An acquired hypocalciuric hypercalcemia autoantibody induces allosteric transition among active human Ca-sensing receptor conformations.

[familial hypocalciuric hypercalcemia]

The seven -spanning calcium-sensing receptor (CaSR ) activates multiple G proteins including Gq and Gi , and thereby activates a variety of second messengers and inhibits parathyroid hormone (PTH ) secretion . However , the exact signaling mechanisms underlying the functional activity of CaSR are not yet fully understood . The heterozygous inactivation of CaSR or its inhibition by antibody blocking results in either familial hypocalciuric hypercalcemia or acquired hypocalciuric hypercalcemia (AHH ), respectively . Here , we report the identification of a unique CaSR autoantibody in an AHH patient . Paradoxically , we find that this autoantibody potentiates the Ca (2 +)/Gq-dependent accumulation of inositol phosphates by slightly shifting the dose dependence curve of the Ca (2 +) mediated activation of phosphatidylinositol turnover to the left , whereas it inhibits the Ca (2 +)/Gi -dependent phosphorylation of ERK 1 /2 in HEK 293 cells stably expressing human CaSR . Treatment of these same cells with a calcimimetic , NPS -R-568 , augments the CaSR response to Ca (2 +), increasing phosphatidylinositol turnover and ERK 1 /2 phosphorylation , and overcoming the autoantibody effects . Our observations thus indicate that a calcium -stimulated CaSR primed by a specific autoantibody adopts a unique conformation that activates Gq but not Gi . Our findings also suggest that CaSR signaling may act via both Gq and Gi to inhibit PTH secretion . This is the first report of a disease-related autoantibody that functions as an allosteric modulator and maintains G protein-coupled receptors (GPCRs ) in a unique active conformation with its agonist . We thus speculate that physiological modulators may exist that enable an agonist to specifically activate only one signaling pathway via a GPCR that activates multiple signaling pathways .

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familial hypocalciuric hypercalcemia

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