Fatty acid amide hydrolase C385A polymorphism affects susceptibility to various diseases

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Abstract

The endocannabinoid (eCB) system is an important neuromodulatory system with its extensive network of receptors throughout the human body that has complex actions in the nervous system, immune system, and all of the body's other organs. Fatty acid amide hydrolase (FAAH) is an important membrane‐bound homodimeric degrading enzyme that controls the biological activity of N‐arachidonoylethanolamide (AEA) in the eCB system and other relevant bioactive lipids. It has been shown that several single nucleotide polymorphisms (SNPs) of FAAH are associated with various phenotypes and diseases including cardiovascular, endocrine, drug abuse, and neuropsychiatric disorders. A common functional and most studied polymorphism of this gene is C385A (rs324420), which results in the replacement of a conserved proline to threonine in the FAAH enzyme structure, leads to a reduction of the activity and expression of FAAH, compromises the inactivation of AEA and causes higher synaptic concentrations of AEA that can be associated with several various phenotypes. The focus of this review is on evidence‐based studies on the associations of the FAAH C385A polymorphism and the various diseases or traits. Although there was variability in the results of these reports, the overall consensus is that the FAAH C385A genotype can affect susceptibility to some multifactorial disorders and can be considered a potential therapeutic target.

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Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System

Shenglong Zou, Ujendra Kumar (2018)

The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.

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Neurobiological Interactions Between Stress and the Endocannabinoid System.

Maria Morena, Sachin Patel, Jaideep S. Bains … (2016)

Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response. In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling have with respect to many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity. More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder. Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response.

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Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase.

B F Cravatt, K Demarest, M Patricelli … (2001)

The medicinal properties of marijuana have been recognized for centuries, but clinical and societal acceptance of this drug of abuse as a potential therapeutic agent remains fiercely debated. An attractive alternative to marijuana-based therapeutics would be to target the molecular pathways that mediate the effects of this drug. To date, these neural signaling pathways have been shown to comprise a cannabinoid receptor (CB(1)) that binds the active constituent of marijuana, tetrahydrocannabinol (THC), and a postulated endogenous CB(1) ligand anandamide. Although anandamide binds and activates the CB(1) receptor in vitro, this compound induces only weak and transient cannabinoid behavioral effects in vivo, possibly a result of its rapid catabolism. Here we show that mice lacking the enzyme fatty acid amide hydrolase (FAAH(-/-)) are severely impaired in their ability to degrade anandamide and when treated with this compound, exhibit an array of intense CB(1)-dependent behavioral responses, including hypomotility, analgesia, catalepsy, and hypothermia. FAAH(-/-)-mice possess 15-fold augmented endogenous brain levels of anandamide and display reduced pain sensation that is reversed by the CB(1) antagonist SR141716A. Collectively, these results indicate that FAAH is a key regulator of anandamide signaling in vivo, setting an endogenous cannabinoid tone that modulates pain perception. FAAH may therefore represent an attractive pharmaceutical target for the treatment of pain and neuropsychiatric disorders.

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Author and article information

Contributors

Leila Hosseinzadeh Anvar: (View ORCID Profile)

Ali Ahmadalipour: (View ORCID Profile)

Journal

Title: BioFactors

Abbreviated Title: BioFactors

Publisher: Wiley

ISSN (Print): 0951-6433

ISSN (Electronic): 1872-8081

Publication date Created: January 2023

Publication date (Electronic): October 27 2022

Publication date (Print): January 2023

Volume: 49

Issue: 1

Pages: 62-78

Affiliations

[1 ] Research Center of Psychiatry and Behavioral Sciences Tabriz University of Medical Sciences Tabriz Iran

Article

DOI: 10.1002/biof.1911

PubMed ID: 36300805

SO-VID: 64c733a6-69e2-47ec-9762-c29da1a0b133

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http://onlinelibrary.wiley.com/termsAndConditions#vor

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