A glycoprotein hormone expressed in corticotrophs exhibits unique binding properties on thyroid-stimulating hormone receptor.
Corticotroph-derived glycoprotein hormone (CGH), also referred to as thyrostimulin, is a noncovalent heterodimer of glycoprotein hormone alpha 2 (GPHA2) and glycoprotein hormone beta 5 (GPHB5). Here, we demonstrate that both subunits of CGH are expressed in the corticotroph cells of the human anterior pituitary, as well as in skin, retina, and testis. CGH activates the TSH receptor (TSHR); (125)I-CGH binding to cells expressing TSHR is saturable, specific, and of high affinity. In competition studies, unlabeled CGH is a potent competitor for (125)I-TSH binding, whereas unlabeled TSH does not compete for (125)I-CGH binding. Binding and competition analyses are consistent with the presence of two binding sites on the TSHR transfected baby hamster kidney cells, one that can interact with either TSH or CGH, and another that binds CGH alone. Transgenic overexpression of GPHB5 in mice produces elevations in serum T(4) levels, reductions in body weight, and proptosis. However, neither transgenic overexpression of GPHA2 nor deletion of GPHB5 produces an overt phenotype in mice. In vivo administration of CGH to mice produces a dose-dependent hyperthyroid phenotype including elevation of T(4) and hypertrophy of cells within the inner adrenal cortex. However, the distinctive expression patterns and binding characteristics of CGH suggest that it has endogenous biological roles that are discrete from those of TSH.
Okada
Shannon L
SL
ZymoGenetics, Inc., 1201 Eastlake Avenue East, Seattle, Washington 98102, USA. shoh@zgi.com
Ellsworth
Jeff L
JL
Durnam
Diane M
DM
Haugen
Harald S
HS
Holloway
James L
JL
Kelley
Merideth L
ML
Lewis
Katherine E
KE
Ren
Hongping
H
Sheppard
Paul O
PO
Storey
Harold M
HM
Waggie
Kimberly S
KS
Wolf
Anitra C
AC
Yao
Lena Y
LY
Webster
Philippa J
PJ
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006023:Glycoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D036361:Peptide Hormones / Q000032:analysis / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000737:chemistry / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000378:metabolism*; D012160:Retina / Q000737:chemistry / Q000378:metabolism; D012867:Skin / Q000737:chemistry / Q000378:metabolism; D013737:Testis / Q000737:chemistry / Q000378:metabolism; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology; D013974:Thyroxine / Q000097:blood; D014018:Tissue Distribution
D006023:Glycoproteins; D036361:Peptide Hormones; D011989:Receptors, Thyrotropin; C458339:thyrostimulin; D013974:Thyroxine