Ryanodine-sensitive Ca
2+ receptors (RyR) are homotetrameric peptides
9 modulating calcium release from intracellular stores. Together with inositol 1,4,5-trisphosphate (IP
3) receptors,
10 they belong to a family displaying calcium-induced calcium release (CICR),
11 the process accounting for cytosolic free Ca
2+ spatiotemporal dynamics. Three RyR isoforms are known,
10 11 12 all found in the nervous system.
13 cADPR is involved in calcium-dependent neural processes, including synaptic transmission, plasticity, and neuronal excitability.
6 8 14 15 16 cADPR-dependent signaling has been identified within the nucleus in several cell types.
17 The cADPR-synthesizing enzymes known to date form a growing family of conserved proteins.
18 The first identified enzyme of this family was isolated from the synaptic terminal cytosol of the mollusc
Aplysia californica.
19 In mammalian systems, the ectoenzymes CD38 and CD157 (or BST-1), membrane-associated
20 and -anchored,
21 proteins, respectively appear to be the major enzymes with ADP-ribosyl cyclase (ADPR-cyclase) activity.
18 The two proteins share approximately 30% sequence identity with the
Aplysia cyclase. CD38 is expressed in the nervous system,
20 principally in the soma of neural cells, and so it is unlikely to play a significant role in relation to ryanodine-sensitive internal stores. Recently, the existence of a novel endocellular mammalian ADPR-cyclase, involved in brain development and functioning,
22 was demonstrated in neural cells from
Cd38 −/− mice.
22 23 Basile et al.
24 demonstrated that, in addition to producing cADPR, ADPR, and NAADP, ADPR-cyclases can generate other adenine dinucleotides that are known to exist naturally and to have biological activity. Therefore, there is incipient evidence of the existence of other types of ADPR-cyclases in mammalian cells.