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RECEPTORS AND SIGNAL TRANSDUCTION

Effect of -secretase inhibitors on muscarinic receptor-mediated calcium signaling in human salivary epithelial cells

Membrane Biology Section, Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Resarch, Bethesda, Maryland

Submitted 12 October 2005 ; accepted in final form 2 February 2006

Altered intracellular Ca²⁺ signaling has been observed in cells derived from Alzheimer’s disease patients, and a possible link between -secretase activity and the content of intracellular Ca²⁺ stores has been suggested. To test this hypothesis we studied the effects of several -secretase inhibitors on muscarinic receptor-mediated intracellular calcium release in the human salivary gland cell line HSG. Although several inhibitors in the peptide aldehyde class partially blocked carbachol-induced Ca²⁺ transients, these effects did not appear to be due to -secretase inhibition, and overall we found no evidence that inhibition of -secretase activity had any significant effect on agonist-induced intracellular calcium release in HSG cells. In complementary experiments with presenilin-null cells we found that the reconstitution of -secretase activity by transfection with wild-type presenilin 1 likewise had no significant effect on thapsigargin-induced Ca²⁺ release. In a test of the specific hypothesis that the level of APP intracellular domain (AICD), the intracellular fragment of the -amyloid precursor protein (APP) resulting from -secretase cleavage, can modulate the Ca²⁺ content of the endoplasmic reticulum, we were unable to demonstrate any effect of APP small interfering RNA on the magnitude of carbachol-induced intracellular calcium release in HSG cells. Together our data cast considerable doubt on the hypothesis that there is a direct link between -secretase activity and the content of intracellular Ca²⁺ stores.

presenilin; carbachol; inositol 1,4,5-trisphosphate; Alzheimer’s disease