DAGLA — Diacylglycerol Lipase Alpha

DAGLA — Diacylglycerol Lipase Alpha

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">DAGLA — Diacylglycerol Lipase Alpha</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>DAGLA</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>DAGLA — Diacylglycerol Lipase Alpha</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=DAGLA" target="_blank">Search NCBI</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Diacylglycerol Lipase Alpha (DAGLA) is a membrane-bound enzyme that catalyzes the hydrolysis of diacylglycerol (DAG) to produce 2-arachidonoylglycerol (2-AG), one of the most abundant endocannabinoids in the brain[@zhang2018]. As the primary biosynthetic enzyme for 2-AG, DAGLA plays crucial roles in endocannabinoid signaling, which modulates synaptic transmission, neuroprotection, neuroinflammation, and motor control throughout the central nervous system[@katona2015].

DAGLA is a 1042-amino acid enzyme with a serine hydrolase domain that localizes to presynaptic terminals and dendritic spines[@zhang2018]. The enzyme is essential for retrograde signaling at synapses, where 2-AG acts as a retrograde messenger to modulate postsynaptic neuron activity and presynaptic neurotransmitter release[@katona2015].

Molecular Biology and Structure

Gene and Protein

DAGLA — Diacylglycerol Lipase Alpha

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">DAGLA — Diacylglycerol Lipase Alpha</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>DAGLA</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>DAGLA — Diacylglycerol Lipase Alpha</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=DAGLA" target="_blank">Search NCBI</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Diacylglycerol Lipase Alpha (DAGLA) is a membrane-bound enzyme that catalyzes the hydrolysis of diacylglycerol (DAG) to produce 2-arachidonoylglycerol (2-AG), one of the most abundant endocannabinoids in the brain[@zhang2018]. As the primary biosynthetic enzyme for 2-AG, DAGLA plays crucial roles in endocannabinoid signaling, which modulates synaptic transmission, neuroprotection, neuroinflammation, and motor control throughout the central nervous system[@katona2015].

DAGLA is a 1042-amino acid enzyme with a serine hydrolase domain that localizes to presynaptic terminals and dendritic spines[@zhang2018]. The enzyme is essential for retrograde signaling at synapses, where 2-AG acts as a retrograde messenger to modulate postsynaptic neuron activity and presynaptic neurotransmitter release[@katona2015].

Molecular Biology and Structure

Gene and Protein

The DAGLA gene is located on chromosome 11 (11p15.4) and encodes a 1042-amino acid transmembrane enzyme[@zhang2018]. The protein contains:

• N-terminal transmembrane region: Anchors the enzyme to the endoplasmic reticulum membrane
• Serine hydrolase domain: Contains the catalytic triad (Ser-Asp-His) essential for enzymatic activity
• Lipase motif (GXSXG): Critical for diacylglycerol hydrolysis

Catalytic Mechanism

DAGLA hydrolyzes DAG to produce 2-AG through the following reaction:

Diacylglycerol (DAG) + H₂O → 2-Arachidonoylglycerol (2-AG) + Fatty acid

The enzyme shows highest activity toward DAG species containing arachidonic acid in the sn-2 position, making 2-AG the primary product[@baggelaar2017].

Brain Expression and Localization

DAGLA exhibits region-specific expression throughout the brain[@katona2015]:

High Expression Regions

• Cerebellum: Highest expression, particularly in Purkinje cells
• Basal Ganglia: Striatum, substantia nigra pars compacta, globus pallidus
• Hippocampus: CA1-CA3 pyramidal neurons, dentate gyrus granule cells
• Cortex: Layer 2/3 pyramidal neurons
• Olfactory bulb: Mitral and tufted cells
• Amygdala: Principal neurons
• Hypothalamus: Paraventricular nucleus, supraoptic nucleus

Cellular Localization

At the cellular level, DAGLA localizes to:

• Presynaptic terminals: Axon terminals of excitatory (glutamatergic) neurons
• Postsynaptic dendritic spines: Especially on pyramidal neurons
• Somatic endoplasmic reticulum: In neuronal cell bodies

Function in Endocannabinoid Signaling

Retrograde Synaptic Signaling

DAGLA-mediated 2-AG production is the cornerstone of endocannabinoid retrograde signaling[@katona2015]:

Types of Synaptic Plasticity

DAGLA-dependent 2-AG signaling regulates several forms of synaptic plasticity[@katona2015]:

• Depolarization-induced suppression of excitation (DSE): Brief suppression of excitatory neurotransmission
• Depolarization-induced suppression of inhibition (DSI): Brief suppression of inhibitory neurotransmission
• Long-term depression (LTD): Persistent weakening of synaptic strength
• Endocannabinoid-LTD (eCB-LTD): A form of LTD mediated by 2-AG signaling

Neuroprotection

2-AG produced by DAGLA exhibits neuroprotective properties[@hershkovitz2016]:

• Anti-inflammatory effects: Reduces microglial activation and pro-inflammatory cytokine release
• Antioxidant activity: Protects neurons from oxidative stress
• Anti-excitotoxic effects: Protects against glutamate-induced excitotoxicity
• Autophagy regulation: Promotes clearance of damaged proteins and organelles

Disease Associations

Parkinson's Disease

DAGLA and the endocannabinoid system are intimately involved in Parkinson's disease pathophysiology[@presland2015]:

• Dopaminergic signaling: The basal ganglia endocannabinoid system modulates dopaminergic neuron activity
• 2-AG levels: Altered 2-AG concentrations reported in PD brains and animal models
• Motor control: CB1 receptor activation affects movement through basal ganglia circuits
• Therapeutic potential: DAGLA modulators may address motor symptoms and levodopa-induced dyskinesias

Alzheimer's Disease

The endocannabinoid system, including DAGLA, is implicated in Alzheimer's disease[@di marzo2011]:

• Amyloid-beta effects: Aβ exposure alters 2-AG signaling in hippocampal neurons
• Tau pathology: Endocannabinoid modulation affects tau phosphorylation
• Neuroinflammation: 2-AG produced by DAGLA modulates microglial activation
• Memory function: DAGLA-dependent eCB-LTD is essential for memory consolidation[@wisniewska2018]

Schizophrenia

Endocannabinoid system dysregulation is implicated in schizophrenia[@hillard2015]:

• DAGLA genetic variants: Association studies link DAGLA polymorphisms with schizophrenia risk
• CB1 receptor density: Altered CB1 receptor expression in schizophrenia brains
• Cognitive function: Endocannabinoid signaling modulates working memory and attention

Addiction

DAGLA plays a modulatory role in reward and addiction pathways[@katona2015]:

• Dopamine release: 2-AG modulates dopamine release in the nucleus accumbens
• Reward learning: Endocannabinoid signaling is involved in reward-related synaptic plasticity
• Relapse: DAGLA inhibition may reduce craving and relapse potential

Neuroinflammation

DAGLA-produced 2-AG has immunomodulatory effects[@guidolin2016]:

• Microglial modulation: 2-AG reduces pro-inflammatory microglial activation
• Cytokine regulation: Modulates TNF-α, IL-1β, and IL-6 production
• Peripheral immune communication: Regulates immune cell trafficking across the blood-brain barrier

Therapeutic Implications

DAGL Inhibitors

Several DAGL inhibitors are under investigation[@farguhar2020]:

• DIDT (Diisopropylfluorophosphate analog): Historical inhibitor with limited selectivity
• DOA: More selective DAGL inhibitor
• KT109: Potent, selective DAGL inhibitor with in vivo activity
• KT672: DAGL inhibitor with anti-inflammatory properties

Clinical Applications

DAGLA modulation may be beneficial for:

• Neurodegenerative diseases: Neuroprotection through enhanced 2-AG signaling
• Pain disorders: Analgesic effects via CB1 receptor activation
• Metabolic disorders: Metabolic regulation through central 2-AG signaling
• Inflammatory conditions: Anti-inflammatory effects

Challenges

• Systemic effects: Global DAGL inhibition affects peripheral endocannabinoid metabolism
• Bidirectional modulation: Both excessive and insufficient 2-AG signaling can be problematic
• Tolerance: Chronic CB1 receptor activation leads to tolerance

Genetic Variation

DAGLA polymorphisms have been associated with:

• Early-onset neurodegenerative disorders[@garcia-gonzalez2019]
• Schizophrenia susceptibility
• Response to cannabinoid-based therapies
• Pain sensitivity

See Also

• [Endocannabinoid System](/entities/endocannabinoid-system)
• [2-Arachidonoylglycerol](/entities/2-ag)
• [CB1 Receptor](/entities/cb1-receptor)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Basal Ganglia](/brain-regions/basal-ganglia)
• [Hippocampus](/brain-regions/hippocampus)
• [Cerebellum](/brain-regions/cerebellum)

References