Cav1.4
Description: calcium channel, voltage-dependent, L type, alpha 1F subunit Gene: Cacna1f Alias: cacna1f, cav1.4, ca1.4
Cav1.4, encoded by the gene cacna1f, is a calcium channel, voltage-dependent, L type, alpha 1F subunit. It is predominantly expressed in the rod and cone active zones of the retina and is responsible for visual signaling and retina architecture. Mutations of the channel are the cause of retinal disorders.
In humans, cacna1f , the gene which encodes Cav1.4, is composed of 48 exons located on the short arm of the X chromosome, in the major region 1, sub-band 1, further divided into the region 23. (Xp11.23). [2411]
cacna1f channel is highly susceptible to alternative splicing during RNA processing and numerous productive and non productive mRNA transcripts have been isolated.
Alternative splicing occurs in [2412]:
- Exon 1-3
- Exon 9, in a region in close proximity to the auxiliary beta subunit interaction site located in the I‑II linker of the channel
- Exon 31-34
| Species | NCBI accession | Length (nt) | |
|---|---|---|---|
| Human | NM_005183.4 | 6039 | |
| Mouse | NM_019582.2 | 6075 | |
| Rat | NM_053701.2 | 5976 |
The human Cav1.4 protein is composed of 1977 amino acids (aa) and has a molecular weight of 220 Kda
There exists a number of protein isoforms that arise from the translation of the aforementioned transcript variants as a result of alternative splicing.
Isoform with alternative splicing of exon 9 is theorized to lead to altered interactions of the channel with auxiliary beta subunits, though concrete experimental evidence has yet to be done.
Skipping of exons 31-34, occurs often in T-lymphocytes. This area encodes for most of the domain IVS3‑IVS5, deleting a portion of the reading frame for domain IV. It is thought that such a removal may render the channel voltage insensitive and thus does not carry out voltage-gating activity in these non neuronal cells. [2412]
Isoforms
Little research has been conducted on Post-Translational Modification (PTM) affecting Cav1.4.
There is some evidence on the effects of PKA phosphorylation within the inhibitor of Ca(2+)-dependent inactivation (ICDI) motif (discussed in Structure). Phosphorylation of this region promotes the occupancy of calmodulin on the channel, thus increasing channel open probability (PO) and Ca(2+)-dependent inactivation. [2413]
Like retinal L-type currents, Cav1.4 channels lack CDI after expression in HEK-293 cells32,33,34. This finding is surprising given the very high structural conservation of Cav1.4 within the C-terminal regions mediating CaM-dependent CDI. Ca(v)1.4 L-type voltage-gated Ca2+ channels (LTCCs) are found at high densities in photoreceptor terminals, and alpha1 subunit mutations cause human congenital stationary night blindness type-2 (CSNB2). Ca(v)1.4 voltage-dependent inactivation is slow and Ca2+-dependent inactivation (CDI) is absent. We show that removal of the last 55 or 122 (C122) C-terminal amino acid residues of the human alpha1 subunit restores calmodulin-dependent CDI and shifts voltage of half-maximal activation to more negative potentials. The C terminus must therefore form part of a mechanism that prevents calmodulin-dependent CDI of Ca(v)1.4 and controls voltage-dependent activation. [2414]
The calcium channel β subunit binding region in the domain I-II linker region of all high-threshold calcium channels is also conserved in Cav1.4. However, the I-II linker contains an additional 29 amino acids, and the remainder of the I-II linker sequence diverges considerably from that of other types of HVA calcium channels, both of which may affect β subunit interaction. [233]
Cav1.4 predicted AlphaFold size
Methodology for AlphaFold size prediction and disclaimer are available here
Cav1.4, along with other L-type channels, has 3 broadly-defined gating modes [2362]:
- Mode 0: the closed state of the channel
- Mode 1: brief ~1 ms opening
- Mode 2: longer opening duration due to strong depolarisation or interaction with other actors
Each of CaV1.4's four voltage sensors play a different role in the kinetics of the channel: one (VSD-I) is crucial for CaV1.4 activation, while the others (VSD-II, VSD-III, VSD-IV) trigger calcium release more rapidly. [2365]
Cav1.4 channels activate at relatively negative potentials and have unusually slow voltage-dependent inactivation, regardless of the type of calcium channel β subunit coexpressed. This, combined with a large window current, makes Cav1.4 channels well-suited for maintaining tonic release at photoreceptor synapses. [233]
Single channel unitary conductance
The single channel unitary conductance of Cav1.4 has not yet been determined.
Models
There are currently no genetic ion channel models available
Cav1.4 is found expressed in both the CNS and PNS but is predominantly expressed within the rod and cone active zones of the retina, particularly in the synapses of the outer and inner plexiform layer as well as on photoreceptor cell bodies [1226] [2411]
However, the channel is not restricted to photoreceptor synapses and has been identified in other areas such as: in other neurons such as dorsal root ganglia [1226]
- Hippocampus
- Cerebellum [2415]
- Spleen
- Thymus
- Adrenal gland
- Spinal cord
- Bone marrow
- Skeletal muscle [233]
Moreover, Cav1.4 appears to be present at high levels in plasma cells and mast cells, suggesting a potential role of Cav1.4 in mediating immune responses. [233]
Within the retina neuronal cells, Cav1.4 channels are primarily located in the presynaptic regions of photoreceptor synapses. [2415]
Visual signaling & retina architecture
Given its predominant expression in cells of the retina, Cav1.4 plays a crucial role in the the proper processing of visual information. Cav1.4 mediates the entry of calcium ions into excitable retinal cells. This in turn, allows for signaling to second-order retinal neurons through the mediated release of photoreceptor neurotransmitters. [2415] [2416]
In addition to voltage sensitivity, Cav1.4 is essential for the molecular assembly of rod synapses and the maintenance of scaffolding proteins in the ribbon synapse [2416] [2417]
Hormone secretion
Interestingly, the slow inactivation kinetics of Cav1.4 would make this channel an ideal candidate for supporting hormone secretion, similar to what has been suggested for Cav1.3 channels in insulin-secreting cells. The presence of Cav1.4 in the adrenal gland and thymus may be consistent with such a role. [233]
Channelopathies
Retinal disorders
Mutations in the gene encoding Cav 1.4, CACNA1F, are associated with visual disorders. Most notable are cacna1f mutations that cause incomplete X-linked congenital stationary night blindness (CSNB2), affecting retinal neurotransmission [2418] [2419]. CSNB2 mutations cause complete or partial loss of Cav1.4 function by altering voltage-dependent gating, channel expression or both [2416]
CACNA1F gene may also be responsible for high myopia. Pathogenic variants in the CACNA1F gene, generally associated with retinal dystrophy, were identified among the genetic causes of high myopia in the patient population. [2420] [2421]
Other pathologies were also shown to display mutations in CACNA1F, the direct involvement of the gene to the disease is less evident. These include [2415]:
- ID/GDD
- Epilepsy
- Autism
- Spastic quadriplegia
- Cortical blindness
- Lebers congenital amaurosis
- Klinefelter syndrome
- Retinitis pigmentosa
- Congenital nystagmus
- Rod cone dystrophy
- Testicular cancer [2422]*
Auxiliary Subunits
Cav1.2 channels typically exist as multi-subunit complexes comprised of the main pore-forming α1 subunit, as previously described, and auxiliary subunits α2δ-2, β2 subunits:
- In rods, α2δ4 is crucial for organizing synaptic ribbons and setting CaV1.4 voltage sensitivity. In cones, α2δ4 is essential for CaV1.4 function, but is not required for ribbon organization, synaptogenesis, or synaptic transmission. [2423]
- α2δ4 exhibit weaker voltage dependence of activation than with α2δ1 [2424]
Dihydropyridines
Cav1.4 is blocked by Dihydropyridines (isradipine and nifedipine), phenylalkylamines (verapamil), and benzothiazepines (diltiazem) [2395] However, DHP sensitivity of Cav1.4 was significantly lower (∼15-fold) than that Cav1.2 at negative holding potentials. Cav1.4 current inhibition by DHP is highly voltage dependent. Therefore, the low apparent affinity of Cav1.4 in comparison with Cav1.2 is likely to be attributable to differences in the voltage-dependent interaction of the DHP antagonists [1226]
Calcium Dependent Inhibition
Interestingly, within its predominant location in the retinal, Cav1.4 does not display calcium dependant inactivation, despite the presence of Calmodulin (CaM) and its binding to the channel. Within these tissues, certain long splice variants of CaV1.4 channels contain a CDI-inhibiting module (inhibitor of CDI, ICDI) within their distal C terminus18 (DCT), which competes with apoCaM (free calmodulin) for binding at the IQ domain. By dislodging CaM, ICDI profoundly suppresses the channel PO and eliminates CDI [2413]
Other proteins
CABP4, a member of the calcium-binding protein (CABP) family, is located in photoreceptor synaptic terminals and is directly associated with the C-terminal domain of the Cav1.4 alpha CABP4 shifted the activation of Ca(v)1.4 to hyperpolarized voltages. Mice lacking either Cabp4 or Cav1.4 alpha display a CSNB2-like phenotype. [2425]
RIM1/2 proteins regulate Cav1.4 channel function in mouse rod photoreceptors. Conditional double knock-out (cdko) of RIM1/2 in rods did not affect Cav1.4 expression or ribbon morphology, but significantly reduced Ca(2+) currents. [2426]
References
Hemara-Wahanui A
et al.
A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation.
Proc. Natl. Acad. Sci. U.S.A.,
2005
May
24
, 102 (7553-8).
Peloquin JB
et al.
Temperature dependence of Cav1.4 calcium channel gating.
Neuroscience,
2008
Feb
19
, 151 (1066-83).
McRory JE
et al.
The CACNA1F gene encodes an L-type calcium channel with unique biophysical properties and tissue distribution.
J. Neurosci.,
2004
Feb
18
, 24 (1707-18).
Doering CJ
et al.
Cav1.4 encodes a calcium channel with low open probability and unitary conductance.
Biophys. J.,
2005
Nov
, 89 (3042-8).
Hofmann F
et al.
Molecular basis for Ca2+ channel diversity.
Annu. Rev. Neurosci.,
1994
, 17 (399-418).
Neely A
et al.
Potentiation by the beta subunit of the ratio of the ionic current to the charge movement in the cardiac calcium channel.
Science,
1993
Oct
22
, 262 (575-8).
Tareilus E
et al.
A Xenopus oocyte beta subunit: evidence for a role in the assembly/expression of voltage-gated calcium channels that is separate from its role as a regulatory subunit.
Proc. Natl. Acad. Sci. U.S.A.,
1997
Mar
4
, 94 (1703-8).
Yasuda T
et al.
Auxiliary subunit regulation of high-voltage activated calcium channels expressed in mammalian cells.
Eur. J. Neurosci.,
2004
Jul
, 20 (1-13).
Morgans CW
Localization of the alpha(1F) calcium channel subunit in the rat retina.
Invest. Ophthalmol. Vis. Sci.,
2001
Sep
, 42 (2414-8).
Koschak A
et al.
Cav1.4alpha1 subunits can form slowly inactivating dihydropyridine-sensitive L-type Ca2+ channels lacking Ca2+-dependent inactivation.
J. Neurosci.,
2003
Jul
9
, 23 (6041-9).
Bannister RA
et al.
Ca(V)1.1: The atypical prototypical voltage-gated Ca²⁺ channel.
Biochim. Biophys. Acta,
2013
Jul
, 1828 (1587-97).
Savalli N
et al.
The distinct role of the four voltage sensors of the skeletal CaV1.1 channel in voltage-dependent activation.
J Gen Physiol, 2021Nov01, 153 ().
Striessnig J
et al.
L-type Ca2+ channels in heart and brain.
Wiley Interdiscip Rev Membr Transp Signal, 2014Mar01, 3 (15-38).
De Silva SR
et al.
The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies.
Prog Retin Eye Res, 2021May, 82 (100898).
Doering CJ
et al.
The Ca(v)1.4 calcium channel: more than meets the eye.
Channels (Austin),
2007 Jan-Feb
, 1 (3-10).
Sang L
et al.
Protein kinase A modulation of CaV1.4 calcium channels.
Nat Commun, 2016Jul26, 7 (12239).
Singh A
et al.
C-terminal modulator controls Ca2+-dependent gating of Ca(v)1.4 L-type Ca2+ channels.
Nat. Neurosci.,
2006
Sep
, 9 (1108-16).
Kessi M
et al.
Calcium channelopathies and intellectual disability: a systematic review.
Orphanet J Rare Dis, 2021May13, 16 (219).
Haeseleer F
et al.
Essential role of Ca2+-binding protein 4, a Cav1.4 channel regulator, in photoreceptor synaptic function.
Nat. Neurosci.,
2004
Oct
, 7 (1079-87).
Zabouri N
et al.
Calcium channel-dependent molecular maturation of photoreceptor synapses.
PLoS ONE,
2013
, 8 (e63853).
Strom TM
et al.
An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness.
Nat. Genet.,
1998
Jul
, 19 (260-3).
Liu X
et al.
Dysregulation of Ca(v)1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2.
Channels (Austin),
2013 Nov-Dec
, 7 (514-23).
Haarman AEG
et al.
Whole exome sequencing of known eye genes reveals genetic causes for high myopia.
Hum Mol Genet, 2022Sep29, 31 (3290-3298).
Sun W
et al.
Exome Sequencing on 298 Probands With Early-Onset High Myopia: Approximately One-Fourth Show Potential Pathogenic Mutations in RetNet Genes.
Invest Ophthalmol Vis Sci, 2015Dec, 56 (8365-72).
Wang CY
et al.
Meta-Analysis of Public Microarray Datasets Reveals Voltage-Gated Calcium Gene Signatures in Clinical Cancer Patients.
PLoS ONE,
2015
, 10 (e0125766).
Wang Y
et al.
The Auxiliary Calcium Channel Subunit α2δ4 Is Required for Axonal Elaboration, Synaptic Transmission, and Wiring of Rod Photoreceptors.
Neuron, 2017Mar22, 93 (1359-1374.e6).
Lee A
et al.
Characterization of Cav1.4 complexes (α11.4, β2, and α2δ4) in HEK293T cells and in the retina.
J. Biol. Chem.,
2015
Jan
16
, 290 (1505-21).
Zeitz C
et al.
Mutations in CABP4, the gene encoding the Ca2+-binding protein 4, cause autosomal recessive night blindness.
Am. J. Hum. Genet.,
2006
Oct
, 79 (657-67).
Grabner CP
et al.
RIM1/2-Mediated Facilitation of Cav1.4 Channel Opening Is Required for Ca2+-Stimulated Release in Mouse Rod Photoreceptors.
J. Neurosci.,
2015
Sep
23
, 35 (13133-47).
Contributors: Katherine Johnston
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