Desmosomes and the sodium channel complex: implications for arrhythmogenic cardiomyopathy and Brugada syndrome

Abstract

Mutations in proteins of the desmosome are associated with arrhythmogenic cardiomyopathy (AC; also referred to as "ARVC" or "ARVD"). Life-threatening ventricular arrhythmias often occur in the concealed phase of the disease before the onset of structural changes. Among the various potential mechanisms for arrhythmogenesis in AC, in this article, we concentrate on the relation between desmosomes and sodium channel function. We review evidence indicating that (1) loss of desmosomal integrity (including mutations or loss of expression of plakophilin-2; PKP2) leads to reduced sodium current (INa), (2) the PKP2-INa relation could be partly consequent to the fact that PKP2 facilitates proper trafficking of proteins to the intercalated disc, and (3) PKP2 mutations can be present in patients diagnosed with Brugada syndrome (BrS), thus supporting the previously proposed notion that AC and BrS are not two completely separate entities, but "bookends" in a continuum of variable sodium current deficiency and structural disease.

Figure 1

Diagram illustrating the potential interactions between the voltage-gated sodium channel complex (VGSC), gap junctions and desmosomes. AnkG: ankyrin-G; DSC/Dsg: desmocolin/desmoglein; PG:plakoglobin; PKP2:plakophilin-2; Cx43: connexin43; DP: desmoplakin Reproduced with permission from Sato et al, 2011.

Figure 2

Voltage clamp data from adult rat cardiomyocytes after PKP2 knockdown (KD) and comparison with cells untreated (UNT) or treated with nonsilencing constructs (ΦKD) as control. A: Examples of sodium current recorded in the three conditions. B: Current- voltage relation for the groups described in A. Reproduced with permission from Sato et al, 2009.

Figure 3

Decreased sodium current, conduction defects and ventricular arrhythmias in a mouse model with PKP2 haploinsufficiency (PKP2-Hz). A: sodium current amplitude recorded from PKP2-Hz and control (WT) isolated ventricular myocytes. B: ECG recorded from a wild-type (WT) and PKP2-Hz anesthetized animal in baseline (left) and 10 minutes after flecainide infusion C: Examples of ventricular arrhythmias elicited by flecainide infusion in PKP2-Hz mice. Reproduced with permission from Cerrone et al, 2012.

Figure 4

Localization of EB-1 (green) and N-cadherin (purple) in adult mouse ventricular myocytes. A: Image by TIRF (left) or dSTORM (right). Inset enlarged in bottom panels to show increased resolution. B: Comparison between wild type and PKP2-Hz myocytes: clusters in WT (left) are closer to each other than in PKP2-Hz cells (right). C: Dot plot of distance from EB-1 to N-cadherin showing increased separation between the proteins in the PKP2-Hz cells. Reproduced with permission from Cerrone et al, 2013.

Figure 5

PKP2 mutations associate with Brugada Syndrome and with reduced sodium current. Top left: Representative ECG showing ST elevation, diagnostic for Brugada Syndrome, in one of the five patients carriers of missense mutations on the PKP2 gene, and correspondent electropherograms showing the specific amino acid substitution R635Q. Bottom left: Sodium current amplitude recorded in HL1 cells silenced for PKP2 (PKP2-KD) transfected with the mutant (red), an empty vector (blue) or wild type PKP2 (black). Right: pedigree of the family showing co-segregation between the PKP2 mutation and the clinical phenotype. Reproduced with permission from Cerrone et al, 2013.