (LC) which is the largest nonadrenergic nucleus in brain. Opioids decrease firing rate of LC neurons by activation of inward rectifying K+ channels and inhibition of slowly depolarizing cation channel as you can see in Figure 20.6 and Figure 20.7. Both actions occur through G-proteins. cAMP levels of neurons are reduced and cAMP-dependent protein kinase is activated. Adenylate cyclase activity is acutely reduced in LC (Aghajanian, 1978; Andrade et al., 1983; Wang and Aghajanian, 1990; Alreja and Aghajanian, 1991).
Chemical– and Drug–Receptor Interactions
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
Protein kinases catalyze the transfer of the γ-phosphate from ATP to specific amino acids in proteins. First, ATP binds to the active site of the kinase. This is succeeded by binding of the substrate to the active site. Once bound, the γ-phosphate of ATP is transferred to a Ser, Thr, or Tyr residue of the substrate. Following phosphorylation, the substrate is discharged from the kinase. The order of the steps alternates for different kinases. For instance, some kinases bind to their protein substrates before binding ATP, and others produce ADP before releasing the protein substrate. Table 11.3 illustrates inhibitors of protein kinases that are undergoing human clinical trials.
Identification of a new structural family of SGK1 inhibitors as potential neuroprotective agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Ines Maestro, Enrique Madruga, Patricia Boya, Ana Martínez
Protein kinases are responsible for modulating the activity of other downstream proteins by means of their phosphorylation of specific residues like serine, threonine or tyrosine. They are found in important cellular processes, like cell proliferation, apoptosis, neuroinflammation and other cell signalling pathways. Pathological imbalance of these protein kinases has been reported in several pathologies, including neurodegenerative diseases. Thus, they have become a perfect target to develop a drug discovery program in order to find new compounds to modulate them6,7. In fact, in December 2021 there were 68 protein kinase inhibitors approved by the FDA, most of them with oncology purposes8. However, none of them are directed to neurodegenerative diseases, which are everyday more prevalent in the society due to the increase in life expectancy.
Discovery of a novel Aurora B inhibitor GSK650394 with potent anticancer and anti-aspergillus fumigatus dual efficacies in vitro
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Yuhua He, Wei Fu, Liyang Du, Huiqiao Yao, Zhengkang Hua, Jinyu Li, Zhonghui Lin
It is well known that ATP is the primary carrier of energy in cells. Upon hydrolysis, it releases energy from the chemical bonds to fuel cellular processes. For example, ATP hydrolysis by motor proteins or DNA helicases can induce conformational changes and thus drive the translocation of these proteins. In addition, the protein kinases regulate various biological processes by transferring a phosphate group from ATP to amino acid residues like serine, threonine, or tyrosine. Interestingly, the mitotic kinases Aurora B, Haspin, and Bub132 also possess intrinsic ATPase activity, producing free inorganic phosphate. It is currently unknown whether this energy-consuming activity has a physiological role in cells, further studies are needed to address this potentially interesting question.
Jing-an oral liquid alleviates Tourette syndrome via the NMDAR/MAPK/CREB pathway in vivo and in vitro
Published in Pharmaceutical Biology, 2022
Leying Xi, Xixi Ji, Wenxiu Ji, Yue’e Yang, Yajie Zhang, Hongyan Long
Microglia are innate immune effector cells in the brain that play a crucial role in physiological processes in the central nervous system (CNS) (Arcuri et al. 2017). It has been found that there is a correlation between the state of microglia and the occurrence of TS. Moreover, it has been reported that the expression of microglia transporter proteins in the bilateral caudate nucleus is increased in children with TS (Kumar et al. 2015). Additionally, an analysis of the autopsy reports for TS patients reveals an increased number of CD45+ expressing microglia cells in striatal areas of the basal ganglia (Lennington et al. 2016). Over-activated microglia cells produce reactive oxygen species, inflammatory cytokines, chemokines, and Glu (Takeuchi and Suzumura 2014). The release of excitatory amino acids by microglia is a key mediator of excitotoxic damage. Microglia cells express various Glu receptors (GluRs); however, the N-methyl-d-aspartate receptor (NMDAR) is crucial for the activity of Glu. Unfortunately, the relationship between NMDAR and signaling mechanisms in TS is unknown. Recent evidence suggests that mitogen-activated protein kinase (MAPK) plays a critical role in regulating the neurochemical and pathophysiological properties of NMDAR (Haddad 2005). As one of the downstream targets of MAPK signaling, cyclic AMP response element-binding protein (CREB) can be phosphorylated. Moreover, MAPK signaling, in the presence of excitatory neurotransmitters and stress is involved in the development of CNS diseases (Koga et al. 2019).