An evolutionarily conserved gene family encodes proton-selective ion channels

Abstract

Ion channels form the basis for cellular electrical signaling. Despite the scores of genetically identified ion channels selective for other monatomic ions, only one type of proton-selective ion channel has been found in eukaryotic cells. By comparative transcriptome analysis of mouse taste receptor cells, we identified Otopetrin1 (OTOP1), a protein required for development of gravity-sensing otoconia in the vestibular system, as forming a proton-selective ion channel. We found that murine OTOP1 is enriched in acid-detecting taste receptor cells and is required for their Zn2+-sensitive proton conductance. Two related murine genes, Otop2 and Otop3, and a Drosophila ortholog also encode proton channels. Evolutionary conservation of the gene family and its widespread tissue distribution suggest a broad role for proton channels in physiology and pathophysiology.

Differential Expression of Immune Related Genes in Taste Buds of Fed and Fasted Mice

“…Type II TRCs express different G-protein coupled receptors (GPCRs), which transduce sweet, bitter, and umami taste qualities (Adler et al 2000; Mueller et al 2005; Nelson et al 2002; Nelson et al 2001; Zhang et al 2003; Zhao et al 2003). The final cell type, Type III TRCs, detect sour tastants via cytoplasmic changes in pH (Huang et al 2008; Ishimaru et al 2006; Tu et al 2018). While many genetic and electrophysiological studies have been conducted on the gustatory system, substantially less data on the TRC transcriptome is available.…”

A subset of broadly responsive Type III taste cells contribute to the detection of bitter, sweet and umami stimuli

“…A separate study reported that Type III cells are heterogeneous and do not uniformly express the same cell markers (Courtney E Wilson, 2017), so it may be that the BR cells are separate from the PKD2L1 expressing Type III cells. Recently, OTOP1, which is expressed in Type III taste cells, has been proposed as the sour receptor (Teng, Wilson et al, 2019, Tu, Cooper et al, 2018, Zhang et al, 2019). Nerve recordings from OTOP1-KO mice were significantly reduced for sour stimuli but also showed some reduction in their responsiveness to bitter, sweet and umami (Teng et al, 2019).…”

Structures of the Otopetrin Proton Channels Otop1 and Otop3

“…Despite their broad roles in biology, knowledge of proton channels has lagged behind that of other types of ion channels. The recent characterization of Otopetrins, previously implicated in vestibular function 11,12 , provides impetus for investigations of this novel proton channel family 10…”

“…Because they were only recently characterized, the physiological roles of Otopetrins are just now beginning to be uncovered. Notably, Otop1 is required for proton currents in murine cells that detect sour taste and is a likely candidate for a sour taste receptor [4][5][6]10 . In addition, prior genetic studies identified Otop1 as the gene mutated in a spontaneously occurring vestibular disorder in mice and required in the vestibular system for normal otoconia development in mice 11 and zebrafish 12,13 .…”

“…Otop1 is also highly expressed in brown and white adipose tissue and plays a role in insulin resistance 14 . Otop2 and Otop3 have been detected in the digestive tract and elsewhere in the body 10,15 suggesting yet unappreciated roles for proton conduction in various cell types.…”