Affinage

CACNA1F

Voltage-dependent L-type calcium channel subunit alpha-1F · UniProt O60840

Length
1977 aa
Mass
220.7 kDa
Annotated
2026-06-09
100 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CACNA1F encodes Cav1.4, an L-type voltage-gated calcium channel specialized for tonic calcium influx at photoreceptor ribbon synapses (PMID:14973233). Its defining biophysical signature is unusually slow voltage-dependent inactivation that is insensitive to calcium and to beta subunits, together with activation near -40 mV that generates a large window current poised to operate at photoreceptor resting potentials (PMID:14973233); single channels display very low open probability and a small (~4 pS) unitary conductance with sustained brief openings that account for the slow macroscopic inactivation (PMID:16085774), and the window current is preserved at physiological temperature to support continuous transmitter release (PMID:18206315). The slow inactivation arises from a C-terminal automodulatory/ICDI domain (encoded in part by exon 47) that suppresses Ca2+-dependent inactivation without displacing pre-associated calmodulin, while also producing a depolarizing shift in activation (PMID:19717559, PMID:27226626). This autoinhibition is relieved by CaBP4, which binds the IQ motif, shifts activation to hyperpolarized voltages and increases channel availability in an ICDI-dependent manner, with the Ca2+-bound CaBP4 structure collapsing around the IQ motif (Cav1.4 Y1595 critical) (PMID:15452577, PMID:22936811, PMID:25258313); PKA phosphorylation of the ICDI domain provides a second layer of regulation by increasing calmodulin occupancy and restoring Ca2+-dependent inactivation (PMID:27456671). Native channels assemble with auxiliary beta2 (including the beta2X13 variant) and alpha2delta4 subunits, and active-zone scaffolds RIM1/2 enhance Ca2+ influx and evoked vesicle release without changing channel localization (PMID:25468907, PMID:26400943). Beyond its conductance role, Cav1.4 is a structural organizer of photoreceptor ribbon synapses: its loss abolishes the ERG b-wave, eliminates ribbon synapses and causes aberrant bipolar/horizontal cell sprouting, and re-introduction of Cav1.4 is necessary and sufficient to rescue synaptic development even in adult retina, with ribbons reciprocally stabilizing Cav1.4/RIM2 clusters (PMID:16155113, PMID:32249787, PMID:31335952). CACNA1F mutations cause X-linked congenital stationary night blindness type 2, acting through a spectrum of loss-of-function (absent current despite membrane targeting, reduced or temperature-dependent expression, increased turnover, gating-charge neutralization) and gain-of-function (hyperpolarizing activation shifts) mechanisms (PMID:15897456, PMID:17949918, PMID:16476079, PMID:24796500, PMID:36943941).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2004 High

    Established the defining biophysical identity of Cav1.4 as an L-type channel with calcium- and beta-independent slow inactivation and a large window current suited to photoreceptor resting potentials, explaining how a calcium channel could support tonic signaling.

    Evidence Whole-cell patch clamp of heterologously expressed human Cav1.4 with CSNB2 mutations in HEK cells

    PMID:14973233

    Open questions at the time
    • Did not resolve the molecular basis of slow inactivation
    • Native subunit composition not addressed
  2. 2004 High

    Identified CaBP4 as a direct C-terminal binding partner that hyperpolarizes Cav1.4 activation and whose loss phenocopies CSNB2, linking channel modulation to disease.

    Evidence Co-IP/binding assay, electrophysiology in transfected cells, and Cabp4 knockout mouse ERG/immunocytochemistry

    PMID:15452577

    Open questions at the time
    • Binding site on Cav1.4 not yet mapped
    • Mechanism relative to autoinhibition unknown
  3. 2005 High

    Resolved the single-channel basis of slow macroscopic inactivation, showing very low open probability and small unitary conductance with sustained brief openings.

    Evidence Cell-attached single-channel recordings in tsA-201 cells with barium and kinetic analysis

    PMID:16085774

    Open questions at the time
    • Structural determinant of low conductance not identified
    • Native-tissue confirmation absent
  4. 2005 High

    Demonstrated in vivo that Cav1.4 is essential for assembly and maintenance of photoreceptor ribbon synapses, not merely for synaptic calcium signaling, by showing ribbon loss and aberrant neurite sprouting in knockouts.

    Evidence Targeted Cacna1f knockout mouse with ERG, calcium imaging in retinal slices, and immunocytochemistry

    PMID:16155113

    Open questions at the time
    • Whether the structural role requires channel conductance was not separated from expression
    • Molecular pathway from channel to ribbon assembly unknown
  5. 2005 High

    Defined gain-of-function as one disease mechanism by showing a CSNB2 mutation that hyperpolarizes activation and slows inactivation.

    Evidence Heterologous expression and whole-cell/voltage-clamp gating analysis of I745T

    PMID:15897456

    Open questions at the time
    • In vivo consequence of the gating shift not tested here
    • Did not address other mutation classes
  6. 2006 High

    Revealed a distinct disease mechanism in which mutations alter channel protein expression density rather than gating, in a temperature-dependent manner.

    Evidence Heterologous expression in oocytes and tsA-201 cells with patch clamp, Western blot, and temperature-dependent assays of R508Q/L1364H

    PMID:16476079

    Open questions at the time
    • Trafficking/folding pathway affected not defined
    • Relevance to native photoreceptor expression untested
  7. 2007 High

    Broadened the mutational spectrum by showing membrane-targeted but current-null loss-of-function and gating-shift gain-of-function alleles can coexist in CSNB2.

    Evidence Whole-cell patch clamp and Western blot of G1007R, R1049W and F742C in HEK tsA-201 cells

    PMID:17949918

    Open questions at the time
    • Why membrane-resident mutants conduct no current is unexplained
    • No structural model of affected residues
  8. 2008 Medium

    Showed that temperature strongly tunes Cav1.4 gating yet preserves the window current near physiological temperature, reconciling biophysics with tonic photoreceptor release.

    Evidence Whole-cell patch clamp of human Cav1.4 across 23-37C compared to Cav1.2

    PMID:18206315

    Open questions at the time
    • Single method, single lab
    • No native-tissue validation of preserved window current
  9. 2008 Medium

    Identified an N-terminal filamin-binding function lost in the nob2 splice variant, hinting at a cytoskeletal anchoring role for Cav1.4.

    Evidence Biochemical pulldown of wild-type vs spliced N-terminus with filamins plus cloning and electrophysiology

    PMID:18596967

    Open questions at the time
    • Single binding assay without reciprocal validation
    • Functional consequence of filamin binding in vivo not established
  10. 2009 High

    Pinpointed the C-terminal ICDI domain as the element that abolishes Ca2+-dependent inactivation without displacing pre-associated calmodulin, mechanistically explaining slow inactivation.

    Evidence FRET, whole-cell patch clamp, and ICDI deletion constructs

    PMID:19717559

    Open questions at the time
    • Atomic structure of the ICDI-CaM-IQ interaction not resolved
    • Regulation of ICDI engagement not addressed
  11. 2012 High

    Showed mechanistically that CaBP4 increases channel availability by binding the IQ motif and relieving ICDI-mediated inhibition, and that disease CaBP4 mutants bind but fail to relieve it.

    Evidence Whole-cell patch clamp, FRET, and ICDI-deletion mutagenesis in heterologous cells

    PMID:22936811

    Open questions at the time
    • Structural basis of CaBP4-IQ engagement not yet defined
    • Native-tissue stoichiometry unknown
  12. 2014 High

    Provided the structural model of CaBP4-Cav1.4 engagement, showing Ca2+-bound CaBP4 collapses around the IQ motif via defined contact residues and that Cav1.4 Y1595 is required.

    Evidence NMR structures of CaBP4 in Mg2+/Ca2+ states with IQ-motif Y1595E mutagenesis binding assay

    PMID:25258313

    Open questions at the time
    • No full-length channel-CaBP4 complex structure
    • Dynamics of CaM/CaBP4 exchange not resolved
  13. 2014 High

    Defined the native retinal channel as a Cav1.4/beta2(beta2X13)/alpha2delta4 complex and showed these specific auxiliary subunits tune activation and inactivation.

    Evidence Co-IP from HEK293 and mouse retina, proximity ligation assays, and patch clamp of defined subunit combinations

    PMID:25468907

    Open questions at the time
    • Stoichiometry of native complex not quantified
    • How subunits influence the structural synaptic role untested
  14. 2014 High

    Distinguished mechanistically distinct disease alleles, including reduced surface channel number with increased turnover and a C-terminal truncation that gains function biophysically but loses tonic Ca2+ influx by unmasking CDI.

    Evidence Whole-cell/single-channel patch clamp, gating current, noise analysis, and turnover assays of L860P and R1827X

    PMID:24796500

    Open questions at the time
    • In vivo synaptic consequences not tested
    • Trafficking machinery responsible for turnover unidentified
  15. 2015 High

    Established RIM1/2 as active-zone regulators that potently enhance Cav1.4 Ca2+ influx and are required for evoked vesicle release without affecting channel localization.

    Evidence Conditional RIM1/2 double knockout in rods with voltage clamp, capacitance measurements, and immunocytochemistry

    PMID:26400943

    Open questions at the time
    • Direct physical RIM-Cav1.4 interaction interface not mapped here
    • Mechanism of current enhancement vs release coupling not separated
  16. 2016 High

    Mapped exon 47 to the C-terminal automodulatory domain, showing it suppresses CDI, shifts activation positive, and is required for CaBP4-mediated modulation of activation.

    Evidence Patch clamp of splice-variant constructs with CaBP4 co-expression and retinal RT-PCR

    PMID:27226626

    Open questions at the time
    • Relative abundance of splice variants in vivo not quantified
    • Regulation of splicing unknown
  17. 2016 High

    Identified PKA phosphorylation of the ICDI domain as a regulatory switch that increases CaM occupancy and restores Ca2+-dependent inactivation, transferable to other Cav1 subtypes.

    Evidence Patch clamp with PKA modulation, CaM FRET, and ICDI domain-swap experiments

    PMID:27456671

    Open questions at the time
    • Phosphorylation site(s) not pinpointed
    • Physiological signaling context in photoreceptors untested
  18. 2016 Medium

    Showed in a gain-of-function mouse that altered Cav1.4 activity disrupts retinal circuit function, causes photoreceptor degeneration, and changes synaptic marker expression with compensatory calcium-handling changes.

    Evidence Multielectrode array recordings, immunohistochemistry, and optokinetic testing in Cav1.4-IT mice

    PMID:26274509

    Open questions at the time
    • Causal chain from gating shift to degeneration not dissected
    • Single model, single lab
  19. 2016 Medium

    Implicated Cav1.4-mediated Ca2+ influx as a contributor to calpain-dependent photoreceptor death by showing its deletion reduces calpain activation in degenerating retina.

    Evidence Cacna1f x rd1 double-mutant mouse with OCT, TUNEL, and calpain activity assays

    PMID:27270916

    Open questions at the time
    • Only short-term preservation shown
    • Generalizability beyond rd1 degeneration unknown
  20. 2019 Medium

    Demonstrated that Cav1.4 expression is necessary and sufficient for rod synaptic terminal development with persisting plasticity in adult retina, though clustered localization requires developmental context.

    Evidence In vivo electroporation and tamoxifen-inducible re-expression in KO rods with immunohistochemistry and behavioral testing

    PMID:31335952

    Open questions at the time
    • Why mature induction yields diffuse rather than clustered channels unexplained
    • Functional restoration of vision incompletely characterized
  21. 2020 Medium

    Showed reciprocity in synaptic organization: ribbons stabilize and dark-adaptation enriches Cav1.4/RIM2 clusters at active zones.

    Evidence RIBEYE knockout mice with quantitative immunofluorescence and dark/light adaptation paradigms

    PMID:32249787

    Open questions at the time
    • Morphological endpoint without electrophysiological validation
    • Molecular mechanism of ribbon-dependent stabilization unknown
  22. 2023 Medium

    Proposed gating-charge neutralization as a disease mechanism in which voltage-sensor mutations reduce expression and gating currents and may generate pathological omega currents.

    Evidence Whole-cell/single-channel patch clamp, gating currents, and molecular dynamics simulations of R964G and R1288L

    PMID:36943941

    Open questions at the time
    • Omega currents inferred from simulation, not directly measured
    • In vivo consequence untested
  23. 2026 High

    Identified Cav3 antagonists as Cav1.4 inhibitors and mapped a DHP-site residue (M1004) critical for ML218 potency, providing pharmacological tools and binding-site insight.

    Evidence Patch clamp of Cav1.4/beta2x13/alpha2delta4 in HEK293T cells with structure-based modeling and M1004/T1007 mutagenesis

    PMID:41489546

    Open questions at the time
    • Therapeutic relevance in retina not tested
    • No experimental structure of the drug-bound channel

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Cav1.4 expression mechanistically drives ribbon synapse assembly — and whether this structural role is separable from ion conduction — remains unresolved.
  • No molecular pathway linking Cav1.4 to ribbon scaffold assembly
  • Conduction-independent structural role not directly tested
  • No atomic-resolution structure of the native channel complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0005198 structural molecule activity 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-112316 Neuronal System 2 R-HSA-162582 Signal Transduction 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
CABP4CACNA2D4CACNB2CALM1FLNARIBEYERIM1RIM2
Complex memberships
Cav1.4/beta2/alpha2delta4 channel complexphotoreceptor ribbon synapse active zone

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 CACNA1F encodes an L-type (dihydropyridine-sensitive) calcium channel (Cav1.4) with unusually slow voltage-dependent inactivation kinetics that are not affected by calcium ions or by coexpression of ancillary beta subunits; the channel supports a large window current and activates near -40 mV in 2 mM external calcium, making it suited for tonic calcium influx at photoreceptor resting potentials. Whole-cell patch clamp of transiently expressed human Cav1.4 in HEK cells; pharmacological profiling; introduction of CSNB2 missense mutations The Journal of neuroscience High 14973233
2005 Single Cav1.4 channels have an extremely low open probability (<0.015) and a unitary conductance of ~4 pS (compared to ~20 pS for Cav1.2), with brief but sustained openings throughout depolarization accounting for the slow whole-cell inactivation; BayK8644 increases open time constant ~45% without introducing an additional gating mode. Cell-attached patch single-channel recordings in tsA-201 cells with 100 mM barium as charge carrier; kinetic analysis; comparison to Cav1.2 Biophysical journal High 16085774
2004 CaBP4 directly associates with the C-terminal domain of the Cav1.4 alpha1-subunit and shifts the activation of Cav1.4 to hyperpolarized voltages in transfected cells; CaBP4 is specifically expressed in photoreceptor synaptic terminals and its loss phenocopies CSNB2. Co-immunoprecipitation / direct binding assay with Cav1.4 C-terminal domain; electrophysiology in transfected cells; Cabp4 knockout mouse with ERG and immunocytochemistry Nature neuroscience High 15452577
2012 CaBP4 increases Cav1.4 channel availability by interacting with the IQ motif of Cav1.4 and relieving the inhibitory effects of the C-terminal ICDI (inhibitor of Ca2+-dependent inactivation) domain on voltage-dependent gating; this effect requires the ICDI domain and is absent in an ICDI-deletion mutant. Disease-associated CaBP4 mutants interact with Cav1.4 but show reduced functional effects, leading to loss of channel availability. Whole-cell patch clamp of heterologously expressed Cav1.4; FRET experiments with fluorescent-protein-tagged constructs; site-directed mutagenesis of ICDI domain The Journal of biological chemistry High 22936811
2009 Calmodulin is pre-associated with the C-terminus of Cav1.4 (shown by FRET) and increases current density and slows voltage-dependent inactivation; the ICDI domain selectively abolishes Ca2+-dependent inactivation without displacing calmodulin or interfering with other calmodulin effects. FRET with cyan fluorescent protein variants; whole-cell patch clamp; ICDI deletion constructs The Journal of biological chemistry High 19717559
2014 NMR structures of CaBP4 in Mg2+- and Ca2+-bound states show that Ca2+-bound CaBP4 exposes residues (Phe137, Glu168, Leu207, Phe214, Met251, Phe264, Leu268) that contact the IQ motif in Cav1.4; the Cav1.4 mutant Y1595E strongly impairs CaBP4 binding, supporting a model in which CaBP4 forms a collapsed structure around the IQ motif to promote channel activation. NMR structure determination; mutational analysis of Cav1.4 IQ motif (Y1595E) with binding assay The Journal of biological chemistry High 25258313
2014 Native retinal Cav1.4 channel complexes comprise the Cav1.4 alpha1 subunit, beta2 (including a novel variant beta2X13), and alpha2delta4; co-immunoprecipitation from transfected HEK293 cells and mouse retina confirmed these interactions. Alpha2delta4 confers weaker voltage-dependent activation than alpha2delta1; beta2X13 (vs. beta2a) produces greater voltage-dependent inactivation specifically in Cav1.4 but not Cav1.2. Co-immunoprecipitation from HEK293 cells and mouse retina; proximity ligation assays in retina; whole-cell patch clamp of defined subunit combinations The Journal of biological chemistry High 25468907
2016 Exon 47 of CACNA1F encodes part of the C-terminal automodulatory domain (CTM) that suppresses Ca2+-dependent inactivation (CDI) and causes a positive shift in voltage-dependent activation; splice variants lacking exon 47 show intense CDI and activate at more hyperpolarized voltages. CaBP4 suppresses CDI of exon-47-lacking variants but does not shift their voltage-dependent activation, indicating exon 47 is necessary for CaBP4-mediated modulation of activation. Electrophysiology (whole-cell patch clamp) of splice variant constructs expressed in HEK cells; CaBP4 co-expression; RT-PCR of human/primate retina The Journal of biological chemistry High 27226626
2016 PKA phosphorylation of the ICDI motif of Cav1.4 increases calmodulin occupancy on the channel, thereby increasing channel open probability and enabling Ca2+-dependent inactivation; introduction of the Cav1.4 ICDI into Cav1.3 or Cav1.2 transfers this PKA-modulation mechanism. Whole-cell patch clamp; PKA activation/inhibition; calmodulin FRET binding assay; domain swap experiments between Cav subtypes Nature communications High 27456671
2005 A missense mutation I745T in transmembrane segment IIS6 of CACNA1F causes a ~-30 mV shift in the voltage dependence of Cav1.4 channel activation (gain-of-function) and significantly slower inactivation kinetics, demonstrating that altered gating underlies this CSNB2-variant retinal disorder. Heterologous expression in Xenopus oocytes or mammalian cells; whole-cell patch clamp; voltage-clamp analysis of gating Proceedings of the National Academy of Sciences of the United States of America High 15897456
2005 Cacna1f knockout mice show 90% less peak calcium signal at photoreceptor synapses (by Fluo-4 calcium imaging), absence of post-receptoral ERG b-wave, profound loss of photoreceptor ribbon synapses, and abnormal dendritic sprouting of bipolar and horizontal cells into the outer nuclear layer, establishing Cav1.4 as essential for functional assembly and maintenance of photoreceptor ribbon synapses. Targeted Cacna1f knockout mouse (Cre-lox insertion in exon 7); ERG; calcium imaging in retinal slices; immunocytochemistry Human molecular genetics High 16155113
2015 Active-zone proteins RIM1 and RIM2 potently enhance Ca2+ influx through Cav1.4 channels in rod photoreceptor terminals; conditional double knockout of RIM1/2 from rods causes profound reduction in Ca2+ currents and ~4-fold reduction in spontaneous miniature release, and near-complete absence of evoked vesicle release, without altering Cav1.4 protein expression or localization at ribbons. Conditional double knockout of RIM1/2 in rods; whole-cell voltage clamp of isolated rods; membrane capacitance measurements; immunocytochemistry The Journal of neuroscience High 26400943
2020 Synaptic ribbons are required to stabilize Cav1.4/RIM2 clusters at rod photoreceptor active zones and are necessary for darkness-induced enrichment of Cav1.4/RIM2 at active zones; ribbon length and Cav1.4/RIM2 cluster length are tightly correlated, and both increase during dark adaptation. RIBEYE knockout mice (ribbon-deficient); immunofluorescence quantification of Cav1.4/RIM2 cluster length; dark/light adaptation paradigms Scientific reports Medium 32249787
2007 CSNB2 missense mutations G1007R and R1049W produce full-length Cav1.4 protein that targets to the membrane but supports no ionic current (loss-of-function); mutation F742C (S6 domain II) produces a ~21 mV hyperpolarizing shift in activation and inactivation (gain-of-function) with slower inactivation kinetics. Whole-cell patch clamp of mutant Cav1.4 transiently expressed in HEK tsA-201 cells; Western blot for protein expression Neuroscience High 17949918
2006 CSNB2 missense mutations R508Q and L1364H alter Cav1.4 protein expression density rather than channel gating; both mutations affect total alpha1 protein expression in a temperature-dependent manner in mammalian cells, providing a distinct pathological mechanism from gating alterations. Heterologous expression in Xenopus oocytes and tsA-201 cells; whole-cell patch clamp; Western blot for protein levels; temperature-dependent experiments Journal of neurochemistry High 16476079
2014 CSNB2 mutation L860P causes loss-of-function via reduced number of functional channels at the plasma membrane (confirmed by gating current and non-stationary noise analyses) associated with increased protein turnover; C-terminal truncation R1827X causes apparent gain-of-function (hyperpolarizing shift of IV-curve, increased single-channel activity) but also unmasks Ca2+-dependent inactivation by removing the C-terminal modulatory domain, thereby failing to support continuous Ca2+ influx. Whole-cell and single-channel patch clamp; gating current measurements; non-stationary noise analysis; protein turnover assays Biochimica et biophysica acta High 24796500
2007 Increasing temperature from 23°C to 37°C shifts Cav1.4 window current to more hyperpolarized voltages and accelerates inactivation ~50-fold (Q10=18.8), compared to only ~10-fold for Cav1.2, yet the window current is preserved at near-physiological temperatures, supporting tonic glutamate release from photoreceptors. Whole-cell patch clamp of human Cav1.4 cDNA at varying temperatures (23–37°C); comparison with Cav1.2 Neuroscience Medium 18206315
2008 The nob2 mouse Cav1.4 alternatively spliced N-terminus (from ETn insertion) fails to interact with cytoskeletal filamin proteins in a pulldown assay, whereas wild-type Cav1.4 N-terminus does interact with filamins, identifying an N-terminal filamin-binding function of Cav1.4. Biochemical pulldown assay; cloning and sequencing of alternatively spliced mRNA; Western blot; electrophysiology PloS one Medium 18596967
2019 Introduction of Cav alpha1F by in vivo electroporation into Cav1.4 knockout rod terminals rescues synaptic development markers (PSD-95 expression, elongated ribbons) even in adult animals; induced expression in mature rods also rescues ribbon formation but yields diffuse rather than clustered channel distribution, demonstrating that Cav1.4 expression is necessary and sufficient for rod synaptic terminal development and that this plasticity persists in adult retina. In vivo electroporation of Cav alpha1F into KO rods; tamoxifen-inducible expression system; immunohistochemistry for PSD-95 and ribbon markers; vision-guided water maze Investigative ophthalmology & visual science Medium 31335952
2016 In the Cav1.4-IT gain-of-function mouse retina, altered Cav1.4 activity leads to loss of contrast enhancement, reduced spatial response, changes in contrast sensitivity of ganglion cells, photoreceptor degeneration (nodular cone axons, enlarged pedicles), and reduced expression of mGluR6 and Connexin 36; plasma-membrane calcium ATPase 1 expression pattern is changed, suggesting a compensatory calcium homeostasis mechanism. Multielectrode array recordings from whole-mounted retinas; immunohistochemistry; optokinetic response testing Channels (Austin, Tex.) Medium 26274509
2016 Genetic deletion of Cav1.4 (Cacna1f) in rd1 mice reduces calpain activation during photoreceptor degeneration and provides short-term preservation of photoreceptors, establishing Cav1.4-mediated Ca2+ influx as a contributor to calpain-dependent photoreceptor cell death. Cacna1f x rd1 double mutant mouse; optical coherence tomography; TUNEL assay; calpain activity measurement PloS one Medium 27270916
2023 Gating charge neutralization mutations R964G and R1288L in Cav1.4 voltage sensor S4 segments reduce channel expression and ON gating currents; R1288L additionally reduces single-channel current amplitude; molecular dynamics simulations indicate R1288L creates water wires in both resting and active states, suggesting pathological omega (ω) currents as a disease mechanism. Whole-cell and single-channel patch clamp; gating current measurements; molecular dynamics simulations Channels (Austin, Tex.) Medium 36943941
2026 The CaV3 channel antagonists ML218 and Z944 inhibit Cav1.4 channels (IC50 ~2 µM and ~30 µM respectively); structure-based modeling and mutagenesis identified methionine M1004 within the DHP-binding site as critical for ML218 potency, with M1004 mutation having a 10-fold greater impact than the conserved threonine T1007 required for DHP sensitivity. Whole-cell patch clamp of HEK293T cells transfected with Cav1.4 + beta2x13 + alpha2delta-4; structure-based homology modeling; M1004 and T1007 mutagenesis The Journal of general physiology High 41489546

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Essential role of Ca2+-binding protein 4, a Cav1.4 channel regulator, in photoreceptor synaptic function. Nature neuroscience 245 15452577
2005 Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina. Human molecular genetics 214 16155113
2006 The nob2 mouse, a null mutation in Cacna1f: anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses. Visual neuroscience 174 16597347
2004 The CACNA1F gene encodes an L-type calcium channel with unique biophysical properties and tissue distribution. The Journal of neuroscience : the official journal of the Society for Neuroscience 160 14973233
1985 Advanced seminoma: treatment with cis-platinum-based combination chemotherapy or carboplatin (JM8). British journal of cancer 123 3893507
2005 A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation. Proceedings of the National Academy of Sciences of the United States of America 110 15897456
1987 Carboplatin (CBDCA, JM-8) and VP-16-213 in previously untreated patients with small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 99 2821197
1987 Carboplatin (Paraplatin; JM8) and etoposide (VP-16) as first-line combination therapy for small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 97 3027268
2006 X linked cone-rod dystrophy, CORDX3, is caused by a mutation in the CACNA1F gene. Journal of medical genetics 77 16505158
2001 A summary of 20 CACNA1F mutations identified in 36 families with incomplete X-linked congenital stationary night blindness, and characterization of splice variants. Human genetics 75 11281458
2000 Clinical variability among patients with incomplete X-linked congenital stationary night blindness and a founder mutation in CACNA1F. Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 73 10900517
2002 Thirty distinct CACNA1F mutations in 33 families with incomplete type of XLCSNB and Cacna1f expression profiling in mouse retina. European journal of human genetics : EJHG 68 12111638
2005 Clinical manifestations of a unique X-linked retinal disorder in a large New Zealand family with a novel mutation in CACNA1F, the gene responsible for CSNB2. Clinical & experimental ophthalmology 66 15807819
2013 Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2. Channels (Austin, Tex.) 53 24051672
2014 Characterization of Cav1.4 complexes (α11.4, β2, and α2δ4) in HEK293T cells and in the retina. The Journal of biological chemistry 52 25468907
2007 A novel CACNA1F gene mutation causes Aland Island eye disease. Investigative ophthalmology & visual science 51 17525176
1986 Ototoxicity of cisplatin vs. platinum analogs CBDCA (JM-8) and CHIP (JM-9). Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery 48 3086808
2015 RIM1/2-Mediated Facilitation of Cav1.4 Channel Opening Is Required for Ca2+-Stimulated Release in Mouse Rod Photoreceptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 46 26400943
2012 Complex regulation of voltage-dependent activation and inactivation properties of retinal voltage-gated Cav1.4 L-type Ca2+ channels by Ca2+-binding protein 4 (CaBP4). The Journal of biological chemistry 45 22936811
1995 Overproduction, purification, and biochemical characterization of a xylanase (Xys1) from Streptomyces halstedii JM8. Applied and environmental microbiology 43 7793962
2001 Novel CACNA1F mutations in Japanese patients with incomplete congenital stationary night blindness. Investigative ophthalmology & visual science 40 11381068
2013 Mosaic synaptopathy and functional defects in Cav1.4 heterozygous mice and human carriers of CSNB2. Human molecular genetics 39 24163243
2003 Retinal and optic disc atrophy associated with a CACNA1F mutation in a Japanese family. Archives of ophthalmology (Chicago, Ill. : 1960) 37 12860808
1985 Carboplatin (JM8) as a single agent and in combination in the treatment of small cell lung cancer. Cancer treatment reviews 37 3002624
2020 Synaptic ribbons foster active zone stability and illumination-dependent active zone enrichment of RIM2 and Cav1.4 in photoreceptor synapses. Scientific reports 34 32249787
2005 Novel mutations in CACNA1F and NYX in Dutch families with X-linked congenital stationary night blindness. Molecular vision 34 15761389
2005 Cav1.4 encodes a calcium channel with low open probability and unitary conductance. Biophysical journal 34 16085774
2001 Expression of the genes coding for the xylanase Xys1 and the cellulase Cel1 from the straw-decomposing Streptomyces halstedii JM8 cloned into the amino-acid producer Brevibacterium lactofermentum ATCC13869. Archives of microbiology 34 11797049
2003 Mutations in the CACNA1F and NYX genes in British CSNBX families. Human mutation 32 12552565
1992 Cloning and nucleotide sequence of celA1, and endo-beta-1,4-glucanase-encoding gene from Streptomyces halstedii JM8. Journal of bacteriology 32 1400190
2013 A novel large in-frame deletion within the CACNA1F gene associates with a cone-rod dystrophy 3-like phenotype. PloS one 31 24124559
2016 Characterization of C-terminal Splice Variants of Cav1.4 Ca2+ Channels in Human Retina. The Journal of biological chemistry 30 27226626
2008 Modified Ca(v)1.4 expression in the Cacna1f(nob2) mouse due to alternative splicing of an ETn inserted in exon 2. PloS one 30 18596967
2007 Temperature dependence of Cav1.4 calcium channel gating. Neuroscience 30 18206315
2006 Effects of congenital stationary night blindness type 2 mutations R508Q and L1364H on Cav1.4 L-type Ca2+ channel function and expression. Journal of neurochemistry 30 16476079
1997 Analysis of xysA, a gene from Streptomyces halstedii JM8 that encodes a 45-kilodalton modular xylanase, Xys1. Applied and environmental microbiology 29 9251186
2011 A novel p.Gly603Arg mutation in CACNA1F causes Åland island eye disease and incomplete congenital stationary night blindness phenotypes in a family. Molecular vision 28 22194652
2007 Functional analysis of congenital stationary night blindness type-2 CACNA1F mutations F742C, G1007R, and R1049W. Neuroscience 28 17949918
2019 Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders. Human mutation 27 30825406
2010 Congenital stationary night blindness in mice - a tale of two Cacna1f mutants. Advances in experimental medicine and biology 27 20238058
2017 The importance of genetic testing as demonstrated by two cases of CACNA1F-associated retinal generation misdiagnosed as LCA. Molecular vision 26 29062221
2009 Calmodulin is a functional regulator of Cav1.4 L-type Ca2+ channels. The Journal of biological chemistry 26 19717559
2014 Spectrum of Cav1.4 dysfunction in congenital stationary night blindness type 2. Biochimica et biophysica acta 25 24796500
2016 Protein kinase A modulation of CaV1.4 calcium channels. Nature communications 23 27456671
2003 Posttranslational processing of the xylanase Xys1L from Streptomyces halstedii JM8 is carried out by secreted serine proteases. Microbiology (Reading, England) 23 12855715
2000 Isolation and characterization of a calcium channel gene, Cacna1f, the murine orthologue of the gene for incomplete X-linked congenital stationary night blindness. Genomics 23 10873387
2021 Cav1.4 dysfunction and congenital stationary night blindness type 2. Pflugers Archiv : European journal of physiology 21 34212239
2003 A novel CACNA1F mutation in a french family with the incomplete type of X-linked congenital stationary night blindness. American journal of ophthalmology 21 12719097
1997 Two genes encoding an endoglucanase and a cellulose-binding protein are clustered and co-regulated by a TTA codon in Streptomyces halstedii JM8. The Biochemical journal 21 9182697
2020 Using an integrative machine learning approach utilising homology modelling to clinically interpret genetic variants: CACNA1F as an exemplar. European journal of human genetics : EJHG 19 32313206
2015 Gain-of-function nature of Cav1.4 L-type calcium channels alters firing properties of mouse retinal ganglion cells. Channels (Austin, Tex.) 19 26274509
2018 Cone dystrophy and ectopic synaptogenesis in a Cacna1f loss of function model of congenital stationary night blindness (CSNB2A). Channels (Austin, Tex.) 16 29179637
2005 Identification of the sequences involved in the glucose-repressed transcription of the Streptomyces halstedii JM8 xysA promoter. Gene 16 15850758
2014 Structural insights into activation of the retinal L-type Ca²⁺ channel (Cav1.4) by Ca²⁺-binding protein 4 (CaBP4). The Journal of biological chemistry 15 25258313
1994 Differential scanning calorimetric study of the thermal stability of xylanase from Streptomyces halstedii JM8. Biochemistry 15 7947789
2021 Optic Atrophy and Inner Retinal Thinning in CACNA1F-related Congenital Stationary Night Blindness. Genes 14 33668843
2016 Cav1.4 L-Type Calcium Channels Contribute to Calpain Activation in Degenerating Photoreceptors of rd1 Mice. PloS one 14 27270916
2013 Visual signal pathway reorganization in the Cacna1f mutant rat model. Investigative ophthalmology & visual science 14 23425697
2008 A naturally-occurring mutation in Cacna1f in a rat model of congenital stationary night blindness. Molecular vision 14 18246026
2001 Construction of a xylanase-producing strain of Brevibacterium lactofermentum by stable integration of an engineered xysA gene from Streptomyces halstedii JM8. Applied and environmental microbiology 13 11722888
2021 A Novel Splice-Site Variant in CACNA1F Causes a Phenotype Synonymous with Åland Island Eye Disease and Incomplete Congenital Stationary Night Blindness. Genes 12 33513752
2018 Photoreceptor degeneration in a new Cacna1f mutant mouse model. Experimental eye research 11 30445045
2022 Two novel CACNA1F gene mutations cause two different phenotypes: Aland Eye Disease and incomplete Congenital Stationary Night Blindness. Experimental eye research 10 35697328
2019 Rescue of Rod Synapses by Induction of Cav Alpha 1F in the Mature Cav1.4 Knock-Out Mouse Retina. Investigative ophthalmology & visual science 10 31335952
2019 An Ashkenazi Jewish founder mutation in CACNA1F causes retinal phenotype in both hemizygous males and heterozygous female carriers. Ophthalmic genetics 10 31651202
2015 Identification of a novel heterozygous missense mutation in the CACNA1F gene in a chinese family with retinitis pigmentosa by next generation sequencing. BioMed research international 10 26075273
2012 Mutation screening of TRPM1, GRM6, NYX and CACNA1F genes in patients with congenital stationary night blindness. International journal of molecular medicine 10 22735794
1992 Quantitative ultrastructural effects of cisplatin (Platinol), carboplatin (JM8), and iproplatin (JM9) on neurons of freshwater snail Lymnaea stagnalis. Cancer research 10 1737358
1984 Cell survival in four ovarian carcinoma xenografts following in vitro exposure to melphalan, cisplatin and cis-diammine-1,1-cyclobutane dicarboxylate platinum II (CBDCA,JM8). Cancer chemotherapy and pharmacology 10 6380788
2018 Novel truncating mutation in CACNA1F in a young male patient diagnosed with optic atrophy. Ophthalmic genetics 9 30260717
2012 Behavioral phenotypic properties of a natural occurring rat model of congenital stationary night blindness with Cacna1f mutation. Journal of neurogenetics 9 22800190
2004 Single mutations of residues outside the active center of the xylanase Xys1 Delta from Streptomyces halstedii JM8 affect its activity. FEMS microbiology letters 8 15522513
1997 Effect of carbon source on the expression of celA1, a cellulase-encoding gene from Streptomyces halstedii JM8. FEMS microbiology letters 8 9252578
1988 Carboplatin (JM8), etoposide (VP16) and thoracic irradiation for small cell lung cancer (S.C.L.C.): an evaluation of lung toxicity. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 8 2841723
2020 Transgenic Expression of Cacna1f Rescues Vision and Retinal Morphology in a Mouse Model of Congenital Stationary Night Blindness 2A (CSNB2A). Translational vision science & technology 7 33117610
2015 Cacna1f gene decreased contractility of skeletal muscle in rat model with congenital stationary night blindness. Gene 7 25748727
2012 Comparison of male chimeric mice generated from microinjection of JM8.N4 embryonic stem cells into C57BL/6J and C57BL/6NTac blastocysts. Transgenic research 7 22422470
2022 Identification of a novel CACNA1F mutation in a Chinese family with CORDX3. Molecular genetics & genomic medicine 6 36165086
1988 Urinary protein and enzyme excretion in patients receiving chemotherapy with the cis-platinum analogs carboplatin (CBDCA, JM8) and iproplatin (CHIP, JM9). Cancer chemotherapy and pharmacology 5 3044631
1987 Comparative antitumour activity of cisplatin and two new cisplatin-analogues JM8 and JM9 in human testicular carcinoma xenografts. International journal of andrology 4 3034790
2022 A clinical and electrophysiological case study of a child with a novel frame shift mutation in the CACNA1F and missense variation of RIMS1 genes. Documenta ophthalmologica. Advances in ophthalmology 3 35947237
2022 Assessing the Pathogenicity of In-Frame CACNA1F Indel Variants Using Structural Modeling. The Journal of molecular diagnostics : JMD 3 36191840
2025 A New Phenotypic Expression in a Patient With a Mutation in the CACNA1F Gene. Cureus 2 40390739
2024 Aland Island Eye Disease with Retinoschisis in the Clinical Spectrum of CACNA1F-Associated Retinopathy-A Case Report. International journal of molecular sciences 2 38474172
2022 Optic nerve involvement in CACNA1F-related disease: observations from a multicentric case series. Ophthalmic genetics 2 36469668
2025 Ȧland Island eye disease in two patients harboring novel CACNA1F variants. Ophthalmic genetics 1 40400241
2025 Identification of a Novel Splice-Site Variant in CACNA1F With Variable Phenotypic Expression in a Chinese Family. Molecular genetics & genomic medicine 1 41381383
2024 Novel CACNA1F pathogenic variant in pediatric incomplete X-linked CSNB: integrating portable ERG and genetic analysis. Documenta ophthalmologica. Advances in ophthalmology 1 39652271
2024 Novel Splice-Altering Variants in the CHM and CACNA1F Genes Causative of X-Linked Choroideremia and Cone Dystrophy. Genes 1 39858572
2023 Characterization of two pathological gating-charge substitutions in Cav1.4 L-type calcium channels. Channels (Austin, Tex.) 1 36943941
2020 Diagnosis of an X-linked type 2 congenital stationary night blindness using electroretinography and CACNA1F sequencing. Archivos de la Sociedad Espanola de Oftalmologia 1 32680768
2015 Establishment and rapid detection of a heterozygous missense mutation in the CACNA1F gene by ARMS technique with double-base mismatched primers. Genetics and molecular research : GMR 1 26436388
2026 Inhibition of CaV1.4 channels by CaV3 channel antagonists ML218 and Z944. The Journal of general physiology 0 41489546
2026 Deletion in CACNA1F gene causes X-linked progressive retinal atrophy in English Cocker Spaniel dogs. BMC veterinary research 0 41882631
2026 Mutation Screening of ARR3, CACNA1F, P4HA2, TRPM1, COL2A1, COL11A1 and PAX6 in a Chinese Cohort of 37 Patients with Early-Onset High Myopia. Genes 0 42074509
2025 A Mutation in the CACNA1F Gene Found by Whole Exome Sequencing (WES) and In Silico Analysis in an Iranian Family with Consanguineous Relationships. Current aging science 0 38778612
2025 Exploring the potential for gene therapy in Cav1.4-related retinal channelopathies. Channels (Austin, Tex.) 0 40129245
2025 Whole exome sequencing reveals pathogenic variants in CNGA3, CACNA1F, and RPGRIP1 in consanguineous Pakistani families with diverse retinal phenotypes. PloS one 0 40737315
2025 Novel structural variant in CACNA1F causing congenital stationary night blindness identified with whole genome sequencing. Ophthalmic genetics 0 40744901
2025 Incomplete congenital stationary night blindness associated with a novel variant in the CACNA1F gene. Documenta ophthalmologica. Advances in ophthalmology 0 41201761

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