Abstract
Endocannabinoid (eCB) signaling plays an important role in the central nervous system (CNS). α/β-Hydrolase domain-containing 6 (ABHD6) is a transmembrane serine hydrolase that hydrolyzes monoacylglycerol (MAG) lipids such as endocannabinoid 2-arachidonoyl glycerol (2-AG). ABHD6 participates in neurotransmission, inflammation, brain energy metabolism, tumorigenesis and other biological processes and is a potential therapeutic target for various neurological diseases, such as traumatic brain injury (TBI), multiple sclerosis (MS), epilepsy, mental illness, and pain. This review summarizes the molecular mechanisms of action and biological functions of ABHD6, particularly its mechanism of action in the pathogenesis of neurological diseases, and provides a theoretical basis for new pharmacological interventions via targeting of ABHD6.
Highlights
The endocannabinoid system (ECS) is a lipid signal transduction system that includes endogenous cannabinoids, cannabinoid receptors and enzymes responsible for the synthesis and hydrolyzation of eCBs, with an important role in the regulation of central nervous system (CNS) function (Jung et al, 2021; Lu and Mackie, 2021). α/β-Hydrolase domain-containing 6 (ABHD6) is an integral membrane protein with recently discovered serine hydrolase activity that is, mainly expressed in immune cell-enriched tissues and the CNS(Poursharifi et al, 2017)
A vital component of the ECS, ABHD6 is an enzyme that regulates hydrolysis of 2-arachidonoyl glycerol (2-AG), which is an endogenous signaling lipid that activates CB1R and CB2R and is an important lipid precursor of the eicosanoic acid signaling pathway (Sugiura et al, 1995). 2-AG is generally believed to be metabolized to arachidonic acid (AA) and glycerol by monoacylglycerol lipase (MAGL); recent evidence suggests that other lipases, such as ABHD6 and ABHD12, are involved in 2-AG degradation in many tissues
By employing ABHD6 inhibitors, we have been able to explore the potential effect of ABHD6 in the treatment of CNS diseases
Summary
The endocannabinoid system (ECS) is a lipid signal transduction system that includes endogenous cannabinoids (eCBs), cannabinoid receptors and enzymes responsible for the synthesis and hydrolyzation of eCBs, with an important role in the regulation of central nervous system (CNS) function (Jung et al, 2021; Lu and Mackie, 2021). α/β-Hydrolase domain-containing 6 (ABHD6) is an integral membrane protein with recently discovered serine hydrolase activity that is, mainly expressed in immune cell-enriched tissues and the CNS(Poursharifi et al, 2017). ECS regulation by ABHD6 can affect the synaptic plasticity of neurons and play a role in CNSinjuring diseases such as epilepsy and brain injury (Deng and Li, 2020b). Evidence shows that mutation of the Ser148 site, which is crucial for the serine hydrolytic activity of ABHD6, does not affect the ability of ABHD6 to regulate postsynaptic membrane expression of AMPAR in either neurons or transfected HEK293T cells, indicating that the ABHD6-AMPAR association is endocannabinoid independent (Wei et al, 2016). Pharmacological blockade of ABHD6 raises the level of 2-AG, especially in microglia and macrophages (Wen et al, 2018); 2AG inhibits infiltration of immune cells into the CNS, resulting in long-term beneficial effects in the chronic phase of autoimmune encephalomyelitis (Mecha et al, 2018). WWL70 has been used to explore the role of ABHD6 inhibition in TBI, genetic tools and more selective ABHD6 inhibitors need to be applied for verification (Tchantchou and Zhang, 2013)
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