Abstract
L-type voltage-gated calcium channels (LTCCs) regulate tonic neurotransmitter release from sensory neurons including retinal photoreceptors. There are three types of LTCCs (Cav1.2, Cav1.3, and Cav1.4) expressed in the retina. While Cav1.2 is expressed in all retinal cells including the Müller glia and neurons, Cav1.3 and Cav1.4 are expressed in the retinal neurons with Cav1.4 exclusively expressed in the photoreceptor synaptic terminals. Mutations in the gene encoding Cav1.4 cause incomplete X-linked congenital stationary night blindness in humans. Even though Cav1.3 is present in the photoreceptor inner segments and the synaptic terminals in various vertebrate species, its role in vision is unclear, since genetic alterations in Cav1.3 are not associated with severe vision impairment in humans or in Cav1.3-null (Cav1.3−/−) mice. However, a failure to regulate Cav1.3 was found in a mouse model of Usher syndrome, the most common cause of combined deafness and blindness in humans, indicating that Cav1.3 may contribute to retinal function. In this report, we combined physiological and morphological data to demonstrate the role of Cav1.3 in retinal physiology and function that has been undervalued thus far. Through ex vivo and in vivo electroretinogram (ERG) recordings and immunohistochemical staining, we found that Cav1.3 plays a role in retinal light responses and synaptic plasticity. Pharmacological inhibition of Cav1.3 decreased ex vivo ERG a- and b-wave amplitudes. In Cav1.3−/− mice, their dark-adapted ERG a-, b-wave, and oscillatory potential amplitudes were significantly dampened, and implicit times were delayed compared to the wild type (WT). Furthermore, the density of ribbon synapses was reduced in the outer plexiform layer of Cav1.3−/− mice retinas. Hence, Cav1.3 plays a more prominent role in retinal physiology and function than previously reported.
Highlights
L-type voltage-gated calcium channels (LTCCs) are multi-subunit channel complexes composed of a pore-forming α1 subunit and auxiliary β and α2δ subunits
A caveat we faced was that the effectiveness of DIL on Cav1.2 vs. Cav1.3 was not compared in the same cell type or preparation in previous reports (Cai et al, 1997; Hockerman et al, 2000; Schnee and Ricci, 2003; Baumann et al, 2004; Tarabova et al, 2007; Bissig et al, 2013; Berkowitz et al, 2014)
We first set forth using HEK 293 cells transfected with Cav1.2 or Cav1.3 and recorded the LTCC currents to identify a concentration of DIL that would inhibit Cav1.2 without affecting Cav1.3
Summary
L-type voltage-gated calcium channels (LTCCs) are multi-subunit channel complexes composed of a pore-forming α1 subunit and auxiliary β and α2δ subunits. Cav1.4 is strongly expressed at the ribbon synapses (Morgans, 2001; Lee et al, 2015), and its function is the most well-characterized in the retina, since mutations in Cav1.4 cause X-linked incomplete congenital stationary night blindness type 2 (CSNB2) in humans (Bech-Hansen et al, 1998; Liu et al, 2013) This is due to the essential role of Cav1.4 in the formation of ribbon synapses between photoreceptor terminals and the second-order neurons during development (Liu et al, 2013). There are small residual inner retinal light responses recorded from CSNB2 patients (Miyake et al, 1986; Bradshaw et al, 2004) suggesting that there might be other LTCCα1 subunits present at the photoreceptor synaptic terminals to transmit light information to the inner retina
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