Abstract
Retro-orbital tissue membranes have been shown to have adenylate cyclase activity which can be stimulated by thyrotropin and by an exophthalmogenic factor derived from the thyrotropin molecule by partial pepsin digestion. This stimulable activity is maximal after 15 min and is optimal in the presence of 3 mM magnesium and 1.5 mM ATP. Calcium salts are exquisitely inhibitory to the hormonal stimulation; sodium, lithium, and ammonium salts are significantly less inhibitory. Thyrotropin and the exophthalmogenic factor induce similar maximal levels of stimulation but a 4- to 5-fold higher concentration of exophthalmogenic factor is required to achieve this level. Fluoride stimulates adenylate cyclase activity 2- to 3-fold higher than either thyrotropin or the exophthalmogenic factor; thyrotropin, luteinizing hormone, the beta subunit of thyrotropin, and the alpha subunit of thyrotropin have relative activities for stimulation of cyclase activity of 100:2:2 less than 0.5. Several other polypeptide and glycoprotein hormones have no effect. The gamma-globulin from patients with malignant exophthalmos has no significant effect on cyclase activity either alone or in the presence of maximal levels of thyrotropin or the exophthalmogenic factor; this gamma-globulin does, however, stimulate cyclase activity at submaximal hormone levels. Trypsin not only destroys the hormone-stimulable adenylate cyclase activity on retro-orbital tissue plasma membranes, but also destroys it on the 15,000 to 30,000 molecular weight receptor fragment released from the membranes by the tryptic action.
Highlights
Factor induce similar maximal levels of stimulation but a 4- to &fold higher concentration of exophthalmogenic factor is required to achieve this level
In our studies on experimental exophthalmos (25%32), we have demonstrated that TSH or an exophthalmogenic factor derived from the TSH molecule by partial pepsin digestion can induce exophthalmos in guinea pigs and that this exophthalmos is associated with an increased synthesis of sulfated and nonsulfated glycosaminoglycans in guinea pig retro-orbital tissue
Tissues and Its Stimulation by Both TSH and exophthalmogenic derivative of the TSH molecule (EPF)-The adenylate cyclase activity of retro-orbital tissue plasma membranes were stimulated by both TSH and the exophthalmogenic derivative (EPF) of the TSH molecule obtained by partial pepsin digestion of TSH preparations
Summary
Factor induce similar maximal levels of stimulation but a 4- to &fold higher concentration of exophthalmogenic factor is required to achieve this level. Our own studies have demonstrated that TSH binding to plasma membranes in vitro can be correlated with adenylate cyclase activation in these membranes in vitro [21,22,23] and that the reappearance of the TSH receptor after trypsinization of thyroid cells in culture ‘The abbreviations used are: CAMP, cyclic adenosine 3’:5’-monophosphate; TSH, thyroid-stimulating hormone or thyrotropin; EPF, the exophthalmos-producing factor derived f’rom the TSH molecule by partial pepsin digestion; LH, luteinizing hormone. We have further demonstrated that plasma membranes from guinea pig retro-orbital tissue have a TSH receptor which is capable of binding either TSH or the exophthalmogenic derivative of the TSH molecule (EPF) produced by partial pepsin of TSH preparations. In the present report we show that TSH and EPF can stimulate adenylate cyclase activity in retro-orbital tissue plasma membranes; we characterize the optimal conditions of this stimulation; and we correlate adenylate cyclase activation with TSH and EPF binding in these membranes
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