ALL-TRANS-RETINOIC ACID STIMULATES SYNTHESIS OF CYCLIC ADP-RIBOSE IN RENAL LLC-PK1 CELLS

Cyclic adenosine diphospho-ribose (cADPR) triggers Ca2+ release from i ntracellular stores and is therefore proposed to function as a second messenger in cellular signaling; however, an extracellular stimulus, i ,e,, first messenger (hormone or autacoid) that modulates cADPR metabo lism has not been identified. We discovered that all-trans-retinoic ac id (atRA) is a potent stimulus to increase cADPR synthesis by cultured LLC-PK1 cells, The stimulation of cADPR synthesis by atRA is dose dep endent between 0.1 nM and 1 mu M (maximum increase similar to Delta 600%), while atRA does not alter the rate of cADPR hydrolysis by LLC-P K1 cells, The activity of other intrinsic apical membrane enzymes was not significantly altered, The stimulation of cADPR synthesis by atRA occurs after a lag period of 6-8 h, and the stimulation is inhibited b y actinomycin D and by cycloheximide, Our results therefore demonstrat e that atRA in physiological concentrations is a potent extracellular stimulus, first messenger, that enhances cADPR synthesis, and the effe ct of atRA requires de novo protein synthesis, We suggest that some of the diverse biologic actions of atRA such as morphogenetic and cell d ifferentiation may be mediated via cADPR.