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  • Zacopride hydrochloride Why do glutamate and glycine bind


    Why do glutamate and glycine bind to the Zacopride hydrochloride in such different ways? Given the overall structural similarity between the GluN2A and GluN1 LBDs, one might conclude that the LBDs also bind ligands via similar processes. NMDA receptors with engineered disulfide linkages that lock the GluN1 lobes shut conduct current with kinetic profiles similar to that of wild-type NMDA receptors, suggesting that glutamate is the primary neurotransmitter, whereas D-serine, the endogenous agonist for GluN1 at synapses, or glycine, play more modulatory roles (Mothet et al., 2000, Kussius and Popescu, 2010). We speculate that the distinct binding mechanisms of glutamate and glycine may reflect the differing physiological roles the ligands play during NMDA receptor activation. Differences in these binding mechanisms may inform strategies for the design of therapeutic agents.
    Acknowledgments We thank Dominique Frueh for helpful discussion. Anton computer time was provided by the Pittsburgh Supercomputing Center (PSC) through NIH grant R01GM116961. The Anton and Anton2 machines at PSC were generously made available by D.E. Shaw Research. This study also used resources provided by the Maryland Advanced Research Computing Center (MARCC) at Johns Hopkins University. This work was supported by NIH grant R01GM094495 (to A.Y.L.).
    Introduction Hypercortisolism is a common endocrine disorder in dogs, and 80 to 85% of hypercortisolism cases are due to Cushing's disease, which is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (Guptill et al. 1997; Feldman et al., 2015). The incidence of Cushing's disease in humans is two to three cases per 1000,000 people per year (Etxabe and Vazquez, 1994; Lindholm et al. 2001), whereas in the canine population, the incidence is one to two cases per 1000 dogs per year (Willeberg and Priester 1982). The primary treatments for Cushing's disease are medication, radiation, and surgical therapy. In human medical science, surgical removal of the ACTH-secreting pituitary adenoma is the primary treatment option. In veterinary medicine, however, most Cushing's disease cases are treated with medicines, such as trilostane and mitotane, that focus on decreasing blood cortisol levels and improving clinical signs (Peterson et al. 1982; Neiger et al., 2002; Barker et al. 2003; Braddock and Church 2003; Alenza et al. 2006; Reine, 2007) However, in 1997, transsphenoidal hypophysectomy was introduced in the veterinary field as a treatment for dogs with Cushing's disease (Meij et al. 1997). Cushing's disease dogs treated with this procedure have a good prognosis, and accordingly, surgical treatment has increased in dogs (Hanson et al. 2005; Hara et al. 2010; Mamelak et al. 2014). In the event of incomplete resection, or recurrence after surgical treatment, medication or radiation therapy is chosen in veterinary medicine as well as in human medicine. Recently, it has been reported that new medications that focus on the ACTH-secreting pituitary adenoma itself, including somatostatin analogs, such as pasireotide and octreotide, and dopamine receptor subtype 2 agonists, such as bromocriptine and cabergoline, might be effective (Pivonello et al. 2009; Godbout et al. 2010; Mancini et al. 2010; Vilar et al. 2010; Ahmed et al. 2012; van der Pas et al. 2012; Murasawa et al. 2014). Somatostatin is synthesized in the hypothalamus periventricular nucleus and is released into the pituitary portal vein. It has been known to reduce growth hormone (GH) secretion. It is also found in the parasympathetic nervous system, digestive tract, pancreas, skin, and other organs. Somatostatin-28 and somatostatin-14 are produced by differential processing of the somatostatin precursor protein (Cuevas-Ramos and Fleseriu 2014). As one would expect, somatostatin binds to somatostatin receptors, of which there are five receptor subtypes, somatostatin receptors (SSTRs) 1–5 (Cuevas-Ramos and Fleseriu 2014). Human SSTRs (hSSTRs) 1–4 have high affinities for somatostatin-14, whereas hSSTR5 has a high affinity for somatostatin-28 (Patel et al. 1993). Among these hSSTR subtypes, only hSSTR2 and hSSTR5 decrease hormone secretions and induce cell cycle arrest (Cuevas-Ramos and Fleseriu 2014).