NCBI Summary:
This gene encodes one of two cannabinoid receptors. The cannabinoids, principally delta-9-tetrahydrocannabinol and synthetic analogs, are psychoactive ingredients of marijuana. The cannabinoid receptors are members of the guanine-nucleotide-binding protein (G-protein) coupled receptor family, which inhibit adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. The two receptors have been found to be involved in the cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana. Multiple transcript variants encoding two different protein isoforms have been described for this gene. [provided by RefSeq, May 2009]
General function
Receptor
Comment
Cellular localization
Plasma membrane
Comment
candidate123
Ovarian function
Steroid metabolism, Luteolysis
Comment
Endocannabinoid 1 and 2 (CB(1); CB(2)) Receptor Agonists Affect Negatively Cow Luteal Function In Vitro. Weems YS et al. Thirty to 40 percent of pregnancies are lost during the first third of pregnancy, which has been hypothesized to be due to inadequate progesterone secretion by the corpus luteum. Loss of luteal progesterone secretion during the estrous cycle is via uterine secretion of prostaglandin F(2)alpha (PGF(2)alpha). Cow luteal tissue secretion of prostaglandins (PG) E (PGE(1)+PGE(2)) and PGF(2)alpha are derived from precursors in membrane phospholipids. Cow luteal tissue secretion of PGE and PGF(2)alpha increased linearly with time in culture with the PGE: ratio being 1:1. PGE(1) or PGE(2) are luteotropic in cows and ewes and antiluteolytic in vitro and in vivo in ewes. Endocannabinoids are also derived from phospholipids and are associated with infertility, presumably by reducing implantation; however, effects of endocannabinoids on luteal function have not been addressed. The objective of this experiment was to determine the effects of endocannabinoid type 1 and 2 receptor agonists and receptor antagonists or a fatty acid amide hydrolase (FAAH; catabolizes endocannabinoids) inhibitor, PGE(1), or PGF(2)alpha on bovine luteal secretion of progesterone, PGE, and PGF(2)alphain vitro. PGE and PGF(2)alpha was increased (P/=0.05) with time in vehicle-treated luteal slices in vitro. Progesterone was increased (P
Expression regulated by
Comment
Effects of Endocannabinoid 1 and 2 (CB1; CB2) Receptor Agonists on Luteal Weight; Circulating Progesterone; Luteal mRNA for Luteinizing Hormone (LH) Recptors; and Luteal Unoccupied and Occupied Receptors for LH In Vivo In Ewes. Tsutahara NM et al. Thirty to forty percent of ruminant pregnancies are lost during the first third of gestation due to inadequate progesterone secretion. During the estrous cycle, luteinizing hormone (LH) regulates progesterone secretion by small luteal cells (SLC). Loss of luteal progesterone secretion during the estrous cycle is via increased uterine secretion of prostaglandin F(2a) (PGF(2a)) starting on days-12-13 post-estrus in ewes with up to 4-6 pulses per day. Prostaglandin F(2a) is synthesized from arachidonic acid, which is released from phospholipids by phospholipase A2. Endocannabinoids are also derived from phospholipids and are associated with infertility. Endocannabinoid-induced infertility has been postulated to occur primarily via negative effects on implantation. Cannabinoid (CB) type 1(CB1) or type 2 (CB2) receptor agonists and an inhibitor of the enzyme fatty acid amide hydrolase, which catabolizes endocannabinoids, decreased luteal progesterone, prostaglandin E (PGE), and prostaglandin F(2a) (PGF(2a)) secretion by the bovine corpus luteum in vitro by thirty percent. The objectiveof the experiment described herein was to determine whether CB1 or CB2 receptor agonists given in vivo affect circulating progesterone, luteal weights, luteal mRNA for LH receptors, and luteal occupied and unoccupied LH receptors during the estrous cycle of ewes. Treatments were: Vehicle, Methanandamide (CB 1 agonist; METH), or 1-(4-chlorobenzoyl) -5-methoxy-1H-indole-3-acetic acid morpholineamide (CB2 agonist; IMMA). Ewes received randomized treatments on day 10 post-estrus. A single treatment (500?g; N=5/treatment group) in a volume of 1ml was given into the interstitial tissue of the ovarian vascular pedicle adjacent to the luteal-containing ovary. Jugular venous blood was collected at 0 hr and every 6 hr through 48 hr for analysis of progesterone by radioimmunoassay (RIA). Corpora lutea were collected at 48 hr, weighed, bisected, and frozen in liquid nitrogen until analysis of unoccupied and occupied LH receptors and mRNA for LH receptors, and. Profiles of jugular venous progesterone, luteal weights, luteal mRNA for LH receptors, and luteal occupied and unoccupied LH receptors were decreased (P< 0.05) by CB1 or CB2 receptor agonists when compared to Vehicle controls. Progesterone in eighty percent of CB1 or CB 2 receptor agonist-treated ewes was decreased (P< 0.05) below one ng/ml by 48 hr post-treatment. It is concluded that stimulation of either CB1 or CB 2 receptors in vivo affected negatively luteal progesterone secretion by decreasing luteal mRNA for LH receptors and also decreasing occupied and unoccupied receptors for LH on luteal membranes. The corpus luteum may be an important site for endocannabinoids to decrease fertility as well as negatively affect implantation, since progesterone is required for implantation.
Dynamic of expression and localization of cannabinoid-degrading enzymes FAAH and MGLL in relation to CB1 during meiotic maturation of human oocytes. Agirregoitia E et al. (2016) The endogenous cannabinoid system has been characterized in some female reproductive organs but little is known about the expression and localization pattern of cannabinoid-degrading enzymes in relation to the CB1 cannabinoid receptor in human oocytes. In this study, we focus on the investigation of the presence and differential distribution of fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in relation to CB1 during the maturation of human oocytes. We used a total of 290 human oocytes not suitable for in vitro fertilization/intracytoplasmic sperm injection (ICSI): germinal-vesicle (GV) and metaphase-I (MI) stages and metaphase-II (MII) oocytes that had not developed into an embryo after ICSI. Cannabinoid-degrading enzymes and the cannabinoid CB1 receptor were present in human oocytes. Specifically, FAAH was detected in the periphery of the oocyte from the GV to MI stage and co-localized with CB1. Later, by the MII stage, FAAH was spread within the oocyte, whereas MGLL immunostaining was homogeneous across the oocyte at all stages of maturation and only overlapped with CB1 at the GV stage. This coordinated redistribution of cannabinoid system proteins suggests a role for this system in the maturation of the female gamete.//////////////////
Dynamics of expression and localization of the cannabinoid system in granulosa cells during oocyte nuclear maturation. Agirregoitia E et al. (2015) To describe the expression of cannabinoid receptors CB1 and CB2 and cannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in human granulosa cells and to investigate their differential distribution with respect to CB1 at various stages during the nuclear maturation of the oocyte. Analysis of granulosa cells from germinal vesicle (GV), metaphase I (MI), and MII oocytes by quantitative reverse transcriptase-polymerase chain reaction, Western blot, and indirect immunofluorescence assays. Academic research laboratory. Patients from the Human Reproduction Unit of Cruces University Hospital undergoing intracytoplasmic sperm injection. We analyzed the granulosa cells of 300 oocytes from 53 patients. The oocyte maturation stages were 75 at GV stage, 51 at MI, and 174 at MII. The mRNA and protein expression of CB1, CB2, FAAH, and MGLL and localization in granulosa cells at each oocyte maturation stage. CB1, FAAH, and MGLL are present in human granulosa cells during oocyte maturation, but the presence of CB2 receptor is not entirely clear in those cells. CB1 and FAAH were detected in the periphery of the granulosa cells from the GV to the MII oocytes, and they colocalized in some portions of the cell membrane. On the other hand, MGLL immunostaining was more homogeneous across the cell and overlapped with CB1 only weakly. The presence of the cannabinoid system in granulosa cells suggests a possible role of this system in the nuclear maturation of the oocyte.//////////////////
Temporal and Spatial Distribution of the Cannabinoid Receptors (CB(1), CB(2)) and Fatty Acid Amide Hydroxylase in the Rat Ovary. Bagavandoss P et al. Although the effects of Delta(9)-tetrahydrocannabinol (THC) on ovarian physiology have been known for many decades, its mechanism of action in the rat ovary remains poorly understood. The effects of THC and endocannabinoids on many cell types appear to be mediated through the G-protein-coupled CB(1) and CB(2) receptors. Evidence also suggests that the concentration of the endocannabinoid anandamide is regulated by cellular fatty acid amide hydrolase (FAAH). Therefore, we examined the rat ovary for the presence of CB(1) and CB(2) receptors and FAAH. The CB(1) receptor was present in the ovarian surface epithelium (OSE), the granulosa cells of antral follicles, and the luteal cells of functional corpus luteum (CL). The granulosa cells of small preantral follicles, however, did not express the CB(1) receptor. Western analysis also demonstrated the presence of a CB(1) receptor. In both preantral and antral follicles, the CB(2) receptor was detected only in the oocytes. In the functional CL, the CB(2) receptor was detected in the luteal cells. FAAH was codistributed with CB(2) receptor in both oocytes and luteal cells. FAAH was also present in the OSE, subepithelial cords of the tunica albuginea (TA) below the OSE, and in cells adjacent to developing preantral follicles. Western analysis also demonstrated the presence of FAAH in oocytes of both preantral and antral follicles. Our observations provide potential explanation for the effects of THC on steroidogenesis in the rat ovary observed by earlier investigators and a role for FAAH in the regulation of ovarian anandamide. Anat Rec 293:1425-1432, 2010. (c) 2010 Wiley-Liss, Inc.
Follicle stages
Antral
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Selected CNR1 polymorphisms and hyperandrogenemia as well as fat mass and fat distribution in women with polycystic ovary syndrome. Jedrzejuk D 2014 et al.
Abstract The endocannabinoid system is postulated to play an important role in the etiology of obesity, insulin resistance, fat distribution and metabolic disorders. Insulin resistance associated with abdominal obesity plays a leading role in the etiology of hyperandrogenism and other clinical features of the polycystic ovary syndrome (PCOS). A total of 174 women 16-38 years old, diagnosed with PCOS according to the Rotterdam criteria are recruited. Control group consisted of 125 healthy women 18-45 years old. Medical history, physical examination, anthropometric parameters and metabolic parameters were carried out. Six CNR1 gene polymorphisms were diagnosed. We observed a significantly three times higher risk of GG genotype in the polymorphism rs12720071 in women with PCOS versus the control group (p?=?0.0344, OR?=?3.01). A similar, significant 8-fold higher risk (p?=?0.0176, OR?=?8.81) was demonstrated for genotype CC polymorphism rs806368 associated with PCOS. We observed a 3.6-fold increased risk of hyperandrogenemia (free androgen index - FAI?>?7) in patients with GG genotype in the rs12720071 polymorphism and AA genotype in the polymorphism rs1049353 (OR?=?2.7). Our study may indicate a role of the endocannabinoid system in the occurrence of a specific hyperandrogenemia phenotype of PCOS.
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