Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • Continuing studies of endocannabinoid ligands at GPR reveal

    2022-01-13

    Continuing studies of endocannabinoid ligands at GPR55 reveal that virodhamine (O-arachidonylethanolamine) and AEA can act as a partial agonists at GPR55; at high micromolar concentrations can inhibit β-arrestin recruitment (Sharir et al., 2012). It is likely that there are allosteric as well as orthosteric ligands for GPR55 in addition to differential signaling pathways for GPR55. Although GPR35 and GPR55 are homologs (30%), the profile of ligands does not overlap. In addition, the natural ligands are distinct, 2-acyl LPA (for GPR35) and 2-acyl LPI (for GPR55). The P2Y5 receptor, which is a homologue to GPR35 (29%), has also been shown to be a receptor for 2-acyl LPA (Yanagida et al., 2009). It is worth noting that 2-acyl LPI is structurally related to 2-acyl LPA. The identification of GPR55 as a LPI receptor is consistent with its phylogeny, since two of its closest homologues GPR23 and GPR92, formerly both orphan receptors, have been shown to respond to a related lipid, lysophosphatidic PF-04620110 (Lee et al., 2006, Noguchi et al., 2003). 2-AG is an endogenous ligand for CB receptors, where it acts as a full agonist. It has already been demonstrated that 2-AG can be metabolized to 2-arachidonoyl LPA through the action of a monoacylglycerol kinase (Fig. 2) (Kanoh et al., 1986, Shim et al., 1989). The opposite direction of this reaction (phosphorylation) has been shown in another study (dephosphorylation) (Nakane et al., 2002). Thus, it appears that mutual interconversion is possible between 2-arachidonoyl LPA and 2-AG within a cell, though the direction of the reaction may be site dependent (Fig. 2). The GPR55 natural ligand, 2-arachidonoyl LPI, can be degraded either to 2-AG by PLC or to 2-arachidonoyl LPA by PLD (reviewed by Pineiro and Falasca, 2012). These findings show that GPR35, GPR55 and CB receptors are linked together through their natural ligand conversions (Fig. 2). Despite the close metabolic relationship and structural similarities between 2-arachidonoyl LPA, 2-arachidonoyl LPI and 2-AG, these lipid mediators interact with different receptors. As stated above, 2-AG interacts with the CB1 and CB2 cannabinoid receptors, but not with GPR55 (Kapur et al., 2009), GPR35 (Zhao et al., 2010) or LPA receptors (Nakane et al., 2002). PF-04620110 In contrast, 2-arachidonoyl LPA activates GPR35, P2Y5 and LPA3 receptors (Bandoh et al., 2000, Oka et al., 2010, Yanagida et al., 2009). There is no report that 2-arachidonoyl LPA activates GPR55 or cannabinoid receptors. On the other hand, 2-arachidonoyl LPI does not activate GPR35 (Kapur et al., 2009, Oka et al., 2010, Zhao et al., 2010). In summary, it is noteworthy that the three types of endogenous ligands for separate types of receptors are metabolically closely related and possibly interconvertible (Fig. 2).
    Therapeutic implications There are five recently recognized areas to which GPR35 signaling may play an important role, metabolic disease (diabetes), hypertension, asthma, pain, and inflammatory bowel disease (IBD) (Milligan, 2011). Each of these areas alone is medically important and each would benefit by the use of selective GPR35 ligands to further the studies of their respective animal models. Moreover, the occurrence of GPR35 receptors outside the CNS also suggests less stringent requirements for the chemical optimization of GPR35 antagonist compounds because a subclass of their medically relevant targets has greater accessibility. GPR35 is expressed in mouse dorsal root ganglion and spinal cord and is implicated in the pain response in the acetic acid-induced writhing models (Cosi et al., 2010, Zhao et al., 2010). In the inflammatory bowel disease area, it was found that GPR35 gene polymorphism was associated with the disease (Imielinski et al., 2009). It was identified that the chromosome region 2q37(rs4676410), which lies within GPR35, was associated with early-onset IBD susceptibility. Interestingly 1,4-dihydroxy-2-naphthoic acid (DHNA), effective in bowel inflammation (Okada et al., 2006), was found to be a GPR35 agonist (Zhao et al., 2010). Cromolyn, another ligand of GPR35, has been shown to prevent obesity and improve oral glucose tolerance (Liu et al., 2009, Yang et al., 2010). The elevated blood pressure in GPR35 knockout mice and association of coronary artery disease with GPR35 Ser294Arg polymorphism indicate a role for GPR35 in cardiovascular function (Min et al., 2010, Sun et al., 2008). It has recently been shown (Zhao et al., 2010) that GPR35 is potently activated by pamoic acid, which had been presumed to be inactive. This compound is used in the formulation of many drugs such as the antihelminthics oxantel pamoate and pyrantel pamoate, the psychoactive compounds Vistaril (hydroxyzine pamoate) and Tofranil-PM (imipramine pamoate), and the peptide hormones Trelstar (triptorelin pamoate) and OncoLar (octreotide pamoate). This suggests that pamoate salts (pamoic acid) may contribute directly to the clinical effectiveness of some FDA approved drugs through novel GPR35-related mechanisms. Several new scaffolds of GPR35 antagonists were recently discovered (Heynen-Genel et al., 2010c). These new GPR35 ligands would certainly facilitate the investigation of the role of GPR35 in human diseases associated with the use of pamoic acid formulations.