Browsing by Author "Souza, Ivana A."

Now showing 1 - 7 of 7
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    Block of T-type calcium channels by protoxins I and II
    (BioMed Central, 2014-05-09) Bladen, Chris; Hamid, Jawed; Souza, Ivana A.; Zamponi, Gerald W.
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    De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy
    (2021-08-16) Stringer, Robin N.; Jurkovicova-Tarabova, Bohumila; Souza, Ivana A.; Ibrahim, Judy; Vacik, Tomas; Fathalla, Waseem M.; Hertecant, Jozef; Zamponi, Gerald W.; Lacinova, Lubica; Weiss, Norbert
    Abstract Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873–4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.
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    Determinants of interactions of a novel next-generation gabapentinoid NVA1309 and mirogabalin with the Cavα2δ-1 subunit
    (2024-08-07) Souza, Ivana A.; Gandini, Maria A.; Ali, Md Y.; Kricek, Franz; Skouteris, George; Zamponi, Gerald W.
    Abstract NVA1309 is a non-brain penetrant next-generation gabapentinoid shown to bind Cavα2δ at R243 within a triple Arginine motif forming the binding site for gabapentin and pregabalin. In this study we have compared the effects of NVA1309 with Mirogabalin, a gabapentinoid drug with higher affinity for the voltage-gated calcium channel subunit Cavα2δ-1 than pregabalin which is approved for post-herpetic neuralgia in Japan, Korea and Taiwan. Both NVA1309 and mirogabalin inhibit Cav2.2 currents in vitro and decrease Cav2.2 plasma membrane expression with higher efficacy than pregabalin. Mutagenesis of the classical binding residue arginine R243 and the newly identified binding residue lysine K615 reverse the effect of mirogabalin on Cav2.2 current, but not that of NVA1309.
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    Effect of the Brugada syndrome mutation A39V on calmodulin regulation of Cav1.2 channels
    (BioMed Central, 2014-04-28) Simms, Brett A.; Souza, Ivana A.; Zamponi, Gerald W.
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    Electrophysiological and computational analysis of Cav3.2 channel variants associated with familial trigeminal neuralgia
    (2022-11-17) Mustafá, Emilio R.; Gambeta, Eder; Stringer, Robin N.; Souza, Ivana A.; Zamponi, Gerald W.; Weiss, Norbert
    Abstract Trigeminal neuralgia (TN) is a rare form of chronic neuropathic pain characterized by spontaneous or elicited paroxysms of electric shock-like or stabbing pain in a region of the face. While most cases occur in a sporadic manner and are accompanied by intracranial vascular compression of the trigeminal nerve root, alteration of ion channels has emerged as a potential exacerbating factor. Recently, whole exome sequencing analysis of familial TN patients identified 19 rare variants in the gene CACNA1H encoding for Cav3.2T-type calcium channels. An initial analysis of 4 of these variants pointed to a pathogenic role. In this study, we assessed the electrophysiological properties of 13 additional TN-associated Cav3.2 variants expressed in tsA-201 cells. Our data indicate that 6 out of the 13 variants analyzed display alteration of their gating properties as evidenced by a hyperpolarizing shift of their voltage dependence of activation and/or inactivation resulting in an enhanced window current supported by Cav3.2 channels. An additional variant enhanced the recovery from inactivation. Simulation of neuronal electrical membrane potential using a computational model of reticular thalamic neuron suggests that TN-associated Cav3.2 variants could enhance neuronal excitability. Altogether, the present study adds to the notion that ion channel polymorphisms could contribute to the etiology of some cases of TN and further support a role for Cav3.2 channels.
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    Regulation of N-type calcium channels by nociceptin receptors and its possible role in neurological disorders
    (2022-11-24) Caminski, Emanuelle S.; Antunes, Flavia T. T.; Souza, Ivana A.; Dallegrave, Eliane; Zamponi, Gerald W.
    Abstract Activation of nociceptin opioid peptide receptors (NOP, a.k.a. opioid-like receptor-1, ORL-1) by the ligand nociceptin/orphanin FQ, leads to G protein-dependent regulation of Cav2.2 (N-type) voltage-gated calcium channels (VGCCs). This typically causes a reduction in calcium currents, triggering changes in presynaptic calcium levels and thus neurotransmission. Because of the widespread expression patterns of NOP and VGCCs across multiple brain regions, the dorsal horn of the spinal cord, and the dorsal root ganglia, this results in the alteration of numerous neurophysiological features. Here we review the regulation of N-type calcium channels by the NOP-nociceptin system in the context of neurological conditions such as anxiety, addiction, and pain.
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    Splice-variant specific effects of a CACNA1H mutation associated with writer’s cramp
    (2021-09-20) Souza, Ivana A.; Gandini, Maria A.; Zamponi, Gerald W.
    Abstract The CACNA1H gene encodes the α1 subunit of the low voltage-activated Cav3.2 T-type calcium channel, an important regulator of neuronal excitability. Alternative mRNA splicing can generate multiple channel variants with distinct biophysical properties and expression patterns. Two major splice variants, containing or lacking exon 26 (± 26) have been found in different human tissues. In this study, we report splice variant specific effects of a Cav3.2 mutation found in patients with autosomal dominant writer’s cramp, a specific type of focal dystonia. We had previously reported that the R481C missense mutation caused a gain of function effect when expressed in Cav3.2 (+ 26) by accelerating its recovery from inactivation. Here, we show that when the mutation is expressed in the short variant of the channel (− 26), we observe a significant increase in current density when compared to wild-type Cav3.2 (− 26) but the effect on the recovery from inactivation is lost. Our data add to growing evidence that the functional expression of calcium channel mutations depends on which splice variant is being examined.