Cyclic ADP-ribose as a universal calcium signal molecule in the nervous system

Abstract

beta-NAD(+) is as abundant as ATP in neuronal cells. beta-NAD(+) functions not only as a coenzyme but also as a substrate. beta-NAD(+)-utilizing enzymes are involved in signal transduction. We focus on ADP-ribosyl cyclase/CD38 which synthesizes cyclic ADP-ribose (cADPR), a universal Ca(2+) mobilizer from intracellular stores, from beta-NAD(+). cADPR acts through activation/modulation of ryanodine receptor Ca(2+) releasing Ca(2+) channels. cADPR synthesis in neuronal cells is stimulated or modulated via different pathways and various factors. Subtype-specific coupling of various neurotransmitter receptors with ADP-ribosyl cyclase confirms the involvement of the enzyme in signal transduction in neurons and glial cells. Moreover, cADPR/CD38 is critical in oxytocin release from the hypothalamic cell dendrites and nerve terminals in the posterior pituitary. Therefore, it is possible that pharmacological manipulation of intracellular cADPR levels through ADP-ribosyl cyclase activity or synthetic cADPR analogues may provide new therapeutic opportunities for treatment of neurodevelopmental disorders.

CD38 and its role in oxytocin secretion and social behavior

“…The adult males did not need to further investigate the intruder females because they recognized the paired female as familiar. In contrast, CD38 -/-males showed sustained high levels of investigation at every encounter with the same female (Jin et al, 2007). This abnormality in social memory found in CD38 -/-mice is due to the males' amnesia with respect to conspecifics.…”

“…It is also required for normal social behavior in mice (Jin et al, 2007). CD38 possesses ADP-ribosyl cyclase activity (Lee, 2001;Higashida et al, 2001a and2007;Boittin et al, 2003;Guse, 2005) that produces cyclic ADP-ribose (cADPR) from β-NAD + , also known as Vitamin B3, an abundant substrate in the brain (Denu, 2005).…”

“…Thus, it is possible that cellular events such as secretion or cell migration depend on the formation of cADPR. We have recently shown that CD38 is required, as shown by the decreased formation of cADPR and by CICR, for some social behaviors in mice via the regulation of OXT secretion from the hypothalamus and pituitary (Jin et al, 2007;Higashida et al, 2010;Salmina et al, 2010).…”

“…In maternal behavior tests, wild-type dams retrieved five of their biological pups precisely and quickly (average latency, 43 ± 3 s) from a remote area of their home cages to a restricted area (Jin et al, 2007;Higashida et al, 2010), while CD38 -/-dams took a significantly longer time to begin retrieval (average latency, 76 ± 8 s; p < 0.01; Lopatina et al, 2011) and moved around, suggesting that their interest was drawn to things other than their pups. In addition, CD38 -/-dams often dropped the pups during retrieval, suggesting that they did not remember the way to the nest and resulting in the pups becoming scattered to multiple locations.…”

“…OXT regulates several complex social behaviors (Carter, 2003: Insel andFernald, 2004;Donaldson and Young, 2008;Carter et al, 2009;Skuse and Gallagher, 2009;Ebstein et al, 2009;Insel, 2010;Higashida et al, 2007 and. In humans, intranasal OXT may promote trust (Kosfeld et al, 2005), generosity (Zak et al, 2007), increased gaze to the eye region (Guastella et al, 2008a), inferring the emotions of others (Domes et al, 2007;Guastella et al, 2010;Kiss et al, 2011) and face recognition (Rimmele et al, 2009).…”