The Ca²⁺-sensing receptor (CaR) is an essential component of the calcium homeostatic system, regulating parathyroid hormone secretion, urinary calcium excretion and bone remodelling (see Brown & McLeod, 2001, for review). Initially identified from bovine parathyroid glands, CaR has been found in organs where the link with mineral ion metabolism has not been elucidated (i.e. brain, pancreas, eye, skin and many other epithelial cells). Functional studies have shown that Ca²⁺ is not the only cation capable of activating the CaR. Other di- and trivalent cations, such as Mg²⁺ and metal ions of the lanthanide series (e.g. Gd³⁺) can all activate the CaR (Brown et al. 1993). In addition, polyvalent cations of various classes including endogenous compounds and pharmaco-therapeutic agents activate the CaR and may thus contribute to several pathological conditions. For instance, cationic N-terminal peptides of β-amyloid activate the CaR in vitro and may contribute to sustained elevations of intracellular Ca²⁺ and associated neuronal degeneration in Alzheimer’s disease (Brown & MacLeod, 2001). Polycations such as the aminoglycoside antibiotic (AGA) neomycin mimic the agonist effect of high Ca²⁺_o on the CaR (Brown et al. 1993). AGAs are frequently used in the treatment of gram-negative infections but are toxic to the kidney. We have recently shown that other aminoglycosides such as gentamicin and tobramycin can also activate the CaR with potencies that correlate with the net cationic charge and number of amino groups. This presentation will discuss the role of the receptor as polycation sensor, the signalling pathways evoked by different agonists and physiological effectors downstream of receptor activation.

This work is funded by The Wellcome Trust.