Nucleotide Contribution to the Functioning of SERT, Na /K ATPase and GPCR Proteins

Purine nucleotides are crucial for the effective operation of cell membrane proteins maintaining the neurotransmitter responses of 5-HT. Major protein targets in the treatment of depression include SERT, N/K ATPase and GPCR. Each protein target is responsive to a specific complement of drugs: antidepressants (SERT), lithium and cardiogenic steroids (N/K ATPase), 5-HT receptor ligands (GPCR). Computational software is useful for comparing molecular similarity within ligand-ligand and ligand-nucleotide structures. Previous studies demonstrate that GPCR ligands of different pharmacologic classes display relative molecular similarity to nucleotide structures. The current study applies this methodology to compound structures modulating SERT and N/K ATPase receptors. Minimum energy conformers of SERT antagonists demonstrate relative molecular similarity to the structural template of GTP nucleotide. GTP template fits of 5-HT and psilocin are similar, whereas a SERT-like fit is one of several for the ketamine structure. Endogenous and pharmaceutical modulators of Na/K ATPase relate to adenine nucleotide. The fits of cardiogenic steroids to a cGMP template demonstrate similarities and differences between compounds. Relative molecular similarity within the structures of hormones, drugs and nucleotides has implications for neurotransmitter transport and cell signal transduction processes.

Exposure of juvenile Chinook salmon to effluent from a large urban wastewater treatment plant.Part 1.physiological responses

Wastewater treatment plants release complex mixtures of chemicals into the aquatic environment as wastewater effluent(WWE);however,the effects of these mixtures are still poorly understood.Chinook salmon(Oncorhynchus tshawytscha)are a culturally important species in the Pacific Northwest and are a vital food resource for southern resident killer whales(Orcinus orca)that are listed as‘critically endangered’under the U.S.Endangered Species Act(ESA).Chinook populations have declined drastically in this region and have failed to show significant recovery despite regional-to-federal efforts,resulting in many populations being listed as threatened under the ESA.One source of stress to juvenile Chinook is chemical pollution from WWE during their outmigration along river corridors and residency in estuaries.In this study,we investigated effects of WWE on juvenile Chinook health in a ten-day exposure to dilutions of WWE from 0.1%to 20%.At the end of the exposure,we measured endpoints associated with endocrine disruption,brain function,osmoregulation,stress,and metabolism.Exposure to WWE significantly(α=0.1 for all analyses)induced vitellogenesis,indicating endocrine system disruption.We saw significant reductions in plasma glucose,an indication of stress,and brain Na+/K+-ATPase(NKA)activity,an enzyme essential for neuronal signaling.Lastly,metabolism was affected as evidenced by altered total protein,cholesterol,and albumin in plasma,a drastic decrease in whole body lipid content,and a significant increase in visible liver anomalies.We compared contaminant concentrations in exposure water with effects concentrations from the literature for chemicals known to induce vitellogenin or inhibit brain NKA.For most contaminants,concentrations in exposure waters were several orders of magnitude below effects concentrations in the literature.The exception was estrogenic hormones,which were detected at similar concentrations in this study compared to concentrations in other studies that induced vitellogenin.Based on comparisons to the literature,contaminants measured in this study could not explain the inhibition of brain NKA;however,WWE mixtures contain many quantified and undetected compounds that are likely acting together to cause harmful effects in Chinook.This research highlights the need for improved wastewater treatment to improve aquatic health and mitigate effects to threatened species like Puget Sound Chinook salmon.