• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • br The L type calcium channel LTCC in


    The L-type calcium channel (LTCC) in heart consists of 4 subunits: α1, β2, α2, and δ [47], encoded by CACNA1C, CACNB2, and CACNA2D, respectively, with the α2 and δ subunits encoded by the gene CANA2D. In 2007, Antzelevitch et al. [48] reported 2 CACNA1C mutations and a CACNB2 mutation from a genotype survey of 82 BrS patients. The corresponding protein mutations were A39V and G490R in CACNA1C and S481L in CACNB2. Carriers of all 3 mutations exhibited short QT intervals, lower OF-1 than 360ms, with a coved-type ST elevation in ECG evaluations. Therefore, BrS patients with LTCC mutations were considered to have short QTc intervals. In their subsequent study, they identified 15 and 5 mutation carriers in a cohort of 152 and 10 probands diagnosed with BrS and BrS with short QT intervals, respectively [49]. Eight mutations were detected in CACNA1C, 6 in CACNB2, and 3 in CACNA2D. We also screened 191 BrS and IVF patients who were negative for SCN5A mutations and identified 2 CACNA1C mutations in 2 BrS patients [50]. Functional analysis using patch-clamp methods was performed to address the impact of the 4 CACNA1C mutations (A39V, G490R, V2014I, and E1829-Q1833dup) and 1 CACNB2 mutation (S481L) reported thus far [48,49]. Current densities in OF-1 expressing any of the mutant LTCCs were decreased, and the expression of one of the mutants, A39V, impaired cell surface trafficking of Ca(v)1.2. The number of LTCC mutations identified in BrS patients and that of mutants whose channel functions have been analyzed, are small compared to SCN5A mutations. Further investigation is essential to elucidate the pathophysiology of BrS patients with LTCC mutations.
    The sodium channel is composed of a pore-forming α subunit and auxiliary function-modifying β subunits [51]. In humans, 4 β subunits have been identified [52]. Among these, SCN1B encodes one of the β subunits, β1. In 2008, Watanabe et al. [53] reported a novel mutation, W179X, in SCN1B from a survey of 282 BrS patients. The mutation was located in the transcriptional variant β1B, which had an alternative 3′ sequence. ECG analysis of the proband with the SCN1B mutation showed an ST segment elevation, which is typical of BrS, and conduction abnormalities (prolonged PR interval of 220ms and left anterior hemiblock). In functional analysis, co-expression of Nav1.5 and WT β1B increased the INa densities and evoked a negative shift in the activation and inactivation curves, whereas these effects were diminished in cells co-expressing Nav1.5 and the W179X β1B mutant.
    KCNE3 is a homolog of KCNE1, which encodes MinK, and the protein encoded by KCNE3 is called MinK-related protein 2 (Mirp2). Thus far, 5 KCNE genes have been identified and all genes encode auxiliary β subunits, which modify many kinds of potassium channels [54]. In a screening study of 105 BrS patients, an R99H Mirp2 mutation was found in a proband who was resuscitated from cardiac arrest [55]. In the analysis of the index family, all 4 mutation carriers showed ST segment elevation, whereas 3 non-carriers had normal ECG. In the normal condition, Mirp2 decreased the transient outward potassium current (Ito). However, the suppression of Ito by the R99H Mirp2 mutant was smaller than that mediated by the WT protein, and the effect was observed even upon co-expression of the WT and R99H. These results showed that expression of the R99H mutant increased the Ito densities and caused BrS. Recently, another KCNE3 mutation, corresponding to T4A in Mrip2, was identified in a Japanese BrS patient [56]. This mutation also failed to suppress the Ito.
    SCN3B encodes the β3 subunit of the sodium channel. An SCN3B-mutation, corresponding to L10P in β3, was identified in a 64-year-old man [57]. The patient was asymptomatic and his ECG showed coved-type ST elevation upon provocation by procainamide. In a heterologous expression system, WT β3 increased the INa densities, whereas co-expression of the WT β3 and L10P β3 strongly decreased the INa densities. The gating of the cardiac sodium channel also changed in cells with L10P β3 and the inactivation curve of the mutant channel moved negatively, which caused the reduction in the total INa. Furthermore, expression of L10P β3 disturbed the normal trafficking of the cardiac sodium channel to the membrane. More recently, another SCN3B mutation, corresponding to V110I in β3, was identified in 3 of 178 Japanese BrS patients [58]. Transfection of HEK 293-derived cells with V110I β3 impaired the cytoplasmic trafficking of Nav1.5 and decreased the cell surface expression of Nav1.5.