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It plays a key role in the regulation of human calcium and thus mineral metabolism. However, the nature of interactions between VFT units and HH bundles, and the impacts of heterozygous or homozygous inactivating mutations, which have implications for disorders of calcium metabolism are not yet clearly defined. Herein we generated CaSR-GABAB1 and CaSR-GABAB2 chimeras subject to GABAB-dependent endoplasmic reticulum sorting to traffic mutant heterodimers to the cell surface. Transfected HEK-293 cells were assessed for Ca2+o-stimulated Ca2+i mobilization using mutations in either the VFT domains and\/or HH bundle intraloop-2 or intraloop-3. When the same mutation was present in both VFT domains of receptor dimers, analogous to homozygous neonatal severe hyperparathyroidism (NSHPT), receptor function was markedly impaired. Mutant heterodimers containing one wild-type (WT) and one mutant VFT domain, however, corresponding to heterozygous familial hypocalciuric hypercalcemia type-1 (FHH-1), supported maximal signaling with reduced Ca2+o potency. Thus two WT VFT domains were required for normal Ca2+o potency and there was a pronounced gene-dosage effect. In contrast, a single WT HH bundle was insufficient for maximal signaling and there was no functional difference between heterodimers in which the mutation was present in one or both intraloops; ie, no gene-dosage effect. Finally, we observed that the Ca2+o-stimulated CaSR operated exclusively via signaling in-trans and not via combined in-trans and in-cis signaling. We consider how receptor asymmetry may support the underlying mechanisms. \u00a9 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4651","type":"journal-article","created":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T03:38:47Z","timestamp":1658115527000},"page":"1787-1807","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Cell Surface Calcium-Sensing Receptor Heterodimers: Mutant Gene Dosage Affects Ca2+ Sensing but Not G Protein Interaction"],"prefix":"10.1093","volume":"37","author":[{"given":"Mahvash A.","family":"Goolam","sequence":"first","affiliation":[{"name":"School of Life and Environmental Sciences, Charles Perkins Centre (D17) University of Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice P.","family":"Brown","sequence":"additional","affiliation":[{"name":"School of Life and Environmental Sciences, Charles Perkins Centre (D17) University of Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly T.","family":"Edwards","sequence":"additional","affiliation":[{"name":"School of Life and Environmental Sciences, Charles Perkins Centre (D17) University of Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen J.","family":"Gregory","sequence":"additional","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences and Department of Pharmacology Monash University Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Leach","sequence":"additional","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences and Department of Pharmacology Monash University Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7232-3891","authenticated-orcid":false,"given":"Arthur 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