THE CA2-SENSING RECEPTOR - A TARGET FOR POLYAMINES()

The Ca2+-sensing receptor (CaR) is activated at physiological levels o f external Ca2+ (Ca-o) but is expressed in a number of tissues that do not have well-established roles in the control of Ca-o, including sev eral regions of the brain and the intestine. Polyamines are endogenous polyvalent cations that can act as agonists for the CaR, as shown by our current studies of human embryonic kidney (HEK-293) cells transfec ted with the human CaR. Cellular parameters altered by polyamines incl uded cytosolic free Ca2+ (Ca-i), inositol phosphate production, and th e activity of a nonselective cation channel. Spermine stimulated Ca-i transients in CaR-transfected HEK cells, with a concentration producin g a half-maximal response (EC50) of similar to 500 mu M in the presenc e of 0.5 mM Ca2+, whereas sustained increases in Ca-i had an EC50 Of s imilar to 200 mu M. The order of potency was spermine > spermidine muc h greater than putrescine. Elevation of Ca-o shifted the EC50 for Sper mine sharply to the left, with substantial stimulation below 100 mu M. Addition of subthreshold concentrations of spermine increased the sen sitivity of CaR-expressing HEK cells to Ca-o. Parathyroid hormone secr etion from bovine parathyroid cells was inhibited by 50% in the presen ce of 200 mu M spermine, a response similar to that elicited by 2.0 mM Ca-o. These data suggest that polyamines could be effective agonists for the CaR, and several tissues, including the brain, may use the CaR as a target for the actions of spermine and other endogenous polycati onic agonists.