کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2514278 1118459 2010 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Conformational flexibility of transmembrane helix VII of the human serotonin transporter impacts ion dependence and transport
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی داروشناسی
پیش نمایش صفحه اول مقاله
Conformational flexibility of transmembrane helix VII of the human serotonin transporter impacts ion dependence and transport
چکیده انگلیسی

The serotonin transporter (SERT) regulates the serotonin concentration in the synapse and is a target of several antidepressant and psychostimulant drugs. Previous work suggested that the middle transmembrane helices (TMHs) of the biogenic amine transporters (TMHs) play a role in substrate and ion recognition. We focused our present studies on exploring the role of TMH VII in transporter function and ion recognition. Residues divergent between human SERT and Drosophila SERT (hSERT and dSERT, respectively) were identified and mutated in hSERT to the corresponding identity in dSERT. hSERT mutants V366S, M370L, S375A, and T381S exhibited a decrease in transport capacity. To further explore the role of these residues in the transport process, we generated cysteine mutants at multiple positions. Pretreatment with [2-(trimethylammonium)ethyl] methanethiosulfonate (MTSET) caused a decrease in transport of [3H]5-HT in the V366C and M370C mutants. The hSERT V366S, M370L, and M370C mutations also altered the sodium and chloride dependence for substrate transport. Interpretation of our results in the context of a homology model of SERT based on the crystal structure of the Aquifex aeolicus leucine transporter suggests flexibility in the conformation of TMH VII that impacts ion dependence and substrate transport.

Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 80, Issue 9, 1 November 2010, Pages 1418–1426
نویسندگان
, , , ,