{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T15:08:17Z","timestamp":1791040097565,"version":"4.1.0"},"reference-count":37,"publisher":"The Endocrine Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1999,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hyperfunctional endocrine thyroid and testicular disorders can frequently be traced back to gain-of-function mutations in glycoprotein hormone receptor genes. Deletion mutations in the third intracellular (i3) loop of the TSH receptor have recently been identified as a cause of constitutive receptor activity. To examine whether the underlying mechanism of receptor activation applies to all glycoprotein hormone receptors, we created deletion mutations in the LH and FSH receptors. In analogy to the situation with the TSH receptor, a deletion of nine amino acids resulted in constitutive activity irrespective of the location of deletions within the i3 loop of the LH receptor. In contrast, only one (\u0394563\u2013566) of four different 4-amino acid deletion mutants displayed agonist-independent activity. Systematic examination of the structural requirements for this effect in the \u0394563\u2013566 mutant revealed that only deletions including D564 resulted in constitutive receptor activity. Replacement of D564 by G, K, and N led to agonist-independent cAMP formation while introduction of a negatively charged E silenced constitutive receptor activity, indicating that an anionic amino acid at this position may be required to maintain an inactive receptor conformation. Insertion of A residues up- and downstream of D564 did not perturb receptor quiescence, showing that a certain degree of spatial freedom of the negatively charged amino acid within the context of the i3 loop is well tolerated. In contrast to the results obtained with the LH receptor, deletion of the corresponding D567 from the i3 loop of the FSH receptor did not cause constitutive receptor activation, highlighting significant differences in the activation mechanism of gonadotropin receptors.<\/jats:p>","DOI":"10.1210\/mend.13.2.0233","type":"journal-article","created":{"date-parts":[[2014,1,8]],"date-time":"2014-01-08T17:30:20Z","timestamp":1389202220000},"page":"181-190","source":"Crossref","is-referenced-by-count":67,"title":["Role of the Third Intracellular Loop for the Activation of Gonadotropin Receptors"],"prefix":"10.1210","volume":"13","author":[{"given":"Angela","family":"Schulz","sequence":"first","affiliation":[{"name":"Institut fu\u0308r Pharmakologie (A.S., T.S., G.S., T.G.) Freie Universita\u0308t Berlin 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Scho\u0308neberg","sequence":"additional","affiliation":[{"name":"Institut fu\u0308r Pharmakologie (A.S., T.S., G.S., T.G.) Freie Universita\u0308t Berlin 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Paschke","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik III (R.P.) Universita\u0308t Leipzig 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gu\u0308nter","family":"Schultz","sequence":"additional","affiliation":[{"name":"Institut fu\u0308r Pharmakologie (A.S., T.S., G.S., T.G.) Freie Universita\u0308t Berlin 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Gudermann","sequence":"additional","affiliation":[{"name":"Institut fu\u0308r Pharmakologie (A.S., T.S., G.S., T.G.) Freie Universita\u0308t Berlin 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071614224092700_R1","doi-asserted-by":"crossref","first-page":"4625","DOI":"10.1016\/S0021-9258(18)53442-6","article-title":"A mutation-induced activated state of the \u03b22-adrenergic receptor. Extending the ternary complex model.","volume":"268","author":"Samama","year":"1993","journal-title":"J Biol Chem"},{"key":"2020071614224092700_R2","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1016\/S0021-9258(18)45962-5","article-title":"Constitutive activation of the \u03b11B-adrenergic receptor by all amino acid substitutions at a single site. 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