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  • GPR and TRPV co localized

    2022-01-13

    GPR35 and TRPV1 co-localized in small- and medium-diameter DRG neurons. Nociceptive (Aδ- and C-fiber) neurons expressing TRPV1 mediate hyperalgesia, neurogenic inflammation, and neuropathic pain [12]. The cAMP-protein kinase A (PKA) dependent modifications of TRPV1 currents have been demonstrated in various cell systems, including DRG neurons. Activators of PKA, such as prostaglandin E2, increased TRPV1 phosphorylation and the sensitivity of the channel [13], [14]. In addition, PKA-mediated phosphorylation not only potentiates heat-activated TRPV1 currents [15], but also counteracts Ca2+-dependent desensitization [16]. Gi/o-coupled GPCRs, such as μ-opioid receptor and cannabinoid receptor, are physiologically coupled to TRPV1 and inhibit its activity via Gi/o proteins and the cAMP pathway [17], [18]. Although a functional coupling between GPR35 and TRPV1 has not been identified, GPR35 may regulate TRPV1 channel activity by modulating cAMP/PKA pathway. GPR35 was also present in large-diameter DRG neurons that were not TRPV1-positive. As large-diameter DRG neurons (Aβ-fiber) primarily convey non-nociceptive information, such as touch and light pressure [12], GPR35 may have participated in the conversion of mechanical stimuli into nerve impulses. Kynurenic Perhexiline maleate is an intermediate in the tryptophan metabolic pathway and its plasma level is elevated during inflammation [19], [20]. Numerous studies have proposed the beneficial effects of kynurenic acid as an anti-convulsant [21], [22], but relatively few studies have reported its role in pain perception. Intraperitoneal injection of kynurenic acid decreases pain sensitivity in both tailflick and the hotplate tests of rats [23]. In addition, intrathecal kynurenic acid suppresses thermal hyperalgesia in carrageenan-injected rats [24]. While these analgesic actions of kynurenic acid have been presumed to be largely mediated through antagonism of spinal NMDA receptors, GPR35 may also contribute this anti-nociceptive activity as kynurenic acid activates GPR35 at concentration comparable to that required for NMDA receptor blockade (IC∼8–15μM in the absence of glycine; IC∼230μM in the presence of 10μM glycine) [3]. Similarly, the PDE5-independent mechanism by which zaprinast inhibits nociception in the formalin test may be mediated in part by GPR35. Additional studies will be required to determine the role of GPR35 in nociceptive modulation. These studies may also provide new insight into the role of kynurenic acid in pain signaling.
    Acknowledgment
    Introduction The G protein-coupled receptors (GPCRs) are a large family of cell surface receptors that account for over 30% of current drug targets [1]. Sequencing of the human genome has led to the discovery of novel GPCRs, and many of them are orphan receptors for which the natural ligands have not yet been identified. To determine the biological functions of these orphan GPCRs, identification of their natural ligands is the first step. However, despite extensive attempts at receptor–ligand pairing, a number of GPCRs are still orphan receptors. GPR35 [2] is one of these orphan GPCRs. It shares homology with some of the purinergic receptors [2], GPR23/P2Y9 (the receptor for lysophosphatidic acid) [3], and HM74 (the receptor for nicotinic acid) [4]. Although chromosomal mapping and the expression of GPR35 in a number of human tissues have been investigated in previous studies [2], [5], [6], little is known about this receptor. Here we report that zaprinast [7], a well-known cGMP specific-phosphodiesterases (cGMP-PDEs) inhibitor [8], acts as an agonist for GPR35. The cyclic nucleotide phosphodiesterases are a large group of structurally-related enzymes [9], [10]. Among them, PDE4, PDE7, and PDE8 are specific enzymes for cyclic adenosine monophosphate (cAMP), whereas PDE5, PDE6, PDE9 are specific enzymes for cyclic guanosine monophosphate [9], [10]. Other PDEs have dual activities [9], [10]. They differ in their mode of action, intracellular distribution, tissue distribution, relative activities, and Km values [9], [10]. Various stimuli induce cellular responses by increasing the intracellular levels of cAMP and cGMP, and PDEs account for degradation of these intracellular second messengers to terminate the signals and the cellular responses [9], [10]. Therefore, regulation of PDEs activities is important to control the intracellular second messenger levels and physiological responses, and specific PDE inhibitors are utilized as both research tools and remedies [10]. For example, sildenafil (Viagra™) is a potent selective PDE5 inhibitor and an orally active drug for erectile dysfunction [7]. Zaprinast, a lead compound for sildenafil, is known as a moderate inhibitor for cGMP-PDEs, especially PDE5 and PDE6 (IC50 values for PDE5, PDE6, PDE9 are 0.5–076, 0.15, and 35μM) [7], [11]. Zaprinast also inhibits PDE10, and PDE11 weakly (IC50 values are 22 and 11–33μM, respectively) [11]. By using an intracellular calcium mobilization assay, we show that zaprinast activates GPR35-G protein pathways and this activity of zaprinast in this Perhexiline maleate assay is not attributable to inhibition of PDEs. We have also found that GPR35 acts as a Gαi/o- and Gα16-coupled receptor for zaprinast when heterologously expressed in human embryonic kidney 293 (HEK293) cells.