CD38 is a multifunctional ectoenzyme that catalyses formation of cyclic ADP ribose (cADPr), a second messenger that opens ryanodine receptor (RyR) Ca2+ channels. Despite its importance in signal transduction processes, little is known about the mechanisms regulating CD38 expression levels. In the current study, ryanodine stimulation of Ca2+ release in Namalwa cells decreased both CD38 protein abundance and cyclase activity. Reductions in cyclase activity were prevented by RyR antagonists, by lysosomal blockers, though not by calpain or proteasomal inhibitors. These findings indicate a novel negative feedback mechanism between RyR channel activity and CD38 abundance acts in cADPr signal transduction.