The Ca2+-sensing receptor: a target for polyamines

The Ca²⁺-sensing receptor(CaR) is activated at physiological levels of externalCa²⁺(Ca_o) but is expressed in anumber of tissues that do not have well-established roles in thecontrol of Ca_o, including several regions of the brain and the intestine. Polyamines are endogenous polyvalent cations that can act as agonists for the CaR, as shown byour current studies of human embryonic kidney (HEK-293) cells transfected with the human CaR. Cellular parameters altered by polyamines included cytosolic freeCa²⁺(Ca_i), inositol phosphateproduction, and the activity of a nonselective cation channel. Sperminestimulated Ca_i transients inCaR-transfected HEK cells, with a concentration producing ahalf-maximal response (EC₅₀) of ~500µM in the presence of 0.5 mMCa²⁺, whereas sustained increasesin Ca_i had anEC₅₀ of ~200 µM. The order ofpotency was spermine > spermidine >> putrescine. Elevation ofCa_o shifted theEC₅₀ for spermine sharply to theleft, with substantial stimulation below 100 µM. Addition ofsubthreshold concentrations of spermine increased the sensitivity ofCaR-expressing HEK cells to Ca_o.Parathyroid hormone secretion from bovine parathyroid cells wasinhibited by 50% in the presence of 200 µM spermine, a responsesimilar to that elicited by 2.0 mMCa_o. These data suggest thatpolyamines could be effective agonists for the CaR, and severaltissues, including the brain, may use the CaR as a target for theactions of spermine and other endogenous polycationic agonists.