期刊
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
卷 473, 期 9, 页码 1437-1454出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00424-021-02570-x
关键词
Calcium channel; Cav1; 4; Channelopathy; Channel modulation; Retinal disease; Congenital stationary night blindness type 2
类别
资金
- University of Innsbruck
- Medical University of Innsbruck
- Austrian Science Fund [FWF P-32747, DOC 30, P-33566]
- Center of Molecular Biosciences Innsbruck
Cav1.4 L-type Ca2+ channels, predominantly expressed in retinal neurons, play an essential role in continuous neurotransmitter release at ribbon synapses. Mutations in the CACNA1F gene encoding these channels are associated with X-linked retinal disorders. Research has shown the significance of Cav1.4 channels in synaptic function at retinal neurons.
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.
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