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Submitted on July 24, 2003
Accepted on August 26, 2003
1 Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York.
* To whom correspondence should be addressed. E-mail: rauf.latif{at}mssm.edu.
The TSH receptor (TSHR) is a prototypic G protein-coupled receptor with a large extracellular domain. We have previously demonstrated homophilic interactions of TSHRs and their existence as constitutive oligomers. However, we have also shown that TSH itself promotes the formation of receptor monomers. We hypothesized, therefore, that TSHR monomers induced by TSH ligand may move into lipid rafts before effective TSH-induced signaling by bringing the cognate signaling molecules resident in such rafts together with the TSHRs. Thus we aimed to determine if the TSHRs would partition into these lipid rafts.
The B subunit of Cholera Toxin (CTxB) binds to lipid raft-enriched GM1 ganglioside and has been widely exploited to visualize lipid rafts. Using such a method we demonstrated the presence of these GM1 enriched lipid microdomains in Chinese Hamster Ovary (CHO) cells by using CTxB labeled with a red dye (Alexa 594). To provide evidence for the presence of TSHRs in lipid rafts we stained CHO cells expressing TSHRGFP with labeled CtxB. Our results demonstrated that the TSHRGFP complexes localized to GM1 enriched lipid raft microdomains as evidenced by co-localization of the GFP tag with the labeled CtxB. Hence, we concluded that a significant proportion of TSHRs were constitutively associated with lipid rafts. Furthermore, on activation of these stained raft-receptor complexes with increasing concentrations of TSH we observed that the raft-receptor complexes decreased significantly. The relevance of such receptor movement out of the rafts suggested that these may be the receptors critical in the initiation of signal transduction
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