ABHD2 Inhibitor Identified by Activity-Based Protein Profiling Reduces Acrosome Reaction

Baggelaar, Marc P.; Dulk, Hans den; Florea, Bogdan I.; Fazio, Domenico; Perruzza, Davide; Bernabò, Nicola; Raspa, Marcello; Janssen, A. M.; Scavizzi, Ferdinando; Barboni, Barbara; Overkleeft, Hermen S.; Maccarrone, Mauro; Stelt, Mario van der

doi:10.1021/acschembio.9b00824

Cited by 18 publications

(15 citation statements)

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“…In this cellular model, possible alterations of the EC system were also interrogated [16,93]. Our study demonstrated that microgravity modulates the expression of the two main cannabinoid receptors of hBDSCs, eliciting an up-regulation of CB 1 and a down-regulation of CB 2 [80]. Since CB 2 is known to induce mitogenic signals in osteoblasts [94,95], and CB 1 and CB 2 stimulate osteoclast formation by promoting bone resorption [96][97][98], these data suggest that prolonged weightlessness might unbalance EC signalling towards loss of bone mass.…”

Section: Endocannabinoidsmentioning

confidence: 74%

“…As for 2-AG, phospholipase (PL)C-catalysed hydrolysis of membrane phospholipids yields diacylglycerol, which is further hydrolysed by DAGL to produce 2-AG [77]; this is then cleaved into AA and glycerol by MAGL [79] and, to a lesser extent, by FAAH [80]. ECs can target several immune cells: AEA is able to suppress the pro-inflammatory activation and cytokine secretion in human lymphocytes [81] and dendritic cells [82], while 2-AG is able to enhance macrophage phagocytosis [83].…”

Section: Endocannabinoids: Chemistry Signalling and Pathophysiologymentioning

confidence: 99%

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Lipid Signalling in Human Immune Response and Bone Remodelling under Microgravity

2020

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Since the first Apollo mission in 1969, microgravity has been linked to many alterations of astronauts’ physiology, among which immunosuppression, altered inflammation and bone loss represent relevant examples. In the past 40 years, extensive investigations have been conducted in order to characterize the molecular mechanisms driving the alterations caused by prolonged weightlessness on human health. However, almost all studies eluded the role played by bioactive lipids, a vastly heterogeneous class of endogenous molecules, which, under normal conditions, control immune and bone homeostasis. This is somewhat surprising, because it is widely accepted that pathological derangement of the production or signalling of these endogenous compounds leads to the onset and/or progression of numerous diseases. In particular, eicosanoids and endocannabinoids are known to play a role in immune responses and bone remodelling. Both classes represent the only lipids as yet investigated in Space, and are increasingly recognised as promising therapeutic candidates to combat different human disorders. This review summarizes evidence gathered in the past two decades on the changes in these two pivotal lipid signalling systems, through both simulated and authentic weightlessness (i.e., on board the International Space Station and in parabolic flights).

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Section: Endocannabinoidsmentioning

confidence: 74%

Section: Endocannabinoids: Chemistry Signalling and Pathophysiologymentioning

confidence: 99%

Lipid Signalling in Human Immune Response and Bone Remodelling under Microgravity

2020

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“…ABHD2 is the core protein that mediates the nongenomic effects of progesterone in spermatozoa. 18 However, it is not known how ABHD2 activates intracellular signalling molecules. Expression of ABHD2 protein in normal spermatozoa was increased after the addition of progesterone.…”

Section: Discussionmentioning

confidence: 99%

“…28 Its regulation is mainly through activation of adenylate cyclase to increase the intracellular content of cAMP, activating cAMP-dependent PKA, and leading to phosphorylation of serine, threonine, and tyrosine in spermatozoa, which in turn regulates sperm capacitation, hyperactivity, and acrosome reaction. 18 At present, the specific mechanism of the progesterone membrane receptor in spermatozoa and the effects of progesterone on spermatozoa are not clear. It has been confirmed that ABHD2 is a membrane receptor of progesterone, and the core functional protein of the nongenomic effects of progesterone in spermatozoa.…”

Section: Discussionmentioning

confidence: 99%

“…15 Recently, it was reported that progesterone could hydrolyse endogenous cannabinoid, which inhibits the CatSper channel, by binding and activating the highly expressed type II domain dehydrogenase ABHD2 (α/β hydrolase domain-containing protein 2) receptor on human spermatozoa. 16–18 The intracellular signalling mechanism underlying the regulation of sperm function by progesterone remains to be elucidated. 19…”

Section: Introductionmentioning

confidence: 99%

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Progesterone activates the cyclic AMP-protein kinase A signalling pathway by upregulating ABHD2 in fertile men

et al. 2021

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Objective This was a prospective study to investigate whether progesterone affects sperm activity by regulating the cyclic AMP-protein kinase A (cAMP-PKA) signalling pathway via α/β hydrolase domain-containing protein 2 (ABHD2). Methods Spermatozoa were collected from healthy and infertile men (with oligoasthenospermia or abnormal acrosome; n = 30/group). The expression of and mutations in ABHD2 were detected by quantitative PCR, western blot, and gene sequencing. The expression of ABHD2 in the presence of progesterone was detected in all groups, and cAMP and PKA levels were detected by ELISA in fertile men after treatment with ABHD2 antibody and PKA inhibitor H-89, respectively. Results Expression of ABHD2 mRNA and protein were reduced in spermatozoa from infertile compared with fertile men. Four gene mutation sites were detected in spermatozoa from the infertile groups. Progesterone increased mRNA and protein levels of ABHD2 in healthy spermatozoa but not in spermatozoa from infertile men. The levels of cAMP and PKA were increased by progesterone in healthy spermatozoa, and the progesterone-increased cAMP and PKA were decreased by ABHD2 antibody and H-89, respectively. Conclusion Progesterone regulates the ABHD2-mediated cAMP-PKA signalling pathway in healthy spermatozoa, which provides a new target for clinical diagnosis and treatment of infertility.

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Olaparib‐Based Photoaffinity Probes for PARP‐1 Detection in Living Cells

et al. 2020

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The poly‐ADP‐ribose polymerase (PARP) is a protein from the family of ADP‐ribosyltransferases that catalyzes polyadenosine diphosphate ribose (ADPR) formation in order to attract the DNA repair machinery to sites of DNA damage. The inhibition of PARP activity by olaparib can cause cell death, which is of clinical relevance in some tumor types. This demonstrates that quantification of PARP activity in the context of living cells is of great importance. In this work, we present the design, synthesis and biological evaluation of photo‐activatable affinity probes inspired by the olaparib molecule that are equipped with a diazirine for covalent attachment upon activation by UV light and a ligation handle for the addition of a reporter group of choice. SDS‐PAGE, western blotting and label‐free LC‐MS/MS quantification analysis show that the probes target the PARP‐1 protein and are selectively outcompeted by olaparib; this suggests that they bind in the same enzymatic pocket. Proteomics data are available via ProteomeXchange with identifier PXD018661.

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ABHD2 Inhibitor Identified by Activity-Based Protein Profiling Reduces Acrosome Reaction

Cited by 18 publications

References 0 publications

Lipid Signalling in Human Immune Response and Bone Remodelling under Microgravity

Lipid Signalling in Human Immune Response and Bone Remodelling under Microgravity

Progesterone activates the cyclic AMP-protein kinase A signalling pathway by upregulating ABHD2 in fertile men

Olaparib‐Based Photoaffinity Probes for PARP‐1 Detection in Living Cells

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