The role of syntaxins in retinal function and health

Abstract

The soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor (SNARE) superfamily plays a pivotal role in cellular trafficking by facilitating membrane fusion events. These SNARE proteins, including syntaxins, assemble into complexes that actively facilitate specific membrane fusion events. Syntaxins, as integral components of the SNARE complex, play a crucial role in initiating and regulating these fusion activities. While specific syntaxins have been extensively studied in various cellular processes, including neurotransmitter release, autophagy and endoplasmic reticulum (ER)-to-Golgi protein transport, their roles in the retina remain less explored. This review aims to enhance our understanding of syntaxins' functions in the retina by shedding light on how syntaxins mediate membrane fusion events unique to the retina. Additionally, we seek to establish a connection between syntaxin mutations and retinal diseases. By exploring the intricate interplay of syntaxins in retinal function and health, we aim to contribute to the broader comprehension of cellular trafficking in the context of retinal physiology and pathology.

Keywords: SNARE; retina; retinal disease; synapse; syntaxin.

Figure 1

(A) Domain structure common to all human Syntaxins identified thus far. NP: N-terminal peptide mediating interactions between SNARE complex and SM proteins like STXBP1 and Sec1. The three helices Ha, Hb, Hc form the regulatory H_abc domain, while TM represents the transmembrane domain. Created with BioRender.com. (B) IHC with two STX antibodies (STX3 detecting all four mouse STX3 isoforms, STX3B specific for isoform B). STX3B is exclusively expressed in the photoreceptor cells.

Figure 2

(A) The mouse Stx3 gene. The different exons included in the different STX3 isoforms are highlighted with colors. (B) Transcript (upper) and protein (lower) resulting from differential splicing of the Stx3 gene. Relation of exons to protein domains depicted by color choice. Asterisk highlights the stop codon, light grey region highlights start of translation. Domains: NP: N-terminal peptide; H_a, H_b and H_c: regulatory helices; SNARE: SNARE domain; TM: transmembrane domain, Designed based on Curtis et al. (2008). Created with BioRender.com.

Figure 3

Mislocalization of PRPH2 is evident in the STX3 conditional knockouts Stx3^f/f(iCre75) and Stx3^f/f(CRX-Cre). Dashed boxes in upper panels highlight the areas magnified in the lower panels. Mislocalization in IS is highlighted with arrows, while mislocalization in ONL is marked with arrowheads. OS, outer segment; IS, inner segment; ONL, outer nuclear layer; OPL, outerplexiform layer.

Figure 4

Scheme describing the hypothesized involvement of STX3B in the transport of PRPH2 and ROM1 towards the outersegment. STX3B mediates the merging of both conventional vesicles loaded with PRPH2 homotetramers and PRPH2/ROM1 heterotretramers, as well as unconvtional vesicles coming from the ER loaded exclusively with PRPH2 homotetramers with the photoreceptor membrane in the apical part of the inner segment. ER, endoplasmic reticulum.