Abstract
There are five mammalian stomatin-domain genes, all of which encode peripheral membrane proteins that can modulate ion channel function. Here we examined the ability of stomatin-like protein 1 (STOML1) to modulate the proton-sensitive members of the acid-sensing ion channel (ASIC) family. STOML1 profoundly inhibits ASIC1a, but has no effect on the splice variant ASIC1b. The inactivation time constant of ASIC3 is also accelerated by STOML1. We examined STOML1 null mutant mice with a β-galactosidase-neomycin cassette gene-trap reporter driven from the STOML1 gene locus, which indicated that STOML1 is expressed in at least 50% of dorsal root ganglion (DRG) neurones. Patch clamp recordings from mouse DRG neurones identified a trend for larger proton-gated currents in neurones lacking STOML1, which was due to a contribution of effects upon both transient and sustained currents, at different pH, a finding consistent with an endogenous inhibitory function for STOML1.
Highlights
Proteins of the stomatin family are characterised by an evolutionarily conserved core domain called the stomatin domain (Tavernarakis et al 1999; Lapatsina et al 2012a)
In this study we have shown that stomatin-like protein 1 (STOML1) largely resides in intracellular vesicles, but that a small proportion is present at the cell membrane where it modulates acid-sensing ion channel (ASIC) in a subunit-specific manner: ASIC1a and ASIC3 are modulated, but ASIC1b and ASIC2a are not
Using a STOML1−/– mouse, we show that STOML1 is expressed in approximately half of dorsal root ganglion (DRG) neurones and that when proton-gated currents are split into transient and sustained groups, a lack of STOML1 is associated with significantly larger sustained proton-gated currents at very low pH and larger transient currents under moderately acidic conditions
Summary
Proteins of the stomatin family are characterised by an evolutionarily conserved core domain called the stomatin domain (Tavernarakis et al 1999; Lapatsina et al 2012a). Stomatin domain-containing proteins are integral membrane proteins with a single membrane insertion domain and intracellular N and C termini; differences within the non-conserved C and N termini may underlie functional diversity of stomatin domain proteins. The crystal structure of the archaeobacterial stomatin core domain from Pyrococcus horikoshii showed that this stomatin domain can form trimeric homooligomers (Yokoyama et al 2008). Our X ray crystallographic and function studies on the mouse stomatin domain from stomatin indicated that this protein forms dimers (Brand et al 2012)
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