Gangliosides inhibit 1251-labeled thyrotropin binding to the thyrotropin receptors on bovine thyroid plasma membranes, on guinea pig retro-orbital tissue plasma membranes, and on human adipocyte membranes. This inhibition by gangliosides is critically altered by the number and location of the sialic acid residues within the ganglioside structure, the efficacy of inhibition having the following order: GD1b > GTI > GM1 > GM2 = GM3 > GD1a. The inhibition results from the interaction of thyrotropin and gangliosides, rather than the interaction of membrane and gangliosides. Fluorescence studies show that the inhibition is associated with a distinct conformational change of the thyrotropin molecule and that the progression from a "noninhibitory conformation" to an "inhibitory conformation" parallels exactly the order of effectiveness in inhibiting 125I-Yabeled thyrotropin binding. The ganglioside inhibition of 1251-labeled thyrotropin binding appears to be hormonally specific in that it is not affected by a umin, glucagon, insulin, prolactin, follicle-stimulating hormone, growth hormone, or corticotropin. The possibility that a ganglioside or ganglioside-like structure is a component of the thyrotropin receptor is suggested by the finding that gangliosides more complex than N-acetylneuraminylgalactosylglucosylceramide are present in bovine thyroid membranes in much higher quantities than have been previously found in extraneural tissue. The finding that the B component of cholera toxin, which also interacts with gangliosides, has a peptide sequence in common with the f, subunit of thyrotropin, suggests that thyrotropin and cholera toxin may be analogous in their mode of action on the membrane.In previous studies that detailed the solubilization of the thyrotropin (TSH) receptor from bovine thyroid plasma membranes, tryptic digestion was shown to yield a receptor fragment that exhibited specific TSH binding and had properties similar to those exhibited by the TSH receptor prior to solubilization (1, 2). This receptor fragment was purified by chromatography over TSH-Sepharose preparations (1, 2); it was shown to have a molecular weight of 25,000-30,000 by gel electrophoresis in the presence of sodium dodecyl sulfate (2), and to contain 30% carbohydrate and 10% sialic acid by weight (1). The sialic acid was vital to receptor function since neuraminidase digestion eliminated the ability of both the purified receptor fragment and the crude solubilized receptor preparation to specifically bind TSH (1).Recent studies have indicated that gangliosides, glycosphingolipids that contain sialic acid, specifically interact with cholera toxin and that variations in the oligosaccharide structure of the gangliosides influence this interaction (3-5). The present report demonstrates that TSH also interacts with gangliosides and that the location and number of the sialic acid residues on the ganglioside molecule is critical to this interaction. The report further shows that there is a sequence homology in the B component of chole...

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Thyroid cell membranes contain a multiplicity of gangliosides, some of which inhibit thyrotropin binding to thyroid membranes. The most potent inhibitor is a ganglioside which is present in only trace amounts and appears to have a novel structure. Thyroid gangliosides may play a role in relaying the hormonal message to the thyroid cell.