ABHD6 selectively controls metabotropic-dependent increases in 2-AG production

Singh, Simar; Sarroza, Dennis; English, Anthony; Whittington, Dale; Dong, Ao; Stelt, Mario van der; Li, Yulong; Zweifel, Larry S.; Bruchas, Michael R.; Land, Benjamin B.; Stella, Nephi

doi:10.1101/2022.05.18.492553

Cited by 3 publications

(2 citation statements)

References 59 publications

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“…The specific differences in basal inhibitory, but not excitatory, neurotransmission onto NAc MSNs may be explained by greater abundance and/or sensitivity for CB1R endocannabinoid signalling on GABAergic synapses 31,78,79 , and the possibility that the unique subcellular localization of postsynaptic ABHD6 within NAc neurons may regulate degradation of distinct 2-AG signalling pools in a non-redundant manner to presynaptic MAGL 4 . As a proof-of-principle example of how subcellular ABHD6 expression patterns may be coupled to pathway-specific control of unique 2-AG signalling pools, recent results have demonstrated stimuli-dependent control of metabotropic-, but not ionotropic-, derived 2-AG degradation by ABHD6 within Neuro2a cells 80 . The potential for synapse-and/or pathway-specific regulation of 2-AG pools by ABHD6 is an attractive hypothesis to distinguish the impact of NAc neuronal ABHD6 loss-of-function from the impact of NAc CB1R signalling generally.…”

Section: Discussionmentioning

confidence: 99%

ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity

Fulton,

Lau,

Tobin

et al. 2024

Preprint

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α/β-hydrolase domain 6 (ABHD6) is a lipase linked to physiological functions affecting metabolism and body weight. Brain ABHD6 degrades 2-arachidonoylglycerol and thereby modulates cannabinoid receptor signaling. However, it’s functional role within mesoaccumbens circuitry that is critical for motivated behavior and known to be significantly modulated by endocannabinoids remained unknown. Using three viral approaches, we show that control of the nucleus accumbens by neuronal ABHD6 is a key determinant of body weight and reward-relevant behavior. Contrary to expected outcomes associated with increasing endocannabinoid tone, ABHD6 loss of function in the nucleus accumbens, but not the ventral tegmental area, inhibited food reward and completely prevented diet-induced obesity and associated physical inactivity without affecting anxiodepressive behavior. These effects are explained by attenuated inhibitory synaptic transmission onto medium spiny neurons. ABHD6 deletion in nucleus accumbens neurons and dopamine ventral tegmental area neurons produced contrasting effects on food-directed behavior. Together, these results reveal functional specificity of pre- and post-synaptic mesoaccumbens neuronal ABHD6 to differentially control energy metabolism and propose ABHD6 inhibition as a potential anti-obesity tool.

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Section: Discussionmentioning

confidence: 99%

ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity

Fulton,

Lau,

Tobin

et al. 2024

Preprint

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“…The effects of ABHD6 inhibition before CSD induction were cannabinoid receptor independent, whereas reversal of periorbital allodynia by ABHD6 blockade required CB 1 R. The cannabinoid receptor independence of ABHD6 inhibition in the prevention paradigm may be explained by how ABHD6 regulates activity-dependent increases of 2-AG levels, as ABHD6 degrades 2-AG prior to release ( 32 ). The difference of cannabinoid receptor dependency between ABHD6 and MAGL inhibition can also be explained by the different localization of the two enzymes, since MAGL is considered to express presynaptically, however ABHD6 localize in postsynaptic neurons ( Figure 7 ).…”

Section: Discussionmentioning

confidence: 99%

ABHD6 and MAGL control 2-AG levels in the PAG and allodynia in a CSD-induced periorbital model of headache

et al. 2023

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IntroductionThe high prevalence and severe symptoms of migraines in humans emphasizes the need to identify underlying mechanisms that can be targeted for therapeutic benefit. Clinical Endocannabinoid Deficiency (CED) posits that reduced endocannabinoid tone may contribute to migraine development and other neuropathic pain conditions. While strategies that increase levels of the endocannabinoid n-arachidonoylethanolamide have been tested, few studies have investigated targeting the levels of the more abundant endocannabinoid, 2-arachidonoylgycerol, as an effective migraine intervention.MethodsCortical spreading depression was induced in female Sprague Dawley rats via KCl (potassium chloride) administration, followed by measures of endocannabinoid levels, enzyme activity, and neuroinflammatory markers. Efficacy of inhibiting 2-arachidonoylglycerol hydrolysis to mitigate periorbital allodynia was then tested using reversal and prevention paradigms.ResultsWe discovered reduced 2-arachidonoylglycerol levels in the periaqueductal grey associated with increased hydrolysis following headache induction. Pharmacological inhibition of the 2-arachidonoylglycerol hydrolyzing enzymes, α/β-hydrolase domain-containing 6 and monoacylglycerol lipase reversed and prevented induced periorbital allodynia in a cannabinoid receptor-dependent manner.DiscussionOur study unravels a mechanistic link between 2-arachidonoylglycerol hydrolysis activity in the periaqueductal grey in a preclinical, rat model of migraine. Thus, 2-arachidonoylglycerol hydrolysis inhibitors represent a potential new therapeutic avenue for the treatment of headache.

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The endocannabinoid 2-arachidonoylglycerol is released and transported on demand via extracellular microvesicles

Straub,

Barti,

Tandar

et al. 2024

Preprint

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While it is known that endocannabinoids (eCB) modulate multiple neuronal functions, the molecular mechanism governing their release and transport remains elusive. Here, we propose an 'on-demand release' model, wherein the formation of microvesicles, a specific group of extracellular vesicles (EVs) containing the eCB, 2-arachidonoylglycerol (2-AG), is the rate-limiting step. A co-culture model system that combines a reporter cell line expressing the fluorescent eCB sensor, GRABeCB2.0, and neuronal cells revealed that neurons release EVs containing 2-AG, but not anandamide, in a stimulus-dependent process regulated by PKC, DAGL, Arf6, and which was sensitive to inhibitors of eCB facilitated diffusion. A vesicle contained approximately 2000 2-AG molecules. Accordingly, hippocampal eCB-mediated synaptic plasticity was modulated by Arf6 and transport inhibitors. This 'on demand release' model, supported by mathematical analysis, offers a cohesive framework for understanding eCB signaling at the molecular level and suggests that microvesicles carrying signaling lipids regulate neuronal functions in parallel to canonical synaptic vesicles.

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ABHD6 selectively controls metabotropic-dependent increases in 2-AG production

Cited by 3 publications

References 59 publications

ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity

ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity

ABHD6 and MAGL control 2-AG levels in the PAG and allodynia in a CSD-induced periorbital model of headache

The endocannabinoid 2-arachidonoylglycerol is released and transported on demand via extracellular microvesicles

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