European Journal of Pharmacology 732 (2014) 169–172
Contents lists available at ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Perspective
Intracellular and nuclear bradykinin B2 receptors Masaoki Takano a,n, Shogo Matsuyama b a b
Laboratory of Molecular Cell Biology, School of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1 Kamiohno, Himeji 670-8524, Japan
art ic l e i nf o
a b s t r a c t
Article history: Received 4 December 2013 Received in revised form 6 March 2014 Accepted 10 March 2014 Available online 18 March 2014
Bradykinin is a vasoactive peptide that participates in numerous inflammatory processes, vasodilation, and cell growth/survival; it mainly acts through two receptor subtypes, bradykinin B1 and bradykinin B2 receptors, which are G protein-coupled receptor (GPCR) family members. Details on ubiquitindependent degradation via the lysosome and/or proteasome, and the recycling process that directs bradykinin B2 receptor to the cell surface after agonist-induced endocytosis remain unclear; nevertheless, intracellular localization and internalization of GPCRs following stimulation by ligands are well known. Evidence concerning the nuclear localization and functions of GPCRs has been accumulating. The bradykinin B2 receptor has been shown to localize in the nucleus and suggested to function as a transcriptional regulator of specific genes. The transfer of membrane GPCRs (regardless of liganding), including the bradykinin B2 receptor to the nucleus can be attributed to the presence of a peptide sequence referred to as the nuclear localization signal (NLS). More recently, we found that nuclear bradykinin B2 receptors form heterodimers with the nuclear lamina protein, lamin C. The function of heterodimerization of the bradykinin B2 receptor with lamin C is still unclear. However, nuclear proteins lamin A/C are involved in a variety of diseases. Although further studies are required to elucidate the precise functions and mechanisms of intracellular and nuclear bradykinin B2 receptors, here we discuss the role of lamin A/C in laminopathies and examine the clinical significance of the bradykinin B2 receptor heterodimer. & 2014 Elsevier B.V. All rights reserved.
Keywords: Bradykinin B2 receptor Nuclear localization Internalization Lamin C
1. Introduction Bradykinin (BK) is at the center of the kallikrein–kinin system. This complex system is an endogenous metabolic cascade, including mainly serine proteases (tissue and plasma kallikreins) that liberate kinins from high- and low- molecular-weight kininogen (HMWK and LMWK). Kinins refer to a group of polypeptides, that include the nonapeptide, BK, the decapeptide, kallidin (KD: LysoBK), and their carboxy-terminal des-Arg metabolites in humans and in most mammals (Bhoola et al., 1992). They function in many physiological and pathological processes as ubiquitous polypeptide mediators involved in inflammation, cardiovascular homeostasis (vasodilation), cell growth/survival, and specific proinflammatory gene expression (Leeb-Lundberg et al., 2005) and ocular hypotension (Sharif et al., 2013). In particular, they play important roles in pathological processes (such as inflammation) by increasing vascular permeability, tissue-type plasminogen activator (t-PA) release, nitric oxide production, and mobilization of arachidonic acid (Moreau et al., 2005), as well as stimulating prostaglandin (PG) synthesis and secretion (Wiernas et al., 1998).
n
Corresponding author. Tel./fax: þ 81 78 974 4716. E-mail address: [email protected] (M. Takano).
http://dx.doi.org/10.1016/j.ejphar.2014.03.011 0014-2999/& 2014 Elsevier B.V. All rights reserved.
Kinins mainly act through two receptor subtypes (bradykinin B1 and B2 receptors) in mammalian cells and tissues. Bradykinin B1 receptor is expressed at a very low level in healthy tissues, but is induced under stressful conditions such as shock or inflammation, whereas the bradykinin B2 receptor is ubiquitous and is constitutively expressed (Leeb-Lundberg et al., 2005). Both receptors belong to the G protein-coupled receptor (GPCR) family and transduce extracellular signals through the activation of G-proteins. The bradykinin B2 receptor, in particular, is coupled to at least two families of heterotrimeric G proteins, Gi2α and Gi3α. Coupling leads to the activation of phospholipase A2, the release of arachidonic acid (Prado et al., 2002; Burch and Axelrod, 1987), PG synthesis (Wiernas et al., 1998) and Gq/11 (which activates phospholipase C), which then leads to the turnover of phosphatidyl inositol (Graness et al., 1998) followed by intracellular Ca2 þ mobilization (Sharif et al., 2013). To date, there have been numerous reports on intracellular localization and trafficking of GPCRs, both in vivo and in vitro (Kallal and Benovic, 2000; Koenig and Edwardson, 1997). Initial studies in yeast indicate that GPCR internalization is mediated by direct ubiquitination (Hicke and Riezman, 1996; Roth and Davis, 1996). However, recent studies have demonstrated that mammalian GPCR ubiquitination is not required for receptor internalization (Marchese and Benovic, 2001; Martin et al., 2003). GPCRs require
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and uptake of extracellular molecules on the plasma membrane surface (Anderson, 1998; Haasemann et al., 1998). Bradykinin B2 receptor internalization in HEK293 cells is largely arrestin- and dynamin-independent (Lamb et al., 2001), suggesting a clathrinindependent mechanism of endocytosis. To the best of our knowledge, ubiquitin-dependent degradation via the lysosome and/or proteasome and the process of recycling the bradykinin B2 receptor (which is not a shared feature with other GPCRs) to the cell surface remain unclear (Fig. 1). Functional desensitization and resensitization of the bradykinin B2 receptor parallels endocytosis, and the internalization and recycling of the bradykinin B2 receptor to the cell surface follows Ser/ Thr phosphorylation/dephosphorylation events (Blaukat et al., 1996). Physiological correlates of bradykinin B2 receptor desensitization/ endocytosis may also be found in biological systems that perform vascular functions in rats (Praddaude et al., 1995; Bartus et al., 1996). Studies of bradykinin B2 receptor fused with green fluorescent protein (GFP) in transfected HEK 293 cells show that agonistinduced endocytosis is largely reversible, owing to the completion of bradykinin B2 receptor-GFP cycling combined with rapid BK degradation (Bachvarov et al., 2001). Most or essentially all internalized bradykinin B2 receptors following agonist stimulation are recycled back to the plasma membrane from the endosomal compartment (Fig. 1) (Bachvarov et al., 2001; Blaukat et al., 1996). However, it is not clear whether the internalized bradykinin B2 receptor enter lysosomes. Thus, agonist-induced endocytosis may not be the mechanism that underlies bradykinin B2 receptor downregulation. Interestingly, the bradykinin B2 receptor is only downregulated to a very limited extent, even after prolonged exposure to agonist for a number of days (Bachvarov et al., 2001; Blaukat et al., 2003). This indicates that agonist-induced bradykinin B2 receptors are not readily downregulated in cellular systems. However, downregulation of bradykinin B2 receptors does occur under pathophysiological conditions in certain cases of intense and chronic inflammation (Bhoola, 1996; Kachur et al., 1986).
agonist-dependent ubiquitination for subsequent intracellular receptor trafficking steps involving proper receptor sorting to lysosomes for degradation. This ubiquitin-dependent degradation occurs via the proteasomal pathway (Alonso and Friedman, 2013; Marceau et al., 2002), and GPCRs following agonist stimulation are known to recycle to the cell surface (Alonso and Friedman, 2013; Marceau et al., 2002). Although the physiological functions of nuclear GPCRs are presently poorly understood, perinuclear and/or nuclear localization of GPCRs have been demonstrated, and these processes reportedly regulate a number of physiological processes, including cell proliferation, survival, inflammatory responses, tumorigenesis, DNA synthesis, and transcription (Boivin et al., 2008). For functional nuclear GPCRs of lipid mediators (such as prostaglandin E2 [PGE2], platelet-activating factor [PAF] and lysophosphatidic acid [LPA] (Zhu et al., 2006)), responses to stimulation of isolated nuclei with these lipids include transcriptional regulation of major genes (namely, the genes encoding c-fos, cyclooxygenase-2, and endothelial cells, as well as inducible nitric oxide synthase (Zhu et al., 2006)). Some researchers have suggested that nuclear GPCRs are derived from the cell membrane (Gobeil et al., 2006). The transfer of membrane GPCRs (regardless of liganding) to the nucleus has been attributed to a peptide sequence referred to as the nuclear localization signal (NLS). A limited number of GPCRs have an NLS motif in the eighth helix and/or in the third intracellular loop, which usually consists of short stretches of the basic amino acids, arginine and lysine (although many atypical NLS sequences have been found (Christophe et al., 2000; Lee et al., 2004)). NLS-bearing receptors may be directed to the nucleus through the Ran-GTP/importin mechanism (Christophe et al., 2000), as is suggested for transmembrane EGF receptors (Lin et al., 2001). Here we provide a brief overview of the localization, functions, and mechanisms of intracellular and nuclear bradykinin B2 receptors, and also present our recent findings concerning heterodimerization of the bradykinin B2 receptor with lamin C in the nucleus.
2. Internalization and trafficking of bradykinin B2 receptors 3. Nuclear localization of the bradykinin B2 receptor Bradykinin B2 receptor is stimulated by agonists, similar to several other GPCRs, and follows an internalization pathway involving redistribution to caveolae, which are sites of endocytosis
Several studies detail the constitutive presence of bradykinin B2 receptor in the nuclei of cells expressed endogenously (Chen agonist
3. ubiquitination?
Ub
B2R
B2R
Ub endocytosis
1. recycling
Ub Lysosome
2. nuclear translocation? LaminC
Proteasome
Nucleus
Fig. 1. Schematic representation of the cellular translocation and nuclear localization of the bradykinin B2 receptor. Pathway 1: Agonist-induced endocytosis and recycling of bradykinin B2 receptor to the cell surface. Pathway 2: Bradykinin B2 receptor may be directed to the nucleus following agonist-induced endocytosis. Pathway 3: Bradykinin B2 receptor may be directed to the lysosome and/or proteasome following ubiquitination. B2R: bradykinin B2 receptor, Ub: ubiquitin.
M. Takano, S. Matsuyama / European Journal of Pharmacology 732 (2014) 169–172
et al., 2000; Arganaraz et al., 2004; Savard et al., 2008) and ectopically (Blaukat et al., 1999; Lee et al., 2004). Indeed, the findings obtained in some of these studies performed in native tissues imply that results obtained in the aforementioned heterologous expression systems may not simply be artifacts of receptor mislocalization due to overexpression. The cytoplasmic tail of the bradykinin B2 receptor contains an NLS motif KRFRK, positioned just downstream of the seventh transmembrane domain within the eighth helix, and the bradykinin B2 receptor may utilize the NLS sequence to migrate to cell nuclei (Fig. 1) (Lee et al., 2004). However, agonist-independent nuclear localization of the bradykinin B2 receptor-GFP construct was shown in HEK-293T cells (Lee et al., 2004). Using live-cell imaging with confocal microscopy, we also found no significant changes in the distribution of bradykinin B2 receptor-GFP after addition of BK to HEK 293T cells (Takano et al., 2014). Moreover, addition of a mutated NLS motif KRFRK to the intracellular C-terminal domain at positions 310 and 314 (CT mutation) did not change the distribution of GFPbradykinin B2 receptor (Takano et al., 2014). These results indicate that neither the agonist nor the NLS motif is involved in the nuclear localization or translocation of bradykinin B2 receptor. Savard et al. (2008) showed that BK induces concentrationdependent transitory mobilization of nucleoplasmic calcium, activation/phosphorylation of Akt, and acetylation of histone H3, and demonstrated that BK ensures iNOS gene induction in isolated-liver nuclei (Savard et al., 2008), suggesting that nuclear-localized bradykinin B2 receptor responsive to BK binding functions is a transcriptional regulator of specific genes. These findings led us to speculate about the existence of proteins bound to bradykinin B2 receptor in the nucleus. Using the yeast two-hybrid system, we identified lamin C, a nuclear lamina protein that interacts with the C-terminus of the bradykinin B2 receptor, and showed colocalization and heterodimerization of the bradykinin B2 receptor with lamin C in the nucleus of HEK 293T cells (Fig. 1) (Takano et al., 2014). Interestingly, neither addition of BK nor bradykinin B2 receptor CT mutations reduced the binding to lamin C and changed the nuclear localization or translocation of bradykinin B2 receptor (Takano et al., 2014). Thus, we propose that heterodimerization of bradykinin B2 receptor with lamin C is essential to nuclear localization of bradykinin B2 receptor and plays an important role in nuclear cell signaling and function.
4. Perspective Lamins A and C are scaffolding (supporting) components of the nuclear envelope, which is a structure that surrounds the nucleus in cells. Specifically, these proteins are located in the nuclear lamina, a mesh-like layer of intermediate filaments and other proteins that are attached to the inner membrane of the nuclear envelope. Mutations in the lamin A/C gene have been found to cause several inherited conditions (i.e., laminopathies) such as Charcot–Marie–Tooth disease, Emery–Dreifuss muscular dystrophy, Hutchinson–Gilford progeria syndrome, limb-girdle muscular dystrophy, and mandibuloacral dysplasia. Emery–Dreifuss muscular dystrophy, for example, is characterized by weakness in voluntary movement of muscles (skeletal muscles) and the heart (cardiac) muscle (Lin and Worman, 1993). Lamin A/C–deficient mice develop rapidly progressive dilated cardiomyopathy characterized by left ventricular dilation and reduced systolic contraction (Nikolaev et al., 2003, 2004). These observations suggest that lamin A/C is responsible for cellular fragility, which is particularly evident in tissues subjected to mechanical stress. BK is also involved in myocardial protection in the early phase of pharmacological preconditioning through a pathway dependent on endogenous NO (Yoshida et al., 2005). Taking our findings and these findings into consideration, we propose that the bradykinin B2
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receptor-lamin C heterodimer is essential for normal physiological functions, and, in particular, is essential for myocardial function. We are at the starting point of our investigation into nuclear bradykinin B2 receptor. We hope to fully elucidate the physiological and pathological functions of nuclear bradykinin B2 receptor in the near future. From a clinical perspective, elucidation of the functions and mechanisms of bradykinin B2 receptor and lamin C heterodimerization could provide novel therapeutic avenues for the aforementioned diseases.
Acknowledgments We would like to thank Dr. Kenji Matsuura for providing beneficial advice. This work was supported by Grants from the Smoking Research Foundation and Kobe Gakuin University for Collaborative Research B. References Alonso, V., Friedman, P.A., 2013. Minireview: ubiquitination-regulated G proteincoupled receptor signaling and trafficking. Mol. Endocrinol. 27, 558–572. Anderson, R.G., 1998. The caveolae membrane system. Annu. Rev. Biochem. 67, 199–225. Arganaraz, G.A., Silva Jr., J.A., Perosa, S.R., Pessoa, L.G., Carvalho, F.F., Bascands, J.L., Bader, M., da Silva Trindade, E., Amado, D., Cavalheiro, E.A., Pesquero, J.B., da Graca Naffah-Mazzacoratti, M., 2004. The synthesis and distribution of the kinin B1 and B2 receptors are modified in the hippocampus of rats submitted to pilocarpine model of epilepsy. Brain Res. 1006, 114–125. Bachvarov, D.R., Houle, S., Bachvarova, M., Bouthillier, J., Adam, A., Marceau, F., 2001. Bradykinin B(2) receptor endocytosis, recycling, and down-regulation assessed using green fluorescent protein conjugates. J. Pharmacol. Exp. Ther. 297, 19–26. Bartus, R.T., Elliott, P.J., Dean, R.L., Hayward, N.J., Nagle, T.L., Huff, M.R., Snodgrass, P. A., Blunt, D.G., 1996. Controlled modulation of BBB permeability using the bradykinin agonist, RMP-7. Exp. Neurol. 142, 14–28. Bhoola, K.D., 1996. Translocation of the neutrophil kinin moiety and changes in the regulation of kinin receptors in inflammation. Immunopharmacology 33, 247–256. Bhoola, K.D., Figueroa, C.D., Worthy, K., 1992. Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol. Rev. 44, 1–80. Blaukat, A., Alla, S.A., Lohse, M.J., Muller-Esterl, W., 1996. Ligand-induced phosphorylation/dephosphorylation of the endogenous bradykinin B2 receptor from human fibroblasts. J. Biol. Chem. 271, 32366–32374. Blaukat, A., Herzer, K., Schroeder, C., Bachmann, M., Nash, N., Muller-Esterl, W., 1999. Overexpression and functional characterization of kinin receptors reveal subtype-specific phosphorylation. Biochemistry 38, 1300–1309. Blaukat, A., Micke, P., Kalatskaya, I., Faussner, A., Muller-Esterl, W., 2003. Downregulation of bradykinin B2 receptor in human fibroblasts during prolonged agonist exposure. Am. J. Physiol. Heart Circ. Physiol. 284, H1909–H1916. Boivin, B., Vaniotis, G., Allen, B.G., Hebert, T.E., 2008. G protein-coupled receptors in and on the cell nucleus: a new signaling paradigm? J. Recept. Signal Transduct. Res. 28, 15–28. Burch, R.M., Axelrod, J., 1987. Dissociation of bradykinin-induced prostaglandin formation from phosphatidylinositol turnover in Swiss 3T3 fibroblasts: evidence for G protein regulation of phospholipase A2. Proc. Natl. Acad. Sci. USA 84, 6374–6378. Chen, E.Y., Emerich, D.F., Bartus, R.T., Kordower, J.H., 2000. B2 bradykinin receptor immunoreactivity in rat brain. J. Comp. Neurol. 427, 1–18. Christophe, D., Christophe-Hobertus, C., Pichon, B., 2000. Nuclear targeting of proteins: how many different signals? Cell Signal. 12, 337–341. Gobeil, F., Fortier, A., Zhu, T., Bossolasco, M., Leduc, M., Grandbois, M., Heveker, N., Bkaily, G., Chemtob, S., Barbaz, D., 2006. G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigm. Can. J. Physiol. Pharmacol. 84, 287–297. Graness, A., Adomeit, A., Heinze, R., Wetzker, R., Liebmann, C., 1998. A novel mitogenic signaling pathway of bradykinin in the human colon carcinoma cell line SW-480 involves sequential activation of a Gq/11 protein, phosphatidylinositol 3-kinase beta, and protein kinase Cepsilon. J. Biol. Chem. 273, 32016–32022. Haasemann, M., Cartaud, J., Muller-Esterl, W., Dunia, I., 1998. Agonist-induced redistribution of bradykinin B2 receptor in caveolae. J. Cell Sci. 111 (Pt 7), 917–928. Hicke, L., Riezman, H., 1996. Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis. Cell 84, 277–287. Kachur, J.F., Allbee, W., Gaginella, T.S., 1986. Effect of bradykinin and desArg9bradykinin on ion transport across normal and inflamed rat colonic mucosa. Gastroenterology 90, 1481. Kallal, L., Benovic, J.L., 2000. Using green fluorescent proteins to study G-proteincoupled receptor localization and trafficking. Trends Pharmacol. Sci. 21, 175–180.
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Martin, D., Feneley, M.P., Fatkin, D., 2004. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice. J. Clin. Invest. 113, 357–369. Praddaude, F., Tack, I., Emond, C., Bascands, J.L., Girolami, J.P., Tran-Van, T., Regoli, D., Ader, J.L., 1995. in vivo and in vitro homologous desensitization of rat glomerular bradykinin B2 receptors. Eur. J. Pharmacol. 294, 173–182. Prado, G.N., Taylor, L., Zhou, X., Ricupero, D., Mierke, D.F., Polgar, P., 2002. Mechanisms regulating the expression, self-maintenance, and signalingfunction of the bradykinin B2 and B1 receptors. J. Cell. Physiol. 193, 275–286. Roth, A.F., Davis, N.G., 1996. Ubiquitination of the yeast a-factor receptor. J. Cell Biol. 134, 661–674. Savard, M., Barbaz, D., Belanger, S., Muller-Esterl, W., Bkaily, G., D’Orleans-Juste, P., Cote, J., Bovenzi, V., Gobeil Jr., F., 2008. Expression of endogenous nuclear bradykinin B2 receptors mediating signaling in immediate early gene activation. J. Cell. Physiol. 216, 234–244. Sharif, N.A., Xu, S., Li, L., Katoli, P., Kelly, C.R., Wang, Y., Cao, S., Patil, R., Husain, S., Klekar, L., Scott, D., 2013. Protein expression, biochemical pharmacology of signal transduction, and relation to intraocular pressure modulation by bradykinin B(2) receptors in ciliary muscle. Mol. Vis. 19, 1356–1370. Takano, M., Kanoh, A., Amako, K., Otani, M., Sano, K., Kanazawa-Hamada, M., Matsuyama, S., 2014. Nuclear localization of bradykinin B2 receptors reflects binding to the nuclear envelope protein lamin C. Eur. J. Pharmacol. 723, 507–514. Wiernas, T.K., Davis, T.L., Griffin, B.W., Sharif, N.A., 1998. Effects of bradykinin on signal transduction, cell proliferation, and cytokine, prostaglandin E2 and collagenase-1 release from human corneal epithelial cells. Br. J. Pharmacol. 123, 1127–1137. Yoshida, H., Kusama, Y., Kodani, E., Yasutake, M., Takano, H., Atarashi, H., Kishida, H., Takano, T., 2005. Pharmacological preconditioning with bradykinin affords myocardial protection through NO-dependent mechanisms. Int. Heart J. 46, 877–887. Zhu, T., Gobeil, F., Vazquez-Tello, A., Leduc, M., Rihakova, L., Bossolasco, M., Bkaily, G., Peri, K., Varma, D.R., Orvoine, R., Chemtob, S., 2006. Intracrine signaling through lipid mediators and their cognate nuclear G-protein-coupled receptors: a paradigm based on PGE2, PAF, and LPA1 receptors. Can. J. Physiol. Pharmacol. 84, 377–391.
Contents lists available at ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Perspective
Intracellular and nuclear bradykinin B2 receptors Masaoki Takano a,n, Shogo Matsuyama b a b
Laboratory of Molecular Cell Biology, School of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1 Kamiohno, Himeji 670-8524, Japan
art ic l e i nf o
a b s t r a c t
Article history: Received 4 December 2013 Received in revised form 6 March 2014 Accepted 10 March 2014 Available online 18 March 2014
Bradykinin is a vasoactive peptide that participates in numerous inflammatory processes, vasodilation, and cell growth/survival; it mainly acts through two receptor subtypes, bradykinin B1 and bradykinin B2 receptors, which are G protein-coupled receptor (GPCR) family members. Details on ubiquitindependent degradation via the lysosome and/or proteasome, and the recycling process that directs bradykinin B2 receptor to the cell surface after agonist-induced endocytosis remain unclear; nevertheless, intracellular localization and internalization of GPCRs following stimulation by ligands are well known. Evidence concerning the nuclear localization and functions of GPCRs has been accumulating. The bradykinin B2 receptor has been shown to localize in the nucleus and suggested to function as a transcriptional regulator of specific genes. The transfer of membrane GPCRs (regardless of liganding), including the bradykinin B2 receptor to the nucleus can be attributed to the presence of a peptide sequence referred to as the nuclear localization signal (NLS). More recently, we found that nuclear bradykinin B2 receptors form heterodimers with the nuclear lamina protein, lamin C. The function of heterodimerization of the bradykinin B2 receptor with lamin C is still unclear. However, nuclear proteins lamin A/C are involved in a variety of diseases. Although further studies are required to elucidate the precise functions and mechanisms of intracellular and nuclear bradykinin B2 receptors, here we discuss the role of lamin A/C in laminopathies and examine the clinical significance of the bradykinin B2 receptor heterodimer. & 2014 Elsevier B.V. All rights reserved.
Keywords: Bradykinin B2 receptor Nuclear localization Internalization Lamin C
1. Introduction Bradykinin (BK) is at the center of the kallikrein–kinin system. This complex system is an endogenous metabolic cascade, including mainly serine proteases (tissue and plasma kallikreins) that liberate kinins from high- and low- molecular-weight kininogen (HMWK and LMWK). Kinins refer to a group of polypeptides, that include the nonapeptide, BK, the decapeptide, kallidin (KD: LysoBK), and their carboxy-terminal des-Arg metabolites in humans and in most mammals (Bhoola et al., 1992). They function in many physiological and pathological processes as ubiquitous polypeptide mediators involved in inflammation, cardiovascular homeostasis (vasodilation), cell growth/survival, and specific proinflammatory gene expression (Leeb-Lundberg et al., 2005) and ocular hypotension (Sharif et al., 2013). In particular, they play important roles in pathological processes (such as inflammation) by increasing vascular permeability, tissue-type plasminogen activator (t-PA) release, nitric oxide production, and mobilization of arachidonic acid (Moreau et al., 2005), as well as stimulating prostaglandin (PG) synthesis and secretion (Wiernas et al., 1998).
n
Corresponding author. Tel./fax: þ 81 78 974 4716. E-mail address: [email protected] (M. Takano).
http://dx.doi.org/10.1016/j.ejphar.2014.03.011 0014-2999/& 2014 Elsevier B.V. All rights reserved.
Kinins mainly act through two receptor subtypes (bradykinin B1 and B2 receptors) in mammalian cells and tissues. Bradykinin B1 receptor is expressed at a very low level in healthy tissues, but is induced under stressful conditions such as shock or inflammation, whereas the bradykinin B2 receptor is ubiquitous and is constitutively expressed (Leeb-Lundberg et al., 2005). Both receptors belong to the G protein-coupled receptor (GPCR) family and transduce extracellular signals through the activation of G-proteins. The bradykinin B2 receptor, in particular, is coupled to at least two families of heterotrimeric G proteins, Gi2α and Gi3α. Coupling leads to the activation of phospholipase A2, the release of arachidonic acid (Prado et al., 2002; Burch and Axelrod, 1987), PG synthesis (Wiernas et al., 1998) and Gq/11 (which activates phospholipase C), which then leads to the turnover of phosphatidyl inositol (Graness et al., 1998) followed by intracellular Ca2 þ mobilization (Sharif et al., 2013). To date, there have been numerous reports on intracellular localization and trafficking of GPCRs, both in vivo and in vitro (Kallal and Benovic, 2000; Koenig and Edwardson, 1997). Initial studies in yeast indicate that GPCR internalization is mediated by direct ubiquitination (Hicke and Riezman, 1996; Roth and Davis, 1996). However, recent studies have demonstrated that mammalian GPCR ubiquitination is not required for receptor internalization (Marchese and Benovic, 2001; Martin et al., 2003). GPCRs require
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and uptake of extracellular molecules on the plasma membrane surface (Anderson, 1998; Haasemann et al., 1998). Bradykinin B2 receptor internalization in HEK293 cells is largely arrestin- and dynamin-independent (Lamb et al., 2001), suggesting a clathrinindependent mechanism of endocytosis. To the best of our knowledge, ubiquitin-dependent degradation via the lysosome and/or proteasome and the process of recycling the bradykinin B2 receptor (which is not a shared feature with other GPCRs) to the cell surface remain unclear (Fig. 1). Functional desensitization and resensitization of the bradykinin B2 receptor parallels endocytosis, and the internalization and recycling of the bradykinin B2 receptor to the cell surface follows Ser/ Thr phosphorylation/dephosphorylation events (Blaukat et al., 1996). Physiological correlates of bradykinin B2 receptor desensitization/ endocytosis may also be found in biological systems that perform vascular functions in rats (Praddaude et al., 1995; Bartus et al., 1996). Studies of bradykinin B2 receptor fused with green fluorescent protein (GFP) in transfected HEK 293 cells show that agonistinduced endocytosis is largely reversible, owing to the completion of bradykinin B2 receptor-GFP cycling combined with rapid BK degradation (Bachvarov et al., 2001). Most or essentially all internalized bradykinin B2 receptors following agonist stimulation are recycled back to the plasma membrane from the endosomal compartment (Fig. 1) (Bachvarov et al., 2001; Blaukat et al., 1996). However, it is not clear whether the internalized bradykinin B2 receptor enter lysosomes. Thus, agonist-induced endocytosis may not be the mechanism that underlies bradykinin B2 receptor downregulation. Interestingly, the bradykinin B2 receptor is only downregulated to a very limited extent, even after prolonged exposure to agonist for a number of days (Bachvarov et al., 2001; Blaukat et al., 2003). This indicates that agonist-induced bradykinin B2 receptors are not readily downregulated in cellular systems. However, downregulation of bradykinin B2 receptors does occur under pathophysiological conditions in certain cases of intense and chronic inflammation (Bhoola, 1996; Kachur et al., 1986).
agonist-dependent ubiquitination for subsequent intracellular receptor trafficking steps involving proper receptor sorting to lysosomes for degradation. This ubiquitin-dependent degradation occurs via the proteasomal pathway (Alonso and Friedman, 2013; Marceau et al., 2002), and GPCRs following agonist stimulation are known to recycle to the cell surface (Alonso and Friedman, 2013; Marceau et al., 2002). Although the physiological functions of nuclear GPCRs are presently poorly understood, perinuclear and/or nuclear localization of GPCRs have been demonstrated, and these processes reportedly regulate a number of physiological processes, including cell proliferation, survival, inflammatory responses, tumorigenesis, DNA synthesis, and transcription (Boivin et al., 2008). For functional nuclear GPCRs of lipid mediators (such as prostaglandin E2 [PGE2], platelet-activating factor [PAF] and lysophosphatidic acid [LPA] (Zhu et al., 2006)), responses to stimulation of isolated nuclei with these lipids include transcriptional regulation of major genes (namely, the genes encoding c-fos, cyclooxygenase-2, and endothelial cells, as well as inducible nitric oxide synthase (Zhu et al., 2006)). Some researchers have suggested that nuclear GPCRs are derived from the cell membrane (Gobeil et al., 2006). The transfer of membrane GPCRs (regardless of liganding) to the nucleus has been attributed to a peptide sequence referred to as the nuclear localization signal (NLS). A limited number of GPCRs have an NLS motif in the eighth helix and/or in the third intracellular loop, which usually consists of short stretches of the basic amino acids, arginine and lysine (although many atypical NLS sequences have been found (Christophe et al., 2000; Lee et al., 2004)). NLS-bearing receptors may be directed to the nucleus through the Ran-GTP/importin mechanism (Christophe et al., 2000), as is suggested for transmembrane EGF receptors (Lin et al., 2001). Here we provide a brief overview of the localization, functions, and mechanisms of intracellular and nuclear bradykinin B2 receptors, and also present our recent findings concerning heterodimerization of the bradykinin B2 receptor with lamin C in the nucleus.
2. Internalization and trafficking of bradykinin B2 receptors 3. Nuclear localization of the bradykinin B2 receptor Bradykinin B2 receptor is stimulated by agonists, similar to several other GPCRs, and follows an internalization pathway involving redistribution to caveolae, which are sites of endocytosis
Several studies detail the constitutive presence of bradykinin B2 receptor in the nuclei of cells expressed endogenously (Chen agonist
3. ubiquitination?
Ub
B2R
B2R
Ub endocytosis
1. recycling
Ub Lysosome
2. nuclear translocation? LaminC
Proteasome
Nucleus
Fig. 1. Schematic representation of the cellular translocation and nuclear localization of the bradykinin B2 receptor. Pathway 1: Agonist-induced endocytosis and recycling of bradykinin B2 receptor to the cell surface. Pathway 2: Bradykinin B2 receptor may be directed to the nucleus following agonist-induced endocytosis. Pathway 3: Bradykinin B2 receptor may be directed to the lysosome and/or proteasome following ubiquitination. B2R: bradykinin B2 receptor, Ub: ubiquitin.
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et al., 2000; Arganaraz et al., 2004; Savard et al., 2008) and ectopically (Blaukat et al., 1999; Lee et al., 2004). Indeed, the findings obtained in some of these studies performed in native tissues imply that results obtained in the aforementioned heterologous expression systems may not simply be artifacts of receptor mislocalization due to overexpression. The cytoplasmic tail of the bradykinin B2 receptor contains an NLS motif KRFRK, positioned just downstream of the seventh transmembrane domain within the eighth helix, and the bradykinin B2 receptor may utilize the NLS sequence to migrate to cell nuclei (Fig. 1) (Lee et al., 2004). However, agonist-independent nuclear localization of the bradykinin B2 receptor-GFP construct was shown in HEK-293T cells (Lee et al., 2004). Using live-cell imaging with confocal microscopy, we also found no significant changes in the distribution of bradykinin B2 receptor-GFP after addition of BK to HEK 293T cells (Takano et al., 2014). Moreover, addition of a mutated NLS motif KRFRK to the intracellular C-terminal domain at positions 310 and 314 (CT mutation) did not change the distribution of GFPbradykinin B2 receptor (Takano et al., 2014). These results indicate that neither the agonist nor the NLS motif is involved in the nuclear localization or translocation of bradykinin B2 receptor. Savard et al. (2008) showed that BK induces concentrationdependent transitory mobilization of nucleoplasmic calcium, activation/phosphorylation of Akt, and acetylation of histone H3, and demonstrated that BK ensures iNOS gene induction in isolated-liver nuclei (Savard et al., 2008), suggesting that nuclear-localized bradykinin B2 receptor responsive to BK binding functions is a transcriptional regulator of specific genes. These findings led us to speculate about the existence of proteins bound to bradykinin B2 receptor in the nucleus. Using the yeast two-hybrid system, we identified lamin C, a nuclear lamina protein that interacts with the C-terminus of the bradykinin B2 receptor, and showed colocalization and heterodimerization of the bradykinin B2 receptor with lamin C in the nucleus of HEK 293T cells (Fig. 1) (Takano et al., 2014). Interestingly, neither addition of BK nor bradykinin B2 receptor CT mutations reduced the binding to lamin C and changed the nuclear localization or translocation of bradykinin B2 receptor (Takano et al., 2014). Thus, we propose that heterodimerization of bradykinin B2 receptor with lamin C is essential to nuclear localization of bradykinin B2 receptor and plays an important role in nuclear cell signaling and function.
4. Perspective Lamins A and C are scaffolding (supporting) components of the nuclear envelope, which is a structure that surrounds the nucleus in cells. Specifically, these proteins are located in the nuclear lamina, a mesh-like layer of intermediate filaments and other proteins that are attached to the inner membrane of the nuclear envelope. Mutations in the lamin A/C gene have been found to cause several inherited conditions (i.e., laminopathies) such as Charcot–Marie–Tooth disease, Emery–Dreifuss muscular dystrophy, Hutchinson–Gilford progeria syndrome, limb-girdle muscular dystrophy, and mandibuloacral dysplasia. Emery–Dreifuss muscular dystrophy, for example, is characterized by weakness in voluntary movement of muscles (skeletal muscles) and the heart (cardiac) muscle (Lin and Worman, 1993). Lamin A/C–deficient mice develop rapidly progressive dilated cardiomyopathy characterized by left ventricular dilation and reduced systolic contraction (Nikolaev et al., 2003, 2004). These observations suggest that lamin A/C is responsible for cellular fragility, which is particularly evident in tissues subjected to mechanical stress. BK is also involved in myocardial protection in the early phase of pharmacological preconditioning through a pathway dependent on endogenous NO (Yoshida et al., 2005). Taking our findings and these findings into consideration, we propose that the bradykinin B2
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receptor-lamin C heterodimer is essential for normal physiological functions, and, in particular, is essential for myocardial function. We are at the starting point of our investigation into nuclear bradykinin B2 receptor. We hope to fully elucidate the physiological and pathological functions of nuclear bradykinin B2 receptor in the near future. From a clinical perspective, elucidation of the functions and mechanisms of bradykinin B2 receptor and lamin C heterodimerization could provide novel therapeutic avenues for the aforementioned diseases.
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