IndraLab

"Recently, we reported that a selective Cacna1a gene deletion in cortical layer VI pyramidal cells, which innervate thalamic relay neurons and reticular thalamic neurons, caused upregulation of T-type calcium current in thalamic relay neurons and resulted in absence epilepsy in mice , suggesting that impaired cortical excitatory input to thalamic regions may cause rebound burst of thalamocortical relay neurons and leads to thalamocortical hyper-synchronous oscillations as may be the case for ethosuximide-sensitive absence-like seizures in Scn2a-deficient mice."

"Ca(v)1.4 voltage-dependent inactivation is slow and Ca2+-dependent inactivation (CDI) is absent."

"In spite of a resemblance between voltage-dependent inactivation of Ca channels and the so-called slow or C-type inactivation found in the whole superfamily of voltage-gated channels, the structural underpinnings of this process have yet to be identified in Ca channels."

"This seems to be a common, although not ubiquitous, feature of “voltage-dependent” inactivation of Ca, Na, and now K channels."

"Initially, TS was thought to arise from a single recurrent mutation, G406R, in the alternatively spliced CACNA1C exon 8a that accounts for ≈20% of the Ca v 1.2 mRNA transcripts in the heart and brain and encodes the distal portion of the domain I transmembrane segment 6 (IS6) known to play a critical role in the voltage-dependent inactivation (VDI) of Ca v 1.2 ( xref ). xref – xref However, shortly after the elucidation of the molecular basis of typical TS now referred to as type I TS (TS1), 2 cases of atypical or type II TS (TS2) were reported in the literature. xref Interestingly, both cases were characterized by extreme QT prolongation (average ≈640 ms) complicated by multiple episodes of cardiac arrest in the absence of syndictyly and harbored de novo mutations in the CACNA1C exon 8–containing heart- and brain-predominant Ca v 1.2 splice variant. xref Interestingly, the exon 8 CACNA1C-G406R–positive TS2 proband displayed severe neurodevelopmental delay, craniofacial/odontic abnormalities, and possible nemaline skeletal myopathy during the first few months of life, whereas the exon 8 CACNA1C-G402S–positive TS2 proband seemed developmentally normal until suffering an out-of-hospital cardiac arrest at age 4. xref It was postulated initially that the lack of syndactyly and the potentially more severe neurological/cardiac phenotypes anecdotally observed in TS2 versus TS1 were likely secondary to the differential tissue-specific expression of exon 8– and exon 8a–containing Ca v 1.2 splice variants. xref Although this is likely the case for exon 8 G406R–mediated TS2, the recent identification of exon 8 G402S in an otherwise developmentally normal adolescent woman with borderline QT prolongation who presented with an out-of-hospital cardiac arrest xref coupled with the normal development of the initial G402S-positive TS2 proband before his first cardiac arrest xref suggest that (1) CACNA1C-G402S results in a milder clinical phenotype more akin to nonsyndromic LQTS and (2) the neurodevelopmental sequelae observed in the initial CACNA1C-G402S–positive TS2 proband are more likely secondary to arrhythmia-induced anoxic brain injury than underlying CACNAlC -mediated developmental delay."

"On the other hand, there is an important distinction between voltage-dependent inactivation of Ca channels and slow inactivation of Na and K channels."

"Molecular genetic studies have revealed that TS patients have mutations with a Gly to Arg substitution at position 406 (G406R) of Ca v 1.2 in the CACNA1C gene, which results in “near-complete” elimination of voltage-dependent inactivation (VDI) of Ca v 1.2 (gain of function). xref , xref Electrophysiological studies have illustrated that G406R-mutated Ca v 1.2 is inactivated at a slow rate xref alongside a high probability of undergoing coordinated openings and closings (coupled gating). xref "

"The much faster voltage-dependent inactivation of vertebrate Ca v 2 channels has been attributed to the more helical, and rigid proximal linker (PL) between the inactivation gate of the transmembrane segment 6 (S6) helix of domain I and the AID sequence for Ca v β subunit binding xref – xref ."

"XREF_BIBR - XREF_BIBR Therefore, it may be that Cacna1a LOF mutations disrupting Ca V 2.1 channels contribute to the development of epilepsy through their impact on cortical interneuron function."

"All of the known beta subunits (beta1-beta5) produced voltage-dependent inhibition of alpha(1B) Ca channels, depending on the gamma subunit found in the heterodimer. beta1-beta4 subunits inhibited Ca channels when paired with gamma1-gamma3."

"We found that roscovitine, a compound that increases the voltage-dependent inactivation of Ca(V)1.2 (refs 6-8), restored the electrical and Ca(2+) signalling properties of cardiomyocytes from Timothy syndrome patients."

"The TS mutation causes loss of normal voltage-dependent inactivation of Ca(V)1.2 current (I(Ca))."

"Simulations show that slowing the voltage-dependent inactivation of Ca current can result in an earlier onset and larger areas of 2 : 1 conduction block [ xref ]."

"Because clear modal separation characterizes slow (C-type) inactivation of Na and K channels, this observation establishes the nature of voltage-dependent inactivation of L-type Ca channels as slow or C-type."

"Genetic deletion of the Cacna1a gene in cortical layer VI neurons enhances T-type Ca 2+ currents in thalamic relay and nRT neurons, thereby generating synchronous SWDs that are inhibited by ethosuximide [XREF_BIBR]."

"Voltage-dependent inactivation of Ca channels is an important mechanism of regulation of Ca 2+ entry during repetitive stimulation."

"Ca 2+ /CaM-dependent protein kinase II (CaMKII) binds to the C-termini of Ca V 1.2 ( xref ; xref ) and Ca V 2.1 ( xref ) and plays a role in Ca V 1.2 ( xref ) and Ca V 2.1 ( xref ) CDF, as well as in Ca V 2.1 voltage-dependent inactivation ( xref )."

"It is assumed that polyglutamine repeats in CACNA1A effects Ca 2+ channel to reduce Ca 2+ influx, leading to eventually cell death [XREF_BIBR]."

"Previous work has shown that voltage dependent slow inactivation of Ca v 1.2 channels is mediated by hydrophobic residues in the cytoplasmic end of the S6 transmembrane helices of domains I-IV xref , xref , xref ."

"Here, we studied the effects of Mg i on voltage-dependent inactivation (VDI) of Ca v 1.2 channels using Na + as permeant ion to eliminate the effects of permeant divalent cations that engage the Ca 2+ -dependent inactivation process."

"The main finding of this study is that voltage-dependent inactivation of heterologously expressed cardiac Ca channels is associated with a large negative shift in the voltage dependence of their charge movement."

"We thereby propose that the NT inhibitory module is indeed central to the voltage-dependent G protein inhibition of N-type Ca channels."

"Recently, we reported that a selective Cacna1a gene deletion in cortical layer VI pyramidal cells, which innervate thalamic relay neurons and reticular thalamic neurons, caused upregulation of T-type calcium current in thalamic relay neurons and resulted in absence epilepsy in mice 59, suggesting that impaired cortical excitatory input to thalamic regions may cause rebound burst of thalamocortical relay neurons and leads to thalamocortical hyper-synchronous oscillations as may be the case for ethosuximide sensitive absence like seizures in Scn2a deficient mice."

"Remarkably, the invertebrate LCa(v)2 channel from the pond snail, Lymnaea stagnalis, does not bear any of the hallmarks of mammalian, voltage-dependent G-protein inhibition of Ca(v)2.2."

"The voltage-dependent inhibition of type N Ca channels is also thought to be mediated by the direct interaction of Gβγ with a channel subunit ."

"Here, Yang et al. demonstrate that D3 dopamine receptors regulate AIS Ca V 3 channels through a non-canonical, arrestin-dependent mechanism, suppressing AIS excitability by hyperpolarizing Ca V 3 voltage-dependent inactivation."

"Cacna1a dysregulation may also disrupt CF maturation, distal CF extension and Ca signaling, as Cav2.1 plays crucial roles in these processes (8, 33, 56)."

"Although a role for CaBP2 in suppressing voltage-dependent inactivation of Ca v 1.3 channels in IHCs of CaBP2 LacZ/LacZ mice has been demonstrated ( Picher et al., 2017 ), the function of CaBP2 in OH[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"Here, we found that D3Rs altered Ca V 3 voltage dependent inactivation, effectively blocking a major fraction of Ca V 3 channels in the AIS at resting membrane potentials."

"AGS1 and Rhes reduced basal current densities and triggered tonic voltage-dependent (VD) inhibition of Ca(V)2.2."

"To test potential therapies, the researchers supplied Roscovitine, a cycline-dependent kinase inhibitor shown to increase voltage-dependent inactivation of Ca v 1.2 channel, and demonstrated that many of these abnormal characteristics were rescued."