Abstract
The paradox of blunted parathormone (PTH) secretion in patients with
severe hypomagnesemia has been known for more than 20 years, but
the underlying mechanism is not deciphered. We determined the effect
of low magnesium on in vitro PTH release and on the signals triggered
by activation of the calcium-sensing receptor (CaSR). Analogous to
the in vivo situation, PTH release from dispersed parathyroid cells
was suppressed under low magnesium. In parallel, the two major signaling
pathways responsible for CaSR-triggered block of PTH secretion, the
generation of inositol phosphates, and the inhibition of cAMP were
enhanced. Desensitization or pertussis toxin-mediated inhibition
of CaSR-stimulated signaling suppressed the effect of low magnesium,
further confirming that magnesium acts within the axis CaSR-G-protein.
However, the magnesium binding site responsible for inhibition of
PTH secretion is not identical with the extracellular ion binding
site of the CaSR, because the magnesium deficiency-dependent signal
enhancement was not altered on CaSR receptor mutants with increased
or decreased affinity for calcium and magnesium. By contrast, when
the magnesium affinity of the G alpha subunit was decreased, CaSR
activation was no longer affected by magnesium. Thus, the paradoxical
block of PTH release under magnesium deficiency seems to be mediated
through a novel mechanism involving an increase in the activity of
G alpha subunits of heterotrimeric G-proteins.
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