Arrhythmogenic cardiomyopathy and Brugada syndrome: diseases of the connexome

Abstract

This review summarizes data in support of the notion that the cardiac intercalated disc is the host of a protein interacting network, called "the connexome", where molecules classically defined as belonging to one particular structure (e.g., desmosomes, gap junctions, sodium channel complex) actually interact with others, and together, control excitability, electrical coupling and intercellular adhesion in the heart. The concept of the connexome is then translated into the understanding of the mechanisms leading to two inherited arrhythmia diseases: arrhythmogenic cardiomyopathy, and Brugada syndrome. The cross-over points in these two diseases are addressed to then suggest that, though separate identifiable clinical entities, they represent "bookends" of a spectrum of manifestations that vary depending on the effect that a particular mutation has on the connexome as a whole.

Keywords: Arrhythmogenic right ventricular cardiomyopathy; Brugada syndrome; Connexin43; Desmosome; Plakophilin-2; Sodium channel.

Figure 1

One possible model of connexome organization. The gap junction is surrounded by the perinexus where Cx43 hemichannels interact with ZO-1, which regulates the transition of connexons to the gap junction. AnkG may be localized at the border of the perinexus restricting the plaque size. When AnkG is silenced (right panel), the perinexal area expands at the expense of the actual pore-forming gap junction. This yields to larger Cx43 plaques but a reduced channel-forming domain and gap junction conductance. From with permission.

Figure 2

Proximity between gap junctions and mitochondria. Transmission electron micrograph image of adult murine heart tissue. The high preservation of structures was achieved by high-pressure freezing and freeze-substitution methods. Notice the close approximation and contact (yellow arrow) between the gap junction and a mitochondria. From with permission.

Figure 3

Vesicular activity at the intercalated disc. Tomographic electron microscopy image of an intercalated disc region. Notice the vesicular activity in the space between the desmosomes and the gap junction, as well as in the intercellular space. From with permission.

Figura 4

Super-resolution fluorescence microscopy: NRVMs stained for Cx43 (green) and PKP2 (magenta). Panels A and B show the same region visualized by TIRF (A) or by SRFM (B). Enlargement of the small white squares show improved resolution after reconstruction (C-E). Panel E shows a Cx43 cluster surrounded by PKP2. Same image is shown as a topological image in F (z-axis: signal intensity). Intensity plot of the dotted line across the image (G) shows the intersection of both signals. Scale bars: 5μm (A and B) and 200nm (C–E). Reproduced from with permission.