{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:05:09Z","timestamp":1790960709762,"version":"4.1.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2011,6,28]],"date-time":"2011-06-28T00:00:00Z","timestamp":1309219200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Pseudohypoparathyroid patients have resistance predominantly to parathyroid hormone (PTH), and here we have examined the ability of an alternative G\u03b1s-related protein to inhibit G\u03b1s activity in a hormone-selective manner. We tested whether the GNAS exon A\/B-derived NH2-terminally truncated (Tr) \u03b1s protein alters stimulation of adenylate cyclase by the PTH receptor (PTHR1), the thyroid-stimulating hormone (TSH) receptor (TSHR), the \u03b22-adrenergic receptor (\u03b22AR), or the AVP receptor (V2R). HEK293\u2009cells cotransfected with receptor and full-length (FL) G\u03b1s\u2009\u00b1\u2009Tr \u03b1s protein expression vectors were stimulated with agonists (PTH [10\u22127 to 10\u22129\u2009M], TSH [1 to 100\u2009mU], isoproterenol [10\u22126 to 10\u22128\u2009M], or AVP [10\u22126 to 10\u22128\u2009M]). Following PTH stimulation, HEK293\u2009cells cotransfected with PTHR1\u2009+\u2009FL G\u03b1s\u2009+\u2009Tr \u03b1s had a significantly lower cAMP response than those transfected with only PTHR1\u2009+\u2009FL G\u03b1s. Tr \u03b1s also exerted an inhibitory effect on the cAMP levels stimulated by TSH via the TSHR but had little or no effect on isoproterenol or AVP acting via \u03b22AR or V2R, respectively. These differences mimic the spectrum of hormone resistance in pseudohypoparathyroidism type 1a (PHP-1a) and type 1b (PHP-1b) patients. In opossum kidney (OK) cells, endogenously expressing the PTHR1 and \u03b22AR, the exogenous expression of Tr \u03b1s at a level similar to endogenous FL G\u03b1s resulted in blunting of the cAMP response to PTH, whereas that to isoproterenol was unaltered. A pseudopseudohypoparathyroid patient with Albright hereditary osteodystrophy harbored a de novo paternally inherited M1I G\u03b1s mutation. Similar maternally inherited mutations at the initiation codon have been identified previously in PHP-1a patients. The M1I \u03b1s mutant (lacking the first 59 amino acids of G\u03b1s) blunted the increase in cAMP levels stimulated via the PTHR1 in both HEK293 and OK cells similar to the Tr \u03b1s protein. Thus NH2-terminally truncated forms of G\u03b1s may contribute to the pathogenesis of pseudohypoparathyroidism by inhibiting the activity of G\u03b1s itself in a GPCR selective manner. \u00a9 2011 American Society for Bone and Mineral Research<\/jats:p>","DOI":"10.1002\/jbmr.461","type":"journal-article","created":{"date-parts":[[2011,6,30]],"date-time":"2011-06-30T13:30:02Z","timestamp":1309440602000},"page":"2473-2485","source":"Crossref","is-referenced-by-count":41,"title":["Parathyroid hormone signaling via G\u03b1s is selectively inhibited by an NH2-terminally truncated G\u03b1s: Implications for pseudohypoparathyroidism"],"prefix":"10.1093","volume":"26","author":[{"given":"Svetlana","family":"Puzhko","sequence":"first","affiliation":[{"name":"Endocrine Research Laboratory, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia Gates","family":"Goodyer","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University, Montreal, Quebec, Canada"},{"name":"Department of Pediatrics, McGill University, Montreal, Quebec, Canada"},{"name":"Endocrine Research Laboratory, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Amin","family":"Kerachian","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, McGill University, Montreal, Quebec, Canada"},{"name":"Calcium Research Laboratory, Royal Victoria Hospital, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Canaff","sequence":"additional","affiliation":[{"name":"Calcium Research Laboratory, Royal Victoria Hospital, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhusmita","family":"Misra","sequence":"additional","affiliation":[{"name":"Pediatric Endocrine Unit, MassGeneral forf Children and Harvard Medical School, Boston, MA, USA"},{"name":"Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"J\u00fcppner","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA"},{"name":"Pediatric Nephrology Unit, MassGeneral for Children and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murat","family":"Bastepe","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey N","family":"Hendy","sequence":"additional","affiliation":[{"name":"Hormones and Cancer Research Unit, Royal Victoria Hospital, Montreal, Quebec, Canada"},{"name":"Department of Physiology, McGill University, Montreal, Quebec, Canada"},{"name":"Department of Human Genetics, McGill University, Montreal, Quebec, Canada"},{"name":"Calcium Research Laboratory, Royal Victoria Hospital, Montreal, Quebec, Canada"},{"name":"Department of Medicine, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,6,28]]},"reference":[{"key":"2024020317565497100_bib1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1138\/20050188","article-title":"Perspectives: pseudohypoparathyroidism, Gs\u03b1, and the GNAS locus","volume":"2","author":"Bastepe","year":"2005","journal-title":"BoneKEy-Osteovision."},{"key":"2024020317565497100_bib2","first-page":"1137","author":"Levine","year":"2002"},{"key":"2024020317565497100_bib3","first-page":"922","article-title":"Pseudohypoparathyroidism: an example of \u201cSeabright-Bantam 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