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Biophysical characterization of CaV1.4 L-type calcium channel mutants causing congenital stationary night blindness type 2 in humans


CaV1.4 L-type calcium channels show unique biophysical properties such as slow inactivation due to the lack of calcium-dependent inactivation (CDI). These properties make CaV1.4 channels appropriate candidates for triggering persistent glutamate release at retinal photoreceptor cell synapses. Mutations in the CACNA1F gene encoding for the CaV1.4 α1 subunit are described in patients with X-linked congenital stationary night blindness type 2 (CSNB2). Impaired transmission between rod photoreceptor cells and second-order neurons manifests as night blindness and various other visual symptoms in the affected individuals.


The aim of this study was to investigate the functional properties of CaV1.4 mutants L849P and R1816stop compared to wild-type (WT) in transiently transfected tsA 201 cells (+β3,+α2δ-1) via whole-cell patch clamp technique using 15 mM Ba2+ and Ca2+ as charge carrier. For statistics, either Mann-Whitney (two groups) or Kruskal-Wallis test and Dunn’s Post hoc test (multiple comparisons) were used.


L849P was mainly characterized by a reduced current density (pA/pF: WT: −16.3 ± 1.6 (n = 38), L849P: −2.5 ± 0.3 (n = 12), p < 0.0001; Ca2+), only minor, not significant (p > 0.05) changes in the voltage-dependent activation properties were observed. In presence of the dihydropyridin-activator BayK8644 (5 μM) the current density was increased ~10-fold (p < 0.001). The fold-increase in current density was comparable to WT. As expected R1816stop, which lacks an intrinsic C-terminal modulator (CTM), exhibited CDI (f-value: WT: 0.11 ± 0.03 (n = 8); R1816stop: 0.63 ± 0.02 (n = 22)) and shifted the voltage-dependence of activation to more negative voltages (V0.5act in mV: WT: 1.8 ± 0.3 (n = 74), R1816stop: −12.3 ± 0.3 (n = 23)). In presence of the CaV1.4-CTM; comprising the last 122 C-terminal residues WT conditions were fully restored, e.g. V0.5act 2.2 ± 1.0 mV (n = 14) (p < 0.0001).


We assume that the reduced current density observed in mutant L849P derives from decreased channel expression, which might be explained by a folding defect of the CaV1.4 channel protein rather than a reduced open probability. Moreover, the fact that the functional phenotype of the R1816stop can be rescued bears a potential pharmacotherapeutic concept based to the C-terminal modulatory mechanism present in CaV1.4 channels.


Financial support was given by the Austrian Science Fund (FWF, grant P22526 to A.K.).

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Correspondence to Alexandra Koschak.

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Klaus W Schicker, Verena Burtscher contributed equally to this work.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Schicker, K.W., Burtscher, V., Knoflach, D. et al. Biophysical characterization of CaV1.4 L-type calcium channel mutants causing congenital stationary night blindness type 2 in humans. BMC Pharmacol Toxicol 13 (Suppl 1), A69 (2012).

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