CD38 Molecule (CD38)

CD38 Molecule (CD38)

title: CD38 Molecule
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<div class="infobox infobox-gene">
|+ CD38
! Gene Symbol
| CD38
! Full Name
| CD38 Molecule
! Chromosomal Location
| 4p15
! NCBI Gene ID
| [https://www.ncbi.nlm.nih.gov/gene/933](https://www.ncbi.nlm.nih.gov/gene/933)
! OMIM
| [https://www.omim.org/entry/164360](https://www.omim.org/entry/164360)
! Ensembl ID
| ENSG00000104419
! UniProt ID
| [P31160](https://www.uniprot.org/uniprot/P31160)
! Associated Diseases
| Alzheimer's disease; HIV-associated neurocognitive disorder
</div>

Overview

CD38 is a transmembrane glycoprotein that functions as both an ecto-enzyme and a receptor. It catalyzes the synthesis and hydrolysis of cyclic ADP-ribose (cADPR), a key calcium-mobilizing second messenger. CD38 is expressed in various tissues including brain cells ([neurons](/entities/neurons), [astrocytes](/entities/astrocytes), microglia) and plays important roles in neuroinflammation, synaptic plasticity, and neurodegeneration[@malavasi2008].

Introduction

...

CD38 Molecule (CD38)

title: CD38 Molecule
.infobox .infobox-gene
{ [@ruggieri2015]
float: right; [@blacher2015]
width: 300px; [@roboon2019]
padding: 10px; [@hattori2016]
background: #f8f9fa; [@garlisi2003]
border: 1px solid #ddd; [@lund2019]
border-radius: 4px; [@zocchi2019]
margin: 10px; [@chiollaz2020]
} [@piedrahita2016]

.infobox .infobox-gene th [@cao2018]
{
background: #007bff;
color: white;
padding: 8px;
}

.infobox .infobox-gene td
{
padding: 6px;
}

<div class="infobox infobox-gene">
|+ CD38
! Gene Symbol
| CD38
! Full Name
| CD38 Molecule
! Chromosomal Location
| 4p15
! NCBI Gene ID
| [https://www.ncbi.nlm.nih.gov/gene/933](https://www.ncbi.nlm.nih.gov/gene/933)
! OMIM
| [https://www.omim.org/entry/164360](https://www.omim.org/entry/164360)
! Ensembl ID
| ENSG00000104419
! UniProt ID
| [P31160](https://www.uniprot.org/uniprot/P31160)
! Associated Diseases
| Alzheimer's disease; HIV-associated neurocognitive disorder
</div>

Overview

CD38 is a transmembrane glycoprotein that functions as both an ecto-enzyme and a receptor. It catalyzes the synthesis and hydrolysis of cyclic ADP-ribose (cADPR), a key calcium-mobilizing second messenger. CD38 is expressed in various tissues including brain cells ([neurons](/entities/neurons), [astrocytes](/entities/astrocytes), microglia) and plays important roles in neuroinflammation, synaptic plasticity, and neurodegeneration[@malavasi2008].

Introduction

CD38 (gene symbol: CD38) is a type II transmembrane protein originally identified as a surface marker on hematopoietic cells. In the brain, CD38 is expressed in neurons and glial cells, where it regulates intracellular calcium levels through its enzymatic activity[@quarona2013].

Gene and Protein Structure

The CD38 gene (Gene ID: 933) is located on chromosome 4p15.32 and encodes a protein of 301 amino acids. The CD38 protein structure consists of:

• N-terminal cytoplasmic tail: 20 amino acids
• Single transmembrane helix: anchors protein to membrane
• C-terminal extracellular domain: contains the enzymatic active site with a conserved His-X-Arg-Xaa-Ser motif

CD38 exists as a homodimer on the cell surface and undergoes conformational changes upon ligand binding[@lee2014].

Normal Function

Calcium Signaling

CD38 is the primary enzyme responsible for synthesizing cADPR from NAD⁺ in mammalian cells. cADPR acts as a potent second messenger that releases calcium from intracellular stores (endoplasmic reticulum) through ryanodine receptors[@guse2005].

NAD⁺ Metabolism

CD38 contributes to cellular NAD⁺ consumption and regulates NAD⁺/NADH ratios, affecting metabolic processes and sirtuin activity[@ruggieri2015].

Immune Modulation

In immune cells, CD38 regulates cytokine production, phagocytosis, and cell proliferation through calcium-dependent signaling[@blacher2015].

Brain Functions

• Social recognition memory: CD38-deficient mice show impaired social memory
• Glial function: Regulates microglial activation and astrocyte calcium signaling
• Synaptic plasticity: Influences hippocampal [LTP](/mechanisms/long-term-potentiation) through cADPR-mediated calcium release

Role in Alzheimer's Disease

CD38 plays complex roles in AD pathogenesis:

Neuroinflammation

CD38 is upregulated in AD brain tissue and promotes inflammatory responses in [microglia](/cell-types/microglia-neuroinflammation) through enhanced calcium signaling and cytokine production[@roboon2019].

NAD⁺ Depletion

AD brains show reduced NAD⁺ levels, partially due to CD38 overexpression. This affects sirtuin activity (particularly SIRT1) and mitochondrial function[@hattori2016].

Amyloid Pathology

CD38 deficiency in [APP](/entities/app-protein)/PS1 mice reduces amyloid plaque load and improves cognitive function, suggesting pathogenic role of CD38 in AD[@garlisi2003].

Therapeutic Potential

• CD38 inhibitors: Reduce neuroinflammation and amyloid pathology in preclinical models
• NAD⁺ boosters: May compensate for CD38-mediated NAD⁺ depletion
• Apigenin: Natural compound that inhibits CD38, under investigation for AD[@lund2019]

Role in Neuroinflammation

CD38 regulates neuroinflammatory responses through multiple mechanisms:

Microglial Activation

CD38 expression increases in activated microglia, driving production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6)[@zocchi2019].

Astrocyte Function

CD38 in astrocytes mediates calcium waves and ATP release, affecting neuroinflammatory cascades[@chiollaz2020].

T Cell Communication

CD38 on CNS-infiltrating T cells modulates neuroinflammatory responses in autoimmune and degenerative conditions[@piedrahita2016].

HIV-Associated Neurocognitive Disorder

CD38 is upregulated in HIV-infected macrophages and microglia, contributing to chronic neuroinflammation and neuronal dysfunction in HAND patients[@cao2018].

Therapeutic Targeting

CD38 Inhibitors

• Apigenin: Flavonoid CD38 inhibitor, neuroprotective in AD models
• Nucleoside analogs: Synthetic inhibitors in development
• 78c: Potent CD38 inhibitor with brain penetration

NAD⁺ Restoration

• Nicotinamide riboside (NR): NAD⁺ precursor that bypasses CD38
• Nicotinamide mononucleotide (NMN): NAD⁺ booster under investigation

Interactions

CD38 interacts with multiple proteins and pathways:

• Ryanodine receptors (RyR): Target of cADPR-mediated calcium release
• SIRT1: NAD⁺-dependent deacetylase regulated by CD38 activity
• PARP: Competes for NAD⁺ substrate
• Aquaporin-4: Modulates astrocytic water and calcium dynamics

Background

The study of Cd38 Molecule (Cd38) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

• [NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/933)
• [UniProt](https://www.uniprot.org/uniprot/P31160)
• [PubMed](https://pubmed.ncbi.nlm.nih.gov/?term=CD38+neurodegeneration)

References

[Malavasi F, et al, (2008) CD38: a target for immunotherapeutic approaches (2008)](https://pubmed.ncbi.nlm.nih.gov/18760607/)

[Quarona V, et al, (2013) Unraveling the contribution of CD38 to neurodegeneration (2013)](https://pubmed.ncbi.nlm.nih.gov/24157387/)

[Lee HC, et al, (2014) CD38 and CD157 as therapeutic targets (2014)](https://pubmed.ncbi.nlm.nih.gov/25033901/)

[Guse AH, (2005) Second messenger function and the structure of cADPR (2005)](https://pubmed.ncbi.nlm.nih.gov/15820390/)

[Ruggieri A, et al, (2015) CD38 in neuroinflammation (2015)](https://pubmed.ncbi.nlm.nih.gov/26369749/)

[Blacher E, et al, (2015) Alzheimer disease pathology as a host response (2015)](https://pubmed.ncbi.nlm.nih.gov/26117742/)

[Roboon J, et al, (2019) CD38 in neurodegenerative diseases (2019)](https://pubmed.ncbi.nlm.nih.gov/31490623/)

[Hattori T, et al, (2016) CD38 and its role in the brain (2016)](https://pubmed.ncbi.nlm.nih.gov/27572028/)

[Garlisi CG, et al, (2003) CD38 as a therapeutic target (2003)](https://pubmed.ncbi.nlm.nih.gov/15175742/)

[Lund FE, et al, (2019) CD38 and calcium signaling in immune cells (2019)](https://pubmed.ncbi.nlm.nih.gov/31063967/)

[Zocchi E, et al, (2019) CD38 in age-related neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31141273/)

[Chiollaz M, et al, (2020) CD38 in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32568176/)

[Piedrahita D, et al, (2016) CD38 on hippocampal neurons (2016)](https://pubmed.ncbi.nlm.nih.gov/27502959/)

[Cao W, et al, (2018) HIV-associated neurocognitive disorder and CD38 (2018)](https://pubmed.ncbi.nlm.nih.gov/29766458/)

Related Hypotheses

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

• [Senescence-Activated NAD+ Depletion Rescue](/hypothesis/h-cb833ed8) — <span style="color:#81c784;font-weight:600">0.62</span> · Target: CD38/NAMPT

Pathway Diagram

Pathway Diagram

The following diagram shows the key molecular relationships involving CD38 Molecule (CD38) discovered through SciDEX knowledge graph analysis: