Biomedical subjects

S Kosugi

Publications and source records attributed to S Kosugi.

At least 109 records · Page 6Linked to original sources

PubMed1994

The intracellular region adjacent to plasma membrane (residues 684-692) of the thyrotropin receptor is important for phosphoinositide signaling but not for agonist-induced adenylate cyclase activation.

We investigated the role of the intracellular region adjacent to transmembrane helix VII of the thyrotropin receptor (TSHR) in signal transduction using mutants as we did on the cytoplasmic loops. Two mutants with a substitution of the alpha 1- or beta 2-adrenergic receptor sequence showed a TSH- or Graves' IgG-stimulated cAMP response despite a low TSH binding Bmax. Both the mutants completely lost or markedly decreased the TSH- or Graves' IgG-stimulated inositol phosphate increase. These findings suggest that the intracellular region adjacent to the transmembrane region (residues 684-692) of the TSHR does not play a crucial role in agonist-induced adenylate cyclase activation but that it is important for phosphoinositide signaling.

Adenylyl Cyclases↗

PubMed1994

The first cytoplasmic loop of the thyrotropin receptor is important for phosphoinositide signaling but not for agonist-induced adenylate cyclase activation.

We investigated the role of the 1st cytoplasmic loop of the thyrotropin receptor (TSHR) on signal transduction using mutants as we did the 2nd and 3rd cytoplasmic loops [Kosugi S. et al. (1994) Mol. Endocrinol., in press; and 7, 1009-1020]. Five substitution mutants involving the first cytoplasmic loop showed a TSH- or Graves' IgG-stimulated cAMP response despite the low TSH binding Bmax. All the mutants completely lost or markedly decreased the TSH- or Graves' IgG-stimulated inositol phosphate increase. These findings suggest that the 1st cytoplasmic loop of the TSHR does not play a crucial role in agonist-induced adenylate cyclase activation but that it is important for phosphoinositide signaling.

Adenylyl Cyclases↗

PubMed1994

[Recent progress in TSH receptor research--relationship of its structural characteristics to ligand binding, glycosylation and signal transduction].

Extensive mutagenesis studies of the long extracellular domain of the TSH receptor (TSHR) revealed important residues (Cys-301, Tyr-385 and Cys-390) for binding of TSH in its C-terminal region. These two cysteines were postulated to form a disulfide bond catalyzed by TSH. On the other hand, binding sites of a thyroid stimulating antibody were located in the N-terminal region of the extracellular domain. The long extracellular domain of the TSHR has 5 or 6 possible asparagine-linked glycosylation sites. However, only two sites are essential for the expression of a functional receptor among them. Although point mutation at residue 113 of the human TSHR lost TSH binding, the equivalent mutation of the rat TSHR did not, implying a difference in the significance of sugar chains among species. G protein interaction sites have recently been defined by mutagenesis studies. However, the details of how TSH binding to the long extracellular domain causes conformational change in the transmembrane domain remains to be elucidated.

Animals↗

PubMed1994

Further studies of amino acids (268-304) in thyrotropin (TSH)--lutropin/chorionic gonadotropin (LH/CG) receptor chimeras: cysteine-301 is important in TSH binding and receptor tertiary structure.

Our previous study of chimeric TSH-LH/CG receptors showed that substituting amino acid residues 268-304 of the TSH receptor with homologous residues from the LH/CG receptor markedly decreased high affinity TSH binding as evidenced by ligand displacement assays [Akamizu et al. Endocr J 40:363-372, 1993]. Despite this change in TSH binding, there was a minimal change in TSH-stimulated activity in cAMP assays. To explain this dissociation of TSH binding and function, further characterization of individual residues within the 268-304 segment was performed. Five additional chimeric TSH-LH/CG receptors within this region were constructed by substituting corresponding residues of rat LH/CG receptor. After transfection in Cos-7 cells, TSH receptor activities of these chimeras were evaluated. A single point mutation of cysteine-301 to glutamate resulted in a mutant receptor that exhibited the same receptor bioactivity as the chimeric receptor with amino acids 268-304 substituted by LH/CG receptor residues: apparent low affinity TSH binding in ligand displacement assays but significant retention of the cAMP response to TSH. The four other chimeric substitutions yielded cDNAs coding for receptors that behaved like wild-type receptors. Western blot analyses using a TSH receptor-specific antibody showed that all five of the new mutants were synthesized and integrated in the membrane. These results suggest that cysteine-301 is the critical residue whose mutation accounts for the original chimeric results and the dissociation of binding and functional activity. The possibility must be considered that cysteine-301 is involved in disulfide bond formation and is important in tertiary structure and that conformational changes in the receptor result from its mutation.

Amino Acid Sequence↗

PubMed1994

Demonstration of a marked reduction in the amount of GPIIb in most type II patients with Glanzmann's thrombasthenia.

In this study employing a sensitive immunoblot assay, we have characterized GPIIb and GPIIIa in thrombasthenic platelets from seven type II and four type I patients from 10 unrelated families. The amounts of GPIIb and GPIIIa were both markedly reduced in all these patients, and abnormal molecular weight GPIIb or GPIIIa was not detected. In all of four type I patients the amount of GPIIb was much lower than that of GPIIIa. In this study, however, we found that the amount of GPIIb was also lower even in six out of seven type II patients. Immunodepletion of patients' platelets with AP2 (a monoclonal antibody specific for the GPIIb-IIIa complex), AP3 (specific for GPIIIa) or AMF7 (specific for alpha v) further confirmed that GPIIIa existed in excess, and demonstrated that excess GPIIIa were mostly in free form and not associated with GPIIb or alpha v. The reduction of GPIIb may represent an abnormality in GPIIb processing in these type II and type I thrombasthenic platelets. It remains unclear whether these two subgroups represent distinct categories.

Blood Platelets↗

PubMed1994

Cyclic thrombocytopenia associated with IgM anti-GPIIb-IIIa autoantibodies.

We studied a female patient with cyclic fluctuation in platelet count following splenectomy for autoimmune thrombocytopenia. The cyclical fluctuation appeared to be in phase with her menstrual cycle and her platelet count was low during menses. Bone marrow examinations performed at the peak as well as the bottom of the platelet count showed normal or increased numbers of megakaryocytes. The patient's platelet count increased rapidly after intravenous gamma-globulin (IVIgG) therapy, suggesting that a failure of platelet production is unlikely to account for the cycle. Platelet-associated IgM (PAIgM) was markedly elevated, whereas PAIgG was normal at any stage of the cycle. MACE assay demonstrated that PAIgM contained IgM anti-glycoprotein (GP) IIb-IIIa autoantibodies. Comparison between MACE assay using untreated and EDTA-treated platelets at 37 degrees C demonstrated that the platelet-associated IgM autoantibodies mainly recognized divalent cation-dependent conformation(s) of GPIIb-IIIa. No antibodies were, however, detected in her serum. The levels of IgM anti-GPIIb-IIIa showed an inverse relationship with the platelet count. In spite of the marked increase in platelet count after IVIgG, however, the levels of IgM anti-GPIIb-IIIa remained elevated. These findings suggest that platelet-associated IgM anti-GPIIb-IIIa autoantibodies are of pathogenic significance in this patient.

Autoantibodies↗

PubMed1994

The middle portion in the second cytoplasmic loop of the thyrotropin receptor plays a crucial role in adenylate cyclase activation.

We have examined the role of the 2nd cytoplasmic loop of the TSH receptor (TSHR) in TSH- and TSHR autoantibody-stimulated cAMP and inositol phosphate formation using mutants created by substituting sequences from the alpha 1- or beta 2-adrenergic receptors (AR). Unlike similar substitution mutants involving the 3rd cytoplasmic loop that lose agonist-induced inositol phosphate but not cAMP increase after transfection into Cos-7 cells, mutants involving the 2nd loop showed significant change in generating both signals. Mutant B525, which substitutes residues 525-527 with a comparable beta 2-AR sequence, exhibited a complete loss in TSH- or Graves' immunoglobulin G-increased cAMP signaling and a lesser loss in phosphoinositide signaling. This is a unique mutant in which cAMP response was completely lost in all those involving the 2nd or 3rd cytoplasmic loop. On the other hand, mutant B528, in which residues 528-532 are substituted with a comparable beta 2-AR sequence, exhibited the most profound loss in phosphoinositide signaling. Mutants involving portions surrounding residues 528-532 in the 2nd cytoplasmic loop had milder losses in agonist-increased phosphoinositide signaling and much lesser losses in agonist-increased cAMP generation. The transfection efficiency of all transfectants was the same. All transfectants with mutant or wild type TSHR had a similar amount and identical profile of TSHR mRNA in Northern blots and TSHR forms on Western blots. Thus, the 2nd cytoplasmic loop is important for agonist-induced cAMP as well as for phosphoinositide signal generation, whereas the 3rd loop appears to be important only for the latter. The most important determinant for agonist-increased cAMP signal generation is in the middle of the 2nd loop, around residues 525-527. In contrast, the determinants most critical for agonist-induced phosphoinositide signaling are also located in the middle of the 2nd loop, around residues 528-532, and those with less importance are broadly distributed.

Adenylyl Cyclases↗

PubMed1994

Recent progress in TSH receptor studies with a new concept of "autoimmune TSH receptor disease".

Recent progress in the studies of epitope analysis of the TSH-R against TSH-R Ab was reviewed extensively. Using both site-directed mutagenesis and synthetic TSH-R peptide, binding and/or action sites of TSH-R Ab have been known to be multiple and discontinuous, but the significance of two unique and TSH-R specific regions has been implicated. Further, the possible existence of heterogeneity among stimulatory TSH-R Ab has also been indicated. As for immunogenetic factors related to autoimmune thyroid diseases, studies on HLA analysis, TSH-R specific T lymphocyte analysis and VH analysis of TSH-R Ab were discussed. Of note was the negative association of HLA-DP w2 antigen in Japanese patients with Graves' disease and hypothyroidism due to blocking TSH-R Ab, and we proposed a new concept of autoimmune TSH receptor disease within autoimmune thyroid disease and emphasized possible critical roles of HLA-DP. Recent evidence of restricted usage of the Ig VH gene in cloned B lymphocytes from Graves' patients producing TSH-R Ab has also been presented.

Autoimmune Diseases↗

PubMed1994

[Anti-thyrotropin (TSH) receptor antibody binding epitopes of TSH receptor: site-directed mutagenesis approach].

Anti-TSH receptor antibodies are thought to be involved in the expression of autoimmune thyroid diseases, especially Graves' disease and idiopathic myxedema. Cloning of TSH receptor gene allowed us to study aspects of its structure and function at the molecular level, including autoantibody-binding sites. The long extracellular domain of TSH receptor was presumed to contain antibody-binding site. Site-directed mutagenesis of this domain defined regions important for autoantibodies. The C-terminal region of the extracellular domain, residues 295-306, 387-395 and tyrosine 385 were determinants of the "blocking-type" antibody, which were present in patients with primary hypothyroidism. And the N-terminal region, residues 34-37, 40, 42-45 and 52-56 were the site of the "stimulatory-type" antibody interactions, important in patients with Graves' disease.

Amino Acid Sequence↗

PubMed1994

High-titer antinuclear antibodies, anti-SSA/Ro antibodies and anti-nuclear RNP antibodies in patients with idiopathic thrombocytopenic purpura.

The clinical significance of high-titer antinuclear antibodies (ANA) and autoantibodies to cellular antigens such as SSA/Ro and nuclear RNP (nRNP) antigens in idiopathic thrombocytopenic purpura (ITP) was examined in a prospective evaluation of 66 adult patients with chronic ITP. ANA were positive in 29 (44%) of 66 patients with chronic ITP. The titers of ANA were high (1:160 or higher) in 14 of 29 ANA-positive patients. Furthermore, 10 of 66 patients had precipitating antibodies to nuclear antigens; seven patients had anti-SSA/Ro antibodies and the other three had anti-nRNP antibodies. None of high-titer ANA- or precipitating antibody-positive patients developed systemic lupus erythematosus (SLE) throughout the follow-up period of 3 years. In addition, we investigated retrospectively precipitating antibodies in stocked sera from 8 patients. These patients had already precipitating antibodies average of 7.7 years before. None of 8 patients developed SLE or Sjogren's syndrome (SS). These data demonstrate that high-titer ANA and antibodies to SSA/Ro or nRNP antigens are often found in patients with ITP, and indicate that the detection of high-titer ANA or the existence of antibodies to SSA/Ro or nRNP antigens by itself is not enough to identify those patients with ITP who are at risk of developing SLE or SS.

Adult↗

PubMed1994

[Signal transduction of the thyrotropin receptor].

The thyrotropin receptor (TSHR) mediates dual signalling, cAMP and phosphoinositide (PIP2) responses. We have characterized the roles of the 2nd and 3rd cytoplasmic loops on signal transduction by site-directed mutagenesis. Middle portion in the 2nd loop (residues 525-527) is found to be important for Gs coupling. On the other hand, N- and C-terminal regions of the 3rd loop and residues 528-532 in the 2nd loop are important for Gq coupling. Further, mutations involving residue 617-620 in the 3rd loop result in constitutive activation. Constitutively activating mutations of the TSHR and LH/CGR (lutropin/choriogonadotropin receptor) are found in functional thyroid adenoma and familial male precocious puberty, respectively, and appear to be the direct cause of each disease.

Cyclic AMP↗

PubMed1993

A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty.

Familial male precocious puberty (FMPP) is a gonadotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern. Affected males generally exhibit signs of puberty by age 4. Testosterone production and Leydig cell hyperplasia occur in the context of prepubertal levels of luteinizing hormone (LH). The LH receptor is a member of the family of G-protein-coupled receptors, and we hypothesized that FMPP might be due to a mutant receptor that is activated in the presence of little or no agonist. A single A-->G base change that results in substitution of glycine for aspartate at position 578 in the sixth transmembrane helix of the LH receptor was found in affected individuals from eight different families. Linkage of the mutation to FMPP was supported by restriction-digest analysis. COS-7 cells expressing the mutant LH receptor exhibited markedly increased cyclic AMP production in the absence of agonist, suggesting that autonomous Leydig cell activity in FMPP is caused by a constitutively activated LH receptor.

Adenine↗

PubMed1993

A novel polymorphism in glycoprotein IV (replacement of proline-90 by serine) predominates in subjects with platelet GPIV deficiency.

To clarify the molecular basis of the deficiency of glycoprotein IV (GPIV) of the platelet surface, we analyzed GPIV cDNA synthesized from platelet RNA of five unrelated Japanese subjects whose platelets did not express GPIV. We confirmed the presence of normal-sized GPIV mRNA in platelets from subjects with GPIV deficiency. The sequence of platelet GPIV cDNA from GPIV deficient subject showed three differences when compared with the published sequence; 1) a replacement of a 478CCT codon for proline-90 by TCT for serine, 2) a four-base insertion in the 3'-noncoding region, and 3) a substitution of A for 79C in the 5'-noncoding region. The replacement of Pro90 by Ser predominates in subjects with GPIV deficiency; that is, four out of five platelets with GPIV deficiency contained GPIV mRNA encoding GPIVSer-90, while all platelets from 17 GPIV positive subjects had GPIV mRNA encoding GPIVPro-90. The sequence of platelet GPIV cDNA which did not encode GPIVSer-90 from a subject with GPIV deficiency revealed no abnormality in the coding region. The four-base insertion in the 3'-noncoding region and the substitution of A for 79C in the 5'-noncoding region seems to be unrelated to the expression of GPIV. The substitution of Ser for Pro90 might alter the GPIV structure or impair GPIV biosynthesis, resulting in a lack of detectable GPIV. This hypothesis remains to be tested.

Amino Acid Sequence↗

PubMed1993

Elevated platelet-associated IgG in SLE patients due to anti-platelet autoantibody: differentiation between autoantibodies and immune complexes by ether elution.

The level of platelet-associated IgG (PAIgG) is reported to be elevated in patients with systemic lupus erythematosus (SLE). However, the nature of PAIgG is unclear. We have investigated whether the PAIgG of SLE consists of anti-platelet autoantibodies or immune complexes (IC). The PAIgG values measured by flow cytometry were elevated in 11/25 patients with SLE. 3/6 SLE patients with thrombocytopenia had a high level of PAIgG (the mean fluorescence intensity > 10). We used an ether elution technique to determine whether elevated PAIgG consists of anti-platelet antibodies or IC. Preliminary experiments showed that the eluates prepared from platelets sensitized with anti-HPA-4a antibody reacted with normal platelets, while the eluates prepared from platelets sensitized with heat-aggregated IgG or model IC failed to react with normal platelets. These results indicate that the reactivity of eluates can distinguish between platelet-bound antibody and IC. We applied this technique to analysis of the PAIgG of SLE platelets. The eluates from SLE platelets (the mean fluorescence intensity > 10) reacted with normal platelets, indicating that the PAIgG of SLE platelets has the nature of antiplatelet autoantibodies. Furthermore, we investigated the target antigens which bind PAIgGs of SLE, using the direct immunoprecipitation procedure and modified antigen capture ELISA (MACE). Both methods identified GPIIb/IIIa as the target antigens. We conclude that the ether elution technique can distinguish between anti-platelet antibodies and IC, and that the PAIgGs of SLE with a high PAIgG value and thrombocytopenia have the nature of anti-platelet autoantibodies.

Antigen-Antibody Complex↗

PubMed1993

Use of thyrotropin receptor (TSHR) mutants to detect stimulating TSHR antibodies in hypothyroid patients with idiopathic myxedema, who have blocking TSHR antibodies.

Deletions of residues 295-306, 299-301, and 387-395 of the TSH receptor, as well as point mutations of cysteine 301 or 390 to serine, and tyrosine 385 to phenylalanine or alanine, markedly diminish the ability of a transfected receptor to measure the activity of blocking TSH receptor autoantibodies (TSHRAbs) in patients with idiopathic myxedema and hypothyroidism, but not stimulating TSHRAbs in Graves' patients. This has allowed us to use these mutants to detect stimulating TSHRAb activity in the sera of hypothyroid patients with idiopathic myxedema who have blocking TSHRAbs. In 7 such patients, we show that 50% or more have significant stimulatory activity in cells transfected with mutant receptors, as evidenced by the ability of the immunoglobulin G to directly increase cAMP levels or to enhance the ability of TSH or a Graves' stimulating TSHRAb to increase cAMP levels. Three of the TSH receptor mutants, deletions of residues 295-306 and 387-395 and the point mutation of cysteine 301 to serine, are shown to be particularly useful in these assays and may be useful to clarify the pathogenetic role and clinical significance of stimulating TSHRAbs in patients with autoimmune thyroid disease who also have blocking TSHRAbs.

Animals↗

PubMed1993

Receptor cross-talk can optimize assays for autoantibodies to the thyrotropin receptor: effect of phenylisopropyladenosine on adenosine 3',5'-monophosphate and inositol phosphate levels in rat FRTL-5 thyroid cells.

Immunoglobulins (IgG) from patients with Graves' disease increase inositol phosphate (IP) as well as cAMP production in rat thyroid FRTL-5 cells; IgGs from normal control subjects do not. Graves' IgG-and TSH-induced IP formation is inhibited by blocking TSH receptor (TSHR) antibodies from hypothyroid patients with primary myxedema, as is the cAMP response; this suggests that the Graves' IgG are acting through the TSHR to induce both the cAMP and phosphatidyl-inositol 4,5-biphosphate signal cascades in FRTL-5 thyroid cells as in cells with recombinant TSHR. Optimal conditions for measuring the Graves' IgG-induced IP increase include a NaCl-free Hanks' Balanced Salt Solution (HBSS) buffer system and a P1 purinergic receptor agonist; the action of each is additive. Optimization by NaCl-free HBSS is similar to that observed in cAMP assays and is specific for TSH or Graves' IgG; thus, NaCl-free HBSS did not affect ATP-induced, and actually inhibited norepinephrine-induced, IP production in FRTL-5 cells. The P1 purinergic receptor agonist acts via receptor cross-talk, which also allows further optimization of cAMP assays. Thus, adenosine deaminase improves Graves' IgG-induced cAMP production by removing adenosine from the medium. Although NaCl-free HBSS improved TSH- or Graves' IgG-induced IP and cAMP production in cells with recombinant TSHR; the modulatory action of phenylisopropyladenosine was lost.

Animals↗

PubMed1993

Identification of thyroid-stimulating antibody-specific interaction sites in the N-terminal region of the thyrotropin receptor.

Using mutants of the N-terminal region (residues 30-76) of the rat TSH receptor (TSHR), which substitute corresponding segments of rat gonadotropin receptors or hydrophilic (serine) and hydrophobic (alanine) amino acids as appropriate, we show that residues 30-33, 34-37, 42-45, 52-56, and 58-61, in addition to threonine-40, are determinants for the interaction of thyroid-stimulating autoantibodies (stimulating TSHRAbs) with the TSHR. The most important, residues 34-37, 42-45, and 52-56, whose mutants lose stimulating TSHRAb activity with at least 11 of 12 (> 90%) of the Graves' immunoglobulins G tested, are, like threonine-40, in regions of the TSHR that are nonhomologous with gonadotropin receptors. These data establish at least in part, therefore, the basis for the thyroid-specific effects of stimulating TSHRAbs. In no case do the same mutants lose their reactivity with TSH or blocking-type TSHR autoantibodies (blocking TSHRAbs) from hypothyroid patients with idiopathic myxedema. Since the latter have been shown to interact with high affinity TSH-binding sites on the C-terminal portion of the external domain of the TSHR, stimulating TSHRAbs and blocking TSHRAbs react with different receptor determinants, which can be presumed to have different roles in receptor function. This can explain the hyper- or hypothyroidism of different thyroid autoimmune diseases with receptor antibodies. Residues 30-33, 42-45, and threonine-40 appear to be related to the agonist action of TSH, since in each case mutation results in low affinity TSH binding, but normal TSH-increased cAMP activity, similar, for example, to a beta-adrenergic agonist. Using a receptor antibody to identify different receptor forms in the membrane, we can also identify determinants in this N-terminal region (residues 30-76) whose mutation results in a loss of all activities without apparently altering receptor synthesis, processing, or integration within the bilayer. These are residues 38 and 39, cysteine-41, residues 46-51, leucine-57, threonine-62, and, within residues 66-76, serine-69, alanine-71, phenylalanine-72, serine-74, leucine-75, and proline-76. We suggest that these residues are at the very least important in the conformational array of receptor determinants necessary for interactions with TSH and stimulating TSHRAbs.

Amino Acid Sequence↗

PubMed1993

Substitutions of different regions of the third cytoplasmic loop of the thyrotropin (TSH) receptor have selective effects on constitutive, TSH-, and TSH receptor autoantibody-stimulated phosphoinositide and 3',5'-cyclic adenosine monophosphate signal generation.

TSH and immunoglobulin G (IgG) preparations from patients with Graves' disease increase inositol phosphate as well as cAMP formation in Cos-7 cells transfected with rat TSH receptor (TSHR) cDNA. In a previous report, we mutated alanine 623 of the third cytoplasmic loop (residues 605-625) of the TSHR and showed it was critical for TSH and Graves' IgG initiation of phosphatidylinositol bisphosphate (PIP2) but not cAMP signaling. In this report, we substituted residues in the third loop of the TSHR with sequences from the N- and C-termini of the third loop of the alpha 1- and beta 2-adrenergic receptors (ARs), which computer analysis has identified as homologous to those in the TSHR. Alanine 623 is conserved in most ARs as well as in glycoprotein hormone receptors; there is, therefore, no change in alanine 623. After transfection of the mutant TSHR cDNAs into Cos-7 cells, we show that the mutant proteins are normally synthesized, processed, and incorporated into the membrane bilayer by Western blotting with a specific receptor antibody. We also show that the dissociation constant for TSH binding in all mutants is the same or lower than wild type TSHR. We then evaluated the ability of TSH or Graves' IgG to increase PIP2 and cAMP signals in each transfectant. Mutants A622 and B621 replace, respectively, residues 622-625 and 621-625 of the TSHR with alpha 1- and beta 2-AR residues from the C-terminus of the third cytoplasmic loop; mutants A607 and B605 replace, respectively, TSHR residues 607-609 and 605-609 with N-terminus residues from alpha 1- and beta 2-AR. All four mutants, like the alanine 623 mutant, result in transfected cells which lose TSH and Graves' IgG initiation of PIP2 but not cAMP signalling. Like the alanine 623 mutation to glutamic acid, the A607, B605, A622, and B621 mutants also result in decreased basal cAMP, but not inositol phosphate levels, relative to wild type receptor. In contrast to these results, mutants A610, B610, A617, and B617, which replace residues 610-613 or 617-620 of the TSHR with corresponding residues of the alpha 1- and beta 2-AR, retain TSH and Graves' IgG responsiveness in both inositol phosphate and cAMP assays. Mutation of residues 610-613, in fact, potentiates TSH-increased inositol phosphate production, despite having no effect on TSH-increased cAMP production.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗