Many hormones or neurotransmitters act at cell surface receptors to increase the intracellular free calcium concentration, triggering a wide range of cellular responses. As the source of this Ca2+ is often internal stores, additional messengers are required to convey the hormonal message from the plasma membrane. Cyclic ADP-ribose (cADPR) has been proposed as the endogenous activator of Ca(2+)-induced Ca2+ release by the ryanodine receptor in sea urchin eggs and in several mammalian cell types. A second messenger role for cADPR requires that its intracellular levels be under the control of extracellular stimuli. Here we demonstrate a novel action of 3',5'-cyclic guanosine monophosphate (cGMP) in stimulating the synthesis of cADPR from beta-NAD+ by activating its synthetic enzyme ADP-ribosyl cyclase in sea urchin eggs and egg homogenates. We suggest that cADPR may transduce signals generated by cell surface receptors or gaseous transmitters linked to cGMP production.