Cav1.4 dysfunction and congenital stationary night blindness type 2

Alexandra Koschak,Marco Ruzza,Hartwig Seitter,Monica L Fernandez-Quintero,Lucia Zanetti,Thomas Heigl

doi:10.1007/s00424-021-02570-x

Alexandra Koschak, Marco Ruzza + Show 4 more

Open Access

https://doi.org/10.1007/s00424-021-02570-x

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Abstract

Cav1.4 L-type Ca2+ channels are predominantly expressed in retinal neurons, particularly at the photoreceptor terminals where they mediate sustained Ca2+ entry needed for continuous neurotransmitter release at their ribbon synapses. Cav1.4 channel gating properties are controlled by accessory subunits, associated regulatory proteins, and also alternative splicing. In humans, mutations in the CACNA1F gene encoding for Cav1.4 channels are associated with X-linked retinal disorders such as congenital stationary night blindness type 2. Mutations in the Cav1.4 protein result in a spectrum of altered functional channel activity. Several mouse models broadened our understanding of the role of Cav1.4 channels not only as Ca2+ source at retinal synapses but also as synaptic organizers. In this review, we highlight different structural and functional phenotypes of Cav1.4 mutations that might also occur in patients with congenital stationary night blindness type 2. A further important yet mostly neglected aspect that we discuss is the influence of alternative splicing on channel dysfunction. We conclude that currently available functional phenotyping strategies should be refined and summarize potential specific therapeutic options for patients carrying Cav1.4 mutations. Importantly, the development of new therapeutic approaches will permit a deeper understanding of not only the disease pathophysiology but also the physiological function of Cav1.4 channels in the retina.

Highlights

Cav1.4 L-type Ca2+ channels (LTCC, Cav1 family) are predominantly expressed in retinal neurons, at the photoreceptor terminals
Cav1.4 expression has further been reported in dorsal root
The gating properties of Cav1.4 channels [11, 53, 64] are perfectly suited to mediate sustained Ca2+ entry needed for continuous release of neurotransmitters at photoreceptor ribbon synapses in the dark [84, 102]

Summary

Introduction

Cav1.4 L-type Ca2+ channels (LTCC, Cav family) are predominantly expressed in retinal neurons, at the photoreceptor terminals. Photoreceptor membrane potential depolarizes (− 36 to − 40 mV) and thereby enhances tonic neurotransmitter (glutamate) release [24] For such tonic release, only a few channels that activate rapidly at relatively negative voltages (< − 40 mV, [10, 34, 101]) and inactivate slowly are needed [10]. Cav1.4 channels lack CDI due to active suppression by an inhibitory domain in their C-terminus [84, 102] This phenomenon is referred to as C-terminal modulation (CTM). CaM is important for Cav1.4 function because it increases current density and slows down VDI [32] in addition to its role as a specific channel-bound Ca2+ sensor that is tethered to upstream regions of the C-terminal tail such as the helical IQ domain adjacent to the so-called EF-hand motif (Fig. 1).

AID GK

Current density relative to WT

Functional characterization