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Fraser Trevor Fraser Trevor Author
Title: Structural Basis for Molecular Recognition at Serotonin Receptors
Author: Fraser Trevor
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 researchers used the 5-HT2B and 5-HT1B structural data to better understand a recently discovered GPCR signaling pathway. When a neurotrans...

 researchers used the 5-HT2B and 5-HT1B structural data to better understand a recently discovered GPCR signaling pathway.

When a neurotransmitter such as serotonin binds to its GPCR receptor and triggers the primary, G protein-mediated activation signal, it also usually triggers another signal, often mediated by a protein called β-arrestin. This second signaling cascade may simply have the effect of "arresting" or inhibiting the primary, G protein-mediated signaling. But it can also have other effects on the cell, and although most molecules bind to their target GPCRs in a way that activates these primary and secondary signals equally, others preferentially activate one or the other. "Such functional selectivity, as we call it, adds another layer of complexity to drug effects on GPCRs," said Roth, a co-senior author of the study.

Roth's laboratory produced several 5-HT receptor subtypes in test cells, and compared the strength of G-protein and β-arrestin signaling when these receptors were bound by ergotamine or various other drugs, including the ergotamine-derived hallucinogen LSD (lysergic acid diethylamide). Most of the tested drugs showed no bias. However, ergotamine, LSD and some of their relatives turned out to be clearly biased in favor of β-arrestin signaling at the 5-HT2B receptor. Comparison of the ergotamine-bound 5-HT2B structure with the ergotamine-bound 5-HT1B structure revealed the likely reason. "We could see that when ergotamine is bound to the 5-HT2B receptor it stabilizes the receptor structure in a conformation that interferes with G protein signaling," said Wacker.

The findings allow scientists to start probing this arrestin-mediated signaling pathway and its downstream effects in a more targeted manner. "These structural data are teaching us to ask better questions about receptor biology," said Stevens.

In addition to Chong, the two other first authors of the first study, "Structural Basis for Molecular Recognition at Serotonin Receptors," were Yi Jiang, a researcher in the Stevens laboratory who was visiting from the Xu laboratory in Shanghai, and Jinming Ma, a researcher in the Stevens laboratory who was visiting from the Van Andel Research Institute in Michigan, where Xu runs a laboratory. Other contributors to this study were Huixian Wu, Daniel Wacker, Vsevolod Katritch, Gye Won Han, Wei Liu and Vadim Cherezov of TSRI; Xi-Ping Huang, Eyal Vardy and John D. McCorvy of Roth's laboratory at UNC; Xiang Gao, Edward X. Zhou, Karsten Melcher and Chenghai Zhang of the Van Andel Research Institute; Fang Bai of the Dalian University of Technology in China; and Huaiyu Yang, Linlin Yang of Xu and Jiang laboratories in Shanghai.

Contributors to the second study, "Structural Features for Functional Selectivity at Serotonin Receptors," included Chong Wang, Vsevolod Katritch, Gye Won Han, Meihua Chu, Fai Yiu Siu, Wei Liu, Yi Jiang and Vadim Cherezov of TSRI; Xi-Ping Huang, Eyal Vardy and John D. McCorvy of the Roth laboratory at UNC; and Eric Xu.

Support for these studies was provided by the National Institute of General Medical Sciences (PSI:Biology grant U54 GM094618), the National Institutes of Health Common Fund in Structural Biology (P50 GM073197), the Jay and Betty Van Andel Foundation, the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK071662), Chinese Ministry of Science and Technology (grants 2012ZX09301001-005 and 2012CB910403); Amway (China); the National Institute of Mental Health (NIMH) (R01 MH61887, U19 MH82441), the National Institute on Drug Abuse (R01 DA27170) and the NIMH Psychoactive Drug Screening Program.

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