Abstract:Voltage-gated Cav1 and Cav2 Ca2+ channels are comprised of a pore-forming a1 subunit (Cav1.1-1.4, Cav2.1-2.3) and auxiliary β (β1-4) and α2δ (α2δ-1-4) subunits. The properties of these channels vary with distinct combinations of Cav subunits and alternative splicing of the encoding transcripts. Therefore, the impact of disease-causing mutations affecting these channels may depend on the identities of Cav subunits and splice variants. Here, we analyzed the effects of a congenital stationary night blindness type… Show more
“…While some found that cones are spared 13 , 17 , 31 , 55 , 56 , other reported drastic changes compared to rods 14 , 27 . Still, a recent study showed that the Ca V 1.4.IT mutation can exert different functional phenotypes depending on splice variant and subunit composition 57 . Deeper knowledge about the channel composition in rods and cones will therefore be essential to elucidate the CSNB2 phenotype.…”
CaV1.4 L-type calcium channels are predominantly expressed in photoreceptor terminals playing a crucial role for synaptic transmission and, consequently, for vision. Human mutations in the encoding gene are associated with congenital stationary night blindness type-2. Besides rod-driven scotopic vision also cone-driven photopic responses are severely affected in patients. The present study therefore examined functional and morphological changes in cones and cone-related pathways in mice carrying the CaV1.4 gain-of function mutation I756T (CaV1.4-IT) using multielectrode array, patch-clamp and immunohistochemical analyses. CaV1.4-IT ganglion cell responses to photopic stimuli were seen only in a small fraction of cells indicative of a major impairment in the cone pathway. Though cone photoreceptors underwent morphological rearrangements, they retained their ability to release glutamate. Our functional data suggested a postsynaptic cone bipolar cell defect, supported by the fact that the majority of cone bipolar cells showed sprouting, while horizontal cells maintained contacts with cones and cone-to-horizontal cell input was preserved. Furthermore a reduction of basal Ca2+ influx by a calcium channel blocker was not sufficient to rescue synaptic transmission deficits caused by the CaV1.4-IT mutation. Long term treatments with low-dose Ca2+ channel blockers might however be beneficial reducing Ca2+ toxicity without major effects on ganglion cells responses.
“…While some found that cones are spared 13 , 17 , 31 , 55 , 56 , other reported drastic changes compared to rods 14 , 27 . Still, a recent study showed that the Ca V 1.4.IT mutation can exert different functional phenotypes depending on splice variant and subunit composition 57 . Deeper knowledge about the channel composition in rods and cones will therefore be essential to elucidate the CSNB2 phenotype.…”
CaV1.4 L-type calcium channels are predominantly expressed in photoreceptor terminals playing a crucial role for synaptic transmission and, consequently, for vision. Human mutations in the encoding gene are associated with congenital stationary night blindness type-2. Besides rod-driven scotopic vision also cone-driven photopic responses are severely affected in patients. The present study therefore examined functional and morphological changes in cones and cone-related pathways in mice carrying the CaV1.4 gain-of function mutation I756T (CaV1.4-IT) using multielectrode array, patch-clamp and immunohistochemical analyses. CaV1.4-IT ganglion cell responses to photopic stimuli were seen only in a small fraction of cells indicative of a major impairment in the cone pathway. Though cone photoreceptors underwent morphological rearrangements, they retained their ability to release glutamate. Our functional data suggested a postsynaptic cone bipolar cell defect, supported by the fact that the majority of cone bipolar cells showed sprouting, while horizontal cells maintained contacts with cones and cone-to-horizontal cell input was preserved. Furthermore a reduction of basal Ca2+ influx by a calcium channel blocker was not sufficient to rescue synaptic transmission deficits caused by the CaV1.4-IT mutation. Long term treatments with low-dose Ca2+ channel blockers might however be beneficial reducing Ca2+ toxicity without major effects on ganglion cells responses.
“…For example, I745T causes Cav1.4ex47 to activate at even more negative voltages and to deactivate with slower kinetics as compared to Cav1.4+ex47. Moreover, I745T causes a breakdown in the Ca 2+ selectivity of Cav1.4ex47 but not in Cav1.4+ex47 (Williams et al 2020). Because Cav1.4ex47 is expressed in human but not in rodent retina (Haeseleer et al 2016), the I745T knock-in mouse strain (Knoflach et al 2013, Liu et al 2013b, Regus-Leidig et al 2014 might not reflect some of the pathological sequelae of the mutation in the context of Cav1.4ex47.…”
Section: Cabp4 and Alternative Splicing As Modifiers Of Cacna1f Mutationsmentioning
Voltage-gated Ca2+ (Cav) channels play pivotal roles in regulating gene transcription, neuronal excitability, and neurotransmitter release. In order to meet the spatial and temporal demands of visual signaling, Cav channels exhibit unusual properties in the retina compared to their counterparts in other areas of the nervous system. Here, we review current concepts regarding the specific subtypes of Cav channels expressed in the retina, their intrinsic properties and forms of modulation, and how their dysregulation could lead to retinal disease.
“…This has been studied for the Cav2.1 FHM1 variant T666M (2 residues N-terminal of the selectivity filter glutamate; Hans et al, 1999;Tottene et al, 2002). Mutations in the activation gate formed by the cytoplasmic ends of the S6 helices also affect ion selectivity and single channel conductance (e.g., Cav2.1-V714L, Cav1.4-I756T in IIS6; Figure 3; Hans et al, 1999;Tottene et al, 2002;Williams et al, 2020). A dramatic effect on ion selectivity has recently been reported for CACNA1F mutation I756T (Figure 3), which depends on C-terminal splicing and the associated β-subunit isoform (Williams et al, 2020).…”
Section: Common Macroscopic Gating Changes Induced By Protein-coding mentioning
This review summarizes our current knowledge of human disease-relevant genetic variants within the family of voltage gated Ca2+ channels. Ca2+ channelopathies cover a wide spectrum of diseases including epilepsies, autism spectrum disorders, intellectual disabilities, developmental delay, cerebellar ataxias and degeneration, severe cardiac arrhythmias, sudden cardiac death, eye disease and endocrine disorders such as congential hyperinsulinism and hyperaldosteronism. A special focus will be on the rapidly increasing number of de novo missense mutations identified in the pore-forming α1-subunits with next generation sequencing studies of well-defined patient cohorts. In contrast to likely gene disrupting mutations these can not only cause a channel loss-of-function but can also induce typical functional changes permitting enhanced channel activity and Ca2+ signaling. Such gain-of-function mutations could represent therapeutic targets for mutation-specific therapy of Ca2+-channelopathies with existing or novel Ca2+-channel inhibitors. Moreover, many pathogenic mutations affect positive charges in the voltage sensors with the potential to form gating-pore currents through voltage sensors. If confirmed in functional studies, specific blockers of gating-pore currents could also be of therapeutic interest.
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