inositol-1-4-5-trisphosphate and Hyperthyroidism

Constitutively activating germline mutations of the thyrotropin receptor (TSHR) gene have been identified as a molecular cause of hereditary nonautoimmune hyperthyroidism. We describe here a Japanese kindred with two affected individuals who showed overt hyperthyroidism and mild goiter in the absence of TSHR antibodies. A novel heterozygous germline point mutation, identified in both individuals, resulted in an amino acid substitution of aspartic acid for tyrosine at codon 617 (Asp617Tyr) in the third intracellular loop of the TSHR. Screening of 7 additional family members led to the identification of the same mutation in 4 relatives: 1 had undergone thyroidectomy due to hyperthyroidism but 3 were asymptomatic with subclinical hyperthyroidism. In vitro functional studies of the Asp617Tyr TSHR demonstrated a constitutive activation of the cyclic adenosine monophosphate pathway, but not of the inositol phosphate cascade, with data similar to those of Asp619Gly, the first constitutively activating mutant TSHR identified. Treatment with inorganic iodine for 7 months successfully relieved all symptoms of hyperthyroidism in both patients.

Topics: Adult; Cyclic AMP; DNA; Female; Germ-Line Mutation; Humans; Hyperthyroidism; Immunoglobulins, Thyroid-Stimulating; Inositol 1,4,5-Trisphosphate; Male; Middle Aged; Pedigree; Polymerase Chain Reaction; Potassium Iodide; Receptors, Thyrotropin; Sequence Analysis, DNA; Thyrotropin; Thyroxine; Triiodothyronine; Ultrasonography

1. Mechanical responses to various stimulants and the distribution of adrenoceptor subtypes were investigated in smooth muscle cells of the rat aorta in eu- (control), hyper- and hypo-thyroid states. 2. Concentration-response relationships for K showed that the KCl EC50 value was slightly higher (28.4 mM K) in hypothyroid than in euthyroid and hyperthyroid states (22.5 mM and 22.8 mM K, respectively). The order of maximum amplitudes of KCl contraction was control greater than hypothyroid greater than hyperthyroid. 3. The EC50 values for the noradrenaline (NA)-induced contraction for eu-, hypo- and hyper-thyroid states were 7.4, 12.5 and 5.5 nM, respectively. The density of alpha 1-adrenoceptors was increased to 1.4 times the control in the hypothyroid state and reduced to 0.26 times the control in the hyperthyroid state. 4. The EC50 values for the phenylephrine-induced contraction in eu-, hypo- and hyper-thyroid states were 43.4, 247 and 41.5 nM, respectively, and those for clonidine 104, 1360 and 56.5 nM, respectively. The IC50 values for prazosin against 0.1 microM NA-induced contractions in eu-, hypo- and hyper-thyroid states were 5.8, 3.5 and 0.7 nM, respectively, and those for yohimbine 8.9, 5.4 and 4.1 microM, respectively. 5. The IC50 values for isoprenaline against phenylephrine-induced contractions were 63 nM and 2.4 microM in hyper- and eu-thyroid states, respectively, and the corresponding IC25 values for eu- and hypo-thyroid states were 72 and 423 nM, respectively. The density of beta-adrenoceptors was increased to 3.91 times the control in the hyperthyroid and reduced to 0.68 times the control in the hypothyroid states. 6. NA consistently increased the amount of inositol 1,4,5-trisphosphate (1P3) within 30s in the three thyroid states. In the hypothyroid state, the amount of IP3 was slightly increased and in the hyperthyroid condition, it occurred to a lesser extent than in the euthyroid state. 7. The results indicate that in hypothyroidism, the density of alpha,-adrenoceptors is increased and that of ,Beta-adrenoceptors reduced in vascular beds. The latter but not the former is accompanied by corresponding mechanical responses. In hyperthyroidism, the density of alpha 1-adrenoceptors is decreased and beta-adrenoceptors increased with parallel changes in mechanical responses.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Aorta, Thoracic; Catecholamines; Hyperthyroidism; Hypothyroidism; Inositol 1,4,5-Trisphosphate; Isometric Contraction; Isoproterenol; Male; Muscle, Smooth, Vascular; Norepinephrine; Potassium; Rats; Rats, Inbred Strains