Clarin-1 acts as a modulator of mechanotransduction activity and presynaptic ribbon assembly

Abstract

The Usher syndrome type 3–associated protein clarin-1 is functionally important for mechanotransduction channel activity and for proper localization of synaptic components in zebrafish hair cells.

Ribbon synapses in zebrafish hair cells

“…Larger and more numerous Ribeye puncta were also reported in zebrafish larvae in which clarin-1 was knocked down (Ogun and Zallocchi, 2014). In morpholino-injected fish, kinocilia were shorter and Pcdh15a was absent from hair bundles.…”

“…In morpholino-injected fish, kinocilia were shorter and Pcdh15a was absent from hair bundles. It is not clear how the lack of Clarin-1 could cause an affect on ribbons as Clarin-1 is most abundant near the kinocilium and was shown to interact with Pcdh15a (Ogun and Zallocchi, 2014). One potential mechanism is through calcium influx, that is, without Pcdh15a, which is essential for mechanotransduction and subsequent opening of Cav1.3a channels, one might expect an increase in the size of ribbons as seen in cav1.3a mutants.…”

Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

“…Additional roles for clarin-1 have also been sought, as mouse Clrn1 transcripts have been detected in both hair cells and the auditory primary neurons, from embryonic day 16 (E16) to adult stages (1,11). Clarin-1 has also been detected at the apical and basal synaptic poles of hair cells and photoreceptor cells in the zebrafish (9,12). The prolonged peak and interpeak latencies of auditory evoked brainstem responses in Clrn1 -/-mice lacking exon 1 suggest a delayed activation of auditory primary neurons and transmission along the central auditory pathway (7).…”

“…CLRN1 isoform 2 encodes a 232-amino acid tetraspan-like glycoprotein (1,4,6). Studies of mutant mice lacking exon 1 of Clrn1 (7,8) and knockdown approaches in zebrafish (9,10) have revealed structural and functional defects of F-actin-enriched stereocilia in hair cells. Additional roles for clarin-1 have also been sought, as mouse Clrn1 transcripts have been detected in both hair cells and the auditory primary neurons, from embryonic day 16 (E16) to adult stages (1,11).…”

Characterization of the Tetraspan Junctional Complex (4JC) superfamily

“…While Claudins and Occludins are known to be constituents of tight junctions, HCMC family members are mechanosensitive ion channels, while CCAγ proteins are believed to be auxiliary subunits of Ca 2+ channels. Clarin 1 is a component of the USH complex involved in mechanotransduction [59], responsible, when defective, for deaf-blindness [60]. It is the causative protein which when mutated gives rise to the human Usher syndrome type 3A [61].…”