Roles and mechanisms of the CD38/cyclic adenosine diphosphate ribose/Ca2+ signaling pathway

Abstract

Mobilization of intracellular Ca²⁺ stores is involved in many diverse cell functions, including: cell proliferation; differentiation; fertilization; muscle contraction; secretion of neurotransmitters, hormones and enzymes; and lymphocyte activation and proliferation. Cyclic adenosine diphosphate ribose (cADPR) is an endogenous Ca²⁺ mobilizing nucleotide present in many cell types and species, from plants to animals. cADPR is formed by ADP-ribosyl cyclases from nicotinamide adenine dinucleotide. The main ADP-ribosyl cyclase in mammals is CD38, a multi-functional enzyme and a type II membrane protein. It has been shown that many extracellular stimuli can induce cADPR production that leads to calcium release or influx, establishing cADPR as a second messenger. cADPR has been linked to a wide variety of cellular processes, but the molecular mechanisms regarding cADPR signaling remain elusive. The aim of this review is to summarize the CD38/cADPR/Ca²⁺ signaling pathway, focusing on the recent advances involving the mechanism and physiological functions of cADPR-mediated Ca²⁺ mobilization.

Keywords: Cyclic adenosine diphosphate ribose, CD38, Ca²⁺, Ryanodine receptors, Nicotinamide adenine dinucleotide

Core tip: This is a comprehensive review regarding the role and mechanism of the CD38/Cyclic adenosine diphosphate ribose (cADPR)/Ca²⁺ signaling pathway in various cellular processes. We introduce the structure and function of cADPR, together with its production and degradation pathways. We also describe CD38, the main enzyme that is responsible for synthesis of cADPR, through its structure and topology. Finally, we summarize the functions of the CD38/cADPR/Ca²⁺ signaling pathway under both physiological and pathological conditions.