An Under-Explored Druggable Ion Channel

NEWS & ANALYSIS BIOBUSINESS BRIEFS TARGET WATCH cause the truncation of the TRIC-B protein, whereas a mutation in intron 3 causes the insertion of two amino acids after position 152, leading to loss of function of the TRIC-B: an under-explored TRIC-B protein. The crystal structure of TRIC-B channels from prokaryotes (Cell Res. 26, 1288–1301; druggable ion channel 2016) and Caenorhabditis elegans (Nature 538, 537–541; 2016) have been reported. Furthermore, the gating behaviour of The human genome encodes more than to intracellular Ca2+ release (Nature 448, TRIC- B has been characterized in detail, 200 pore- forming subunits of plasma 78–82; 2007). highlighting the role of a conserved lysine membrane ion channels, and various The TRIC family consists of two residue in controlling the conductance diseases (channelopathies) caused by members: TRIC-A (encoded by TMEM38A) properties of the TRIC- B complex in a Ca2+- mutations in these ion-conducting pore and TRIC-B (encoded by TMEM38B), dependent manner (Proc. Natl Acad. Sci. subunits or the proteins that interact which share 44% and 42% identity on USA 116, 4238–4243; 2019). with them have been identified. Here, the RNA and protein levels, respectively. we highlight the poorly studied trimeric TRIC-A and B are homotrimers that share Potential therapeutic opportunities intracellular cation (TRIC) channels, based biochemical functions but possess distinct TMEM38B is annotated as Tbio in the on their therapeutically relevant biological modes of regulation as well as expression Pharos database, reflecting the lack of functions and their druggability. We focus patterns. They both have higher affinity chemical probes for the TRIC-B protein, on TRIC- B because of its clear causal towards potassium over sodium, but TRIC-A despite the understanding of its structure relationship with osteogenesis imperfecta is predominantly expressed in excitable and biological function. So, the NIH (also known as brittle bone disease) cells such as muscle and is scattered in Illuminating the Druggable Genome (IDG) in humans. the sarcoplasmic reticulum membrane, initiative included TMEM38B on the list whereas TRIC- B is located in the ER of understudied ion channel genes in order Biological functions membrane of many cell types and tissues. to generate resources and probes that The channels that mediate the mobilization The TMEM38B gene is relatively conserved could lead to the development of selective of Ca2+ from intracellular stores during cell among eukaryotic species, sharing ~57–81% drug candidates targeting TRIC-B. signalling were cloned and characterized homology with lizard, chicken and mouse Phenotypic observations in humans and over 25 years ago. However, the molecular proteins, and some similarity with abundant mice suggest that conditions such as identity of the counter-channels remained but poorly characterized prokaryotic sclerosing bone dysplasia (overly thick a mystery for many years, until the counterparts. bones) and phospholipidosis (excess discovery in 2007 that TRIC channels Tmem38b- deficient mice exhibit accumulation of phospholipids) could regulate counter-movement of ions across multiple drastic phenotypes (Fig. 1), be improved by inhibition of TRIC-B. the sarcoplasmic/endoplasmic reticulum including ER swelling, impaired collagen Additionally, delivery of functional (ER) membrane to balance the transient release and poor bone ossification, TMEM38B using viral vectors could be negative membrane potential arising due highlighting the requirement of Tmem38b a potential curative approach for severe for Ca2+ balance in osteoblasts (Sci. Signal. 9, osteogenesis imperfecta. ra49; 2016). Additionally, Tmem38b is Zicheng Hu1,2 and Olga Gulyaeva3* TMEM38B phenotypes crucial for maintaining Ca2+ balance in 1Bakar Computational Health Sciences Institute, Mouse knockout the lung, where type II epithelial cells that University of California, San Francisco, San Francisco, CA, USA. • Poor bone ossiﬁcation lack Tmem38b fail to secrete sufficient 2Department of Pediatrics, University of California, • Impaired lung development surfactant phospholipids into the alveolar • Insuﬃcient surfactant San Francisco, San Francisco, CA, USA. phospholipid secretion space, leading to respiratory failure and 3Department of Microbiology and Immunology, • Neonatal lethality neonatal lethality (Development 136, UCSF Diabetes Center, University of California, 2355–2361; 2009). San Francisco, San Francisco, CA, USA. *e-mail: [email protected] Genetic studies in humans have found https://doi.org/10.1038/d41573-019-00131-7 that recessive mutations in TMEM38B Human mutations but not TMEM38A cause osteogenesis Acknowledgements This article is part of a series from the NIH Common Fund • Osteogenesis imperfecta, a rare genetic disorder Illuminating the Druggable Genome (IDG) programme. The imperfecta characterized by increased bone fragility, goal of IDG is to catalyse research on understudied proteins from druggable gene families by providing reagents, pheno- low bone mass and other connective tissue Fig. 1 | Potential human disease relevance types and a mineable database, focusing on G protein- manifestations (see Biol. Pharm. Bull. 39, coupled receptors, kinases and ion channels. For more of TRIC- B. Knockouts of Tmem38b, the gene information, see https://druggablegenome.net/. encoding the TRIC- B channel in mice, exhibit 1743–1747; 2016 for a review). Osteogenesis poor bone ossification, impaired lung imperfecta cases caused by TMEM38B Competing interests The authors declare no competing interests. development, insufficient surfactant mutation were first reported in individuals phospholipids secretion and neonatal lethality. in Arabia and later in Israeli Bedouin, Mutations of TMEM38B in humans can cause Albanian and Chinese populations. Most RELateD LINKS Pharos (TMEM38B): https://pharos.nih.gov/targets/Q9NVV0 osteogenesis imperfecta. of the recorded disease-causing mutations NATURE REVIEWS | DRUG DISCOVERY VOLUME 18 | SEPTEMBER 2019 | 657.

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