List of Publications (2011-Current)
2023
Kim, Hye In; Lee, Gi Baek; Song, Da Eun; Sanjel, Babina; Lee, Wook-Joo; Shim, Won-Sik
In: Life Sciences, vol. 325, 2023, ISSN: 0024-3205.
Abstract | Links | BibTeX | Tags: Calcium imaging, FSLLRY, Itch, MrgprC11, MRGPRX1, PAR2, Scratching behavior
@article{InKim2023,
title = {FSLLRY-NH2, a protease-activated receptor 2 (PAR2) antagonist, activates mas-related G protein-coupled receptor C11 (MrgprC11) to induce scratching behaviors in mice},
author = {Hye In Kim and Gi Baek Lee and Da Eun Song and Babina Sanjel and Wook-Joo Lee and Won-Sik Shim},
doi = {10.1016/j.lfs.2023.121786},
issn = {0024-3205},
year = {2023},
date = {2023-07-00},
urldate = {2023-07-00},
journal = {Life Sciences},
volume = {325},
publisher = {Elsevier BV},
abstract = {Aims: Protease-activated receptor 2 (PAR2), a type of G protein-coupled receptor (GPCR), plays a significant role in pathophysiological conditions such as inflammation. A synthetic peptide SLIGRL-NH2 (SLIGRL) can activate PAR2, while FSLLRY-NH2 (FSLLRY) is an antagonist. A previous study showed that SLIGRL activates both PAR2 and mas-related G protein-coupled receptor C11 (MrgprC11), a different type of GPCR expressed in sensory neurons. However, the impact of FSLLRY on MrgprC11 and its human ortholog MRGPRX1 was not verified. Hence, the present study aims to verify the effect of FSLLRY on MrgprC11 and MRGPRX1.
Methods: The calcium imaging technique was applied to determine the effect of FSLLRY in HEK293T cells expressing MrgprC11/MRGPRX1 or dorsal root ganglia (DRG) neurons. Scratching behavior was also investigated in wild-type and PAR2 knockout mice after injecting FSLLRY.
Key findings: It was surprisingly discovered that FSLLRY specifically activates MrgprC11 in a dose-dependent manner, but not other MRGPR subtypes. Furthermore, FSLLRY also moderately activated MRGPRX1. FSLLRY stimulates downstream pathways including Gαq/11, phospholipase C, IP3 receptor, and TRPC ion channels to evoke an increase in the intracellular calcium levels. The molecular docking analysis predicted that FSLLRY interacts with the orthosteric binding pocket of MrgprC11 and MRGPRX1. Finally, FSLLRY activated primary cultures of mouse sensory neurons, and induced scratching behaviors in mice.
Significance: The present study has revealed that FSLLRY is capable of triggering itch sensation through activation of MrgprC11. This finding highlights the importance of considering the unexpected activation of MRGPRs in future therapeutic approaches aimed at the inhibition of PAR2.},
keywords = {Calcium imaging, FSLLRY, Itch, MrgprC11, MRGPRX1, PAR2, Scratching behavior},
pubstate = {published},
tppubtype = {article}
}
Aims: Protease-activated receptor 2 (PAR2), a type of G protein-coupled receptor (GPCR), plays a significant role in pathophysiological conditions such as inflammation. A synthetic peptide SLIGRL-NH2 (SLIGRL) can activate PAR2, while FSLLRY-NH2 (FSLLRY) is an antagonist. A previous study showed that SLIGRL activates both PAR2 and mas-related G protein-coupled receptor C11 (MrgprC11), a different type of GPCR expressed in sensory neurons. However, the impact of FSLLRY on MrgprC11 and its human ortholog MRGPRX1 was not verified. Hence, the present study aims to verify the effect of FSLLRY on MrgprC11 and MRGPRX1.
Methods: The calcium imaging technique was applied to determine the effect of FSLLRY in HEK293T cells expressing MrgprC11/MRGPRX1 or dorsal root ganglia (DRG) neurons. Scratching behavior was also investigated in wild-type and PAR2 knockout mice after injecting FSLLRY.
Key findings: It was surprisingly discovered that FSLLRY specifically activates MrgprC11 in a dose-dependent manner, but not other MRGPR subtypes. Furthermore, FSLLRY also moderately activated MRGPRX1. FSLLRY stimulates downstream pathways including Gαq/11, phospholipase C, IP3 receptor, and TRPC ion channels to evoke an increase in the intracellular calcium levels. The molecular docking analysis predicted that FSLLRY interacts with the orthosteric binding pocket of MrgprC11 and MRGPRX1. Finally, FSLLRY activated primary cultures of mouse sensory neurons, and induced scratching behaviors in mice.
Significance: The present study has revealed that FSLLRY is capable of triggering itch sensation through activation of MrgprC11. This finding highlights the importance of considering the unexpected activation of MRGPRs in future therapeutic approaches aimed at the inhibition of PAR2.
Methods: The calcium imaging technique was applied to determine the effect of FSLLRY in HEK293T cells expressing MrgprC11/MRGPRX1 or dorsal root ganglia (DRG) neurons. Scratching behavior was also investigated in wild-type and PAR2 knockout mice after injecting FSLLRY.
Key findings: It was surprisingly discovered that FSLLRY specifically activates MrgprC11 in a dose-dependent manner, but not other MRGPR subtypes. Furthermore, FSLLRY also moderately activated MRGPRX1. FSLLRY stimulates downstream pathways including Gαq/11, phospholipase C, IP3 receptor, and TRPC ion channels to evoke an increase in the intracellular calcium levels. The molecular docking analysis predicted that FSLLRY interacts with the orthosteric binding pocket of MrgprC11 and MRGPRX1. Finally, FSLLRY activated primary cultures of mouse sensory neurons, and induced scratching behaviors in mice.
Significance: The present study has revealed that FSLLRY is capable of triggering itch sensation through activation of MrgprC11. This finding highlights the importance of considering the unexpected activation of MRGPRs in future therapeutic approaches aimed at the inhibition of PAR2.
2022
Kim, Hyesu; Kim, Hyungsup; Cho, Hawon; Lee, Byeongjun; Lu, Huan-Jun; Kim, Kyungmin; Chung, Sooyoung; Shim, Won-Sik; Shin, Young Kee; Dong, Xinzhong; Wood, John N.; Oh, Uhtaek
Anoctamin 1/TMEM16A in pruritoceptors is essential for Mas-related G protein receptor–dependent itch Journal Article
In: PAIN, vol. 163, no. 11, pp. 2172–2184, 2022, ISSN: 1872-6623.
Abstract | Links | BibTeX | Tags: Anoctamin 1, Itch, MrgprA3, MrgprC11
@article{Kim2022,
title = {Anoctamin 1/TMEM16A in pruritoceptors is essential for Mas-related G protein receptor–dependent itch},
author = {Hyesu Kim and Hyungsup Kim and Hawon Cho and Byeongjun Lee and Huan-Jun Lu and Kyungmin Kim and Sooyoung Chung and Won-Sik Shim and Young Kee Shin and Xinzhong Dong and John N. Wood and Uhtaek Oh},
doi = {10.1097/j.pain.0000000000002611},
issn = {1872-6623},
year = {2022},
date = {2022-00-00},
urldate = {2022-00-00},
journal = {PAIN},
volume = {163},
number = {11},
pages = {2172--2184},
publisher = {Ovid Technologies (Wolters Kluwer Health)},
abstract = {<jats:title>Abstract</jats:title>
<jats:p>Itch is an unpleasant sensation that evokes a desire to scratch. Pathologic conditions such as allergy or atopic dermatitis produce severe itching sensation. Mas-related G protein receptors (Mrgprs) are receptors for many endogenous pruritogens. However, signaling pathways downstream to these receptors in dorsal root ganglion (DRG) neurons are not yet understood. We found that anoctamin 1 (ANO1), a Ca<jats:sup>2+</jats:sup>-activated chloride channel, is a transduction channel mediating Mrgpr-dependent itch signals. Genetic ablation of <jats:italic toggle="yes">Ano1</jats:italic> in DRG neurons displayed a significant reduction in scratching behaviors in response to acute and chronic Mrgpr-dependent itch models and the epidermal hyperplasia induced by dry skin. In vivo Ca<jats:sup>2+</jats:sup> imaging and electrophysiological recording revealed that chloroquine and other agonists of Mrgprs excited DRG neurons via ANO1. More importantly, the overexpression of <jats:italic toggle="yes">Ano1</jats:italic> in DRG neurons of <jats:italic toggle="yes">Ano1</jats:italic>-deficient mice rescued the impaired itching observed in <jats:italic toggle="yes">Ano1</jats:italic>-deficient mice. These results demonstrate that ANO1 mediates the Mrgpr-dependent itch signaling in pruriceptors and provides clues to treating pathologic itch syndromes.</jats:p>},
keywords = {Anoctamin 1, Itch, MrgprA3, MrgprC11},
pubstate = {published},
tppubtype = {article}
}
<jats:title>Abstract</jats:title>
<jats:p>Itch is an unpleasant sensation that evokes a desire to scratch. Pathologic conditions such as allergy or atopic dermatitis produce severe itching sensation. Mas-related G protein receptors (Mrgprs) are receptors for many endogenous pruritogens. However, signaling pathways downstream to these receptors in dorsal root ganglion (DRG) neurons are not yet understood. We found that anoctamin 1 (ANO1), a Ca<jats:sup>2+</jats:sup>-activated chloride channel, is a transduction channel mediating Mrgpr-dependent itch signals. Genetic ablation of <jats:italic toggle="yes">Ano1</jats:italic> in DRG neurons displayed a significant reduction in scratching behaviors in response to acute and chronic Mrgpr-dependent itch models and the epidermal hyperplasia induced by dry skin. In vivo Ca<jats:sup>2+</jats:sup> imaging and electrophysiological recording revealed that chloroquine and other agonists of Mrgprs excited DRG neurons via ANO1. More importantly, the overexpression of <jats:italic toggle="yes">Ano1</jats:italic> in DRG neurons of <jats:italic toggle="yes">Ano1</jats:italic>-deficient mice rescued the impaired itching observed in <jats:italic toggle="yes">Ano1</jats:italic>-deficient mice. These results demonstrate that ANO1 mediates the Mrgpr-dependent itch signaling in pruriceptors and provides clues to treating pathologic itch syndromes.</jats:p>
<jats:p>Itch is an unpleasant sensation that evokes a desire to scratch. Pathologic conditions such as allergy or atopic dermatitis produce severe itching sensation. Mas-related G protein receptors (Mrgprs) are receptors for many endogenous pruritogens. However, signaling pathways downstream to these receptors in dorsal root ganglion (DRG) neurons are not yet understood. We found that anoctamin 1 (ANO1), a Ca<jats:sup>2+</jats:sup>-activated chloride channel, is a transduction channel mediating Mrgpr-dependent itch signals. Genetic ablation of <jats:italic toggle="yes">Ano1</jats:italic> in DRG neurons displayed a significant reduction in scratching behaviors in response to acute and chronic Mrgpr-dependent itch models and the epidermal hyperplasia induced by dry skin. In vivo Ca<jats:sup>2+</jats:sup> imaging and electrophysiological recording revealed that chloroquine and other agonists of Mrgprs excited DRG neurons via ANO1. More importantly, the overexpression of <jats:italic toggle="yes">Ano1</jats:italic> in DRG neurons of <jats:italic toggle="yes">Ano1</jats:italic>-deficient mice rescued the impaired itching observed in <jats:italic toggle="yes">Ano1</jats:italic>-deficient mice. These results demonstrate that ANO1 mediates the Mrgpr-dependent itch signaling in pruriceptors and provides clues to treating pathologic itch syndromes.</jats:p>
2019
Sanjel, Babina; Maeng, Han-Joo; Shim, Won-Sik
BAM8-22 and its receptor MRGPRX1 may attribute to cholestatic pruritus Journal Article
In: Sci Rep, vol. 9, no. 1, 2019, ISSN: 2045-2322.
Abstract | Links | BibTeX | Tags: Animal model, Calcium imaging, Cholestasis, Dorsal root ganglia, MrgprC11, MRGPRX1, Scratching behavior
@article{Sanjel2019,
title = {BAM8-22 and its receptor MRGPRX1 may attribute to cholestatic pruritus},
author = {Babina Sanjel and Han-Joo Maeng and Won-Sik Shim},
doi = {10.1038/s41598-019-47267-5},
issn = {2045-2322},
year = {2019},
date = {2019-12-00},
urldate = {2019-12-00},
journal = {Sci Rep},
volume = {9},
number = {1},
publisher = {Springer Science and Business Media LLC},
abstract = {Pruritus is an unexpected symptom observed in cholestasis and its mechanism is still unclear. Here, we show that bovine adrenal medulla (BAM) 8–22, an endogenous itch-inducing peptide, could be involved in cholestatic pruritus. It was found that bile duct ligation (BDL) mice, an obstructive cholestasis model, showed increased spontaneous scratching behaviour. Importantly, the mRNA level of proenkephalin, a precursor polypeptide of BAM8-22, was significantly increased in the skin of BDL mice. Furthermore, the mRNA level of Mrgprx1, which encodes a receptor for BAM8-22, was significantly increased in the dorsal root ganglia (DRG) of BDL mice. This was further confirmed by elevation of intracellular calcium levels upon BAM8-22 treatment in primarily-cultured DRG neurons. In addition, BDL mice showed augmented scratching behaviour by BAM8-22, indicating enhanced activity of MRGPRX1. Moreover, the skin homogenate of BDL mice induced elevation of intracellular calcium levels through MRGPRX1. Finally, among the various bile acids, chenodeoxycholic acid significantly increased proenkephalin transcription in a human keratinocyte cell line (HaCaT). In conclusion, cholestatic pruritus could be attributed in part to enhanced action of both BAM8-22 in the skin and its receptor MRGPRX1 in sensory neurons.},
keywords = {Animal model, Calcium imaging, Cholestasis, Dorsal root ganglia, MrgprC11, MRGPRX1, Scratching behavior},
pubstate = {published},
tppubtype = {article}
}
Pruritus is an unexpected symptom observed in cholestasis and its mechanism is still unclear. Here, we show that bovine adrenal medulla (BAM) 8–22, an endogenous itch-inducing peptide, could be involved in cholestatic pruritus. It was found that bile duct ligation (BDL) mice, an obstructive cholestasis model, showed increased spontaneous scratching behaviour. Importantly, the mRNA level of proenkephalin, a precursor polypeptide of BAM8-22, was significantly increased in the skin of BDL mice. Furthermore, the mRNA level of Mrgprx1, which encodes a receptor for BAM8-22, was significantly increased in the dorsal root ganglia (DRG) of BDL mice. This was further confirmed by elevation of intracellular calcium levels upon BAM8-22 treatment in primarily-cultured DRG neurons. In addition, BDL mice showed augmented scratching behaviour by BAM8-22, indicating enhanced activity of MRGPRX1. Moreover, the skin homogenate of BDL mice induced elevation of intracellular calcium levels through MRGPRX1. Finally, among the various bile acids, chenodeoxycholic acid significantly increased proenkephalin transcription in a human keratinocyte cell line (HaCaT). In conclusion, cholestatic pruritus could be attributed in part to enhanced action of both BAM8-22 in the skin and its receptor MRGPRX1 in sensory neurons.