ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1, ADPRC1, also known as CD38, is a member of the ADP-ribosyl cyclase family. CD38 can act as an enzyme with NAD-depleting and intracellular signaling activity or as a receptor with adhesive functions.^1,2

CD38, composed of 300 amino acids, is a single chain glycoprotein with a single transmembrane segment that can behave topologically as either a type II or type III membrane protein depending on its orientation within the membrane. CD38 functions as an enzyme that utilizes nicotinamide adenine dinucleotide (NAD⁺) as a substrate and catalyzes the synthesis of nicotinamide (NAM) and ADPR. NAD⁺ is an essential cofactor that regulates energy metabolism and can be converted to cADPR, releasing NAM. CD38 can also hydrolyze cADPR to ADP-ribose. These enzymatic functions are significant as both ADPR and cADPR serve as second messengers that regulate various cellular processes by inducing Ca²⁺ mobilization.^1,2

In addition to its enzymatic activity, CD38 can function as a receptor for CD31, allowing it to act as an adhesion molecule that mediates selectin-like binding of hematopoietic cells to endothelial cells and facilitates their migration to tissues.^1,2

CD38 is found in various tissues, with high levels of expression in hematopoietic tissues such as the bone marrow and lymph nodes. In immune cells, it has been detected in B cells, macrophages, dendritic cells, innate lymphoid cells, natural killer cells, T cells, neutrophils, and monocytes. CD38 has been shown to play a role in regulating the release of cytokines, cell adhesion, and cellular migration towards areas of inflammation.^1,2,3

CD38 is also found in non-hematopoietic tissues, including prostatic epithelial cells, pancreatic islet astrocytes, smooth muscle cells, retinal tubes, kidney, gut, and brain.^1,2

In the context of the brain, CD38 is expressed in various cell types, including neurons and glial cells. Its role in the central nervous system is multifaceted, and research suggests that it may be involved in processes such as neurotransmission, synaptic plasticity, and neuroinflammation.⁴

As mentioned above, CD38 is a major NAD+-consuming enzyme. NAD has emerged as a key player in energy metabolism, serving as a coenzyme in the production of adenosine triphosphate (ATP) through processes like glycolysis and oxidative phosphorylation. Declines in NAD levels have been observed with aging, and this reduction may impact cellular energy production and contribute to age-related decline in various tissues.^4,5 In accordance to that, mice lacking CD38 show increased NAD+ concentrations in the brain, liver, and muscles. Furthermore, due to their resulting enhanced energy expenditure and higher metabolic rates, these animals are protected against obesity, despite a high-fat diet. ^4,5

In the brain, CD38 expression and activity increases during aging or neuroinflammation conditions, which contributes significantly to age-related NAD+ depletion and mitochondrial dysfunction. In fact, Alzheimer disease pathology is significantly attenuated in mice lacking CD38. ^5,6

Based on the key role of CD38 in the immune system and the regulation of the immune response, as well as its central role as a regulator of metabolism, through maintenance of NAD+ homeostasis, it is unsurprising that it has emerged as a pharmacological target in various disease contexts, particularly in the fields of cancer, neurodegenerative diseases, and autoimmune disorders.