Tentonin 3/TMEM150C regulates glucose-stimulated insulin secretion in pancreatic b-cells

Jungwon Wee,1,4,5 Sungmin Pak,2,4,5 Tahnbee Kim,4 Gyu-Sang Hong,4 Ji Seon Lee,3 Jinyan Nan,3 Hyungsup Kim,4 Mi-Ock Lee,2 Kyong Soo Park,1,3,* and Uhtaek Oh1,4,6,*
1Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 03080, Korea

2College of Pharmacy, Seoul National University, Seoul 08826, Korea
3Department of Internal Medicine, College of Medicine, Seoul National University, Seoul 03080, Korea 4Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea 5These authors contributed equally
6Lead contact
*Correspondence: kspark@snu.ac.kr (K.S.P.), utoh@kist.re.kr (U.O.)

SUMMARY

Glucose homeostasis is initially regulated by the pancreatic hormone insulin. Glucose-stimulated insulin secretion in b-cells is composed of two cellular mechanisms: a high glucose concentration not only depolar- izes the membrane potential of the b-cells by ATP-sensitive K+ channels but also induces cell inflation, which is sufficient to release insulin granules. However, the molecular identity of the stretch-activated cation chan- nel responsible for the latter pathway remains unknown. Here, we demonstrate that Tentonin 3/TMEM150C (TTN3), a mechanosensitive channel, contributes to glucose-stimulated insulin secretion by mediating cation influx. TTN3 is expressed specifically in b-cells and mediates cation currents to glucose and hypotonic stim- ulations. The glucose-induced depolarization, firing activity, and Ca2+ influx of b-cells were significantly lower in Ttn3/ mice. More importantly, Ttn3/ mice show impaired glucose tolerance with decreased insulin secretion in vivo. We propose that TTN3, as a stretch-activated cation channel, contributes to glucose-stim- ulated insulin secretion.

A plant-derived TRPV3 inhibitor suppresses pain and itch

PUBLISHED IN:- JOURNAL OF BRITISH PHARMACOLOGY. DOI: 10.1111/BPH.15390

Abstract

Background and Purpose: Itching is the most frequent pathology in dermatology that has significant impacts on people’s mental health and social life. Transient receptor potential vanilloid 3 (TRPV3) channel is a promising target for treating pruritus. However, few selecetive and potent antagonists have been reported. This study was designed to identify selective TRPV3 antagonist and elucidate its anti-pruritus pharmacology.

Experimental Approach: FlexStation and calcium fluorescence imaging were conducted to track the functional compounds. Whole-cell patch clamp was used to record itch-related ion channel currents. Homologous recombination and site-directed mutagenesis were employed to construct TRPV3 channel chimeras and point mutations for exploring pharmacological mechanism. Mouse models were used for in vivo anti-pruritus assay.

Key Results: An acridone alkaloid (citrusinine-II) was purified and characterized from Atalantia monophylla. It directly interacts with Y564 within S4 helix of TRPV3 to selectively inhibit the channel with a half maximal inhibitory concentration (IC50) of 12.43 μM. Citrusinine-II showed potential efficacy to attenuate both chronic and acute itch. Intradermal administration of citrusinine-II (143 ng/skin site) nearly completely inhibited itch behaviours. It also shows significant analgesic effects. Little side effects of the compound are observed.

Conclusion and Implications: By acting as a selective and potent inhibitor of TRPV3 channel, citrusinine-II shows valuable therapeutic effects in pruritus animal models and is a promising candidate drug and/or lead molecule for the development of anti- pruritus drugs.

KEYWORDS: citrusinine-II, Inhibition, Itch, Pain, TRPV3