1. Figure 4 Intercalated disc maturation
Figure 4 | Intercalated disc maturation. Cadherin 2 molecules are the first to be incorporated into the membrane63. Plakoglobin is required to link actin filaments to the complex, whereas plakophilin 2 (PKP2) is associated with Rho-GTPase in the membrane to modulate the cortical ring of the actin filament99 (step 1). This process seems to be essential to nascent desmosome formation. The cytoplasmic pool of PKP2 and plakoglobin participate in the trafficking of desmoglein 2 (DSG2) and desmocollin 2 (DSC2), mediated by kinesin 1 and kinesin 2, respectively100,101 (step 2). PKP2 also regulates the trafficking of the desmin (DES)–desmoplakin (DSP)–protein kinase C α-type (PKCα) complex towards the membrane through its interaction with the actin filament102 (step 3). Adherens junctions and desmosomes are both required for connexin 43 (Cx43, also known as gap junction-α1 protein) anchoring104. Cadherin 2 and catenin-β1 interact with the dynein activator complex72, whereas the N-terminal of DSP interacts with microtubule-associated protein RP/EB family member 1 (EB1)77. This process brings the plus end of the microtubule close to the membrane, facilitating Cx43 delivery (step 4). After Cx43 has been incorporated into the membrane, gap-junction formation is regulated by the scaffolding protein tight junction protein ZO-1 (ZO-1)74, whereas ankyrin-G (also known as ankyrin 3 or ANK3) and PKP2 limit the area of the gap junction80 (step 5). Ankyrin-G and PKP2 are also involved in the trafficking and stabilization of Nav1.5 in the membrane30,80 (step 6). Maturation of the intercalated disc finishes with the incorporation of Nav1.5 into the membrane, for which the interaction between the C-terminal region of Cx43 with ZO-1 and EB1 is essential89,90 (step 7). p150, dynactin subunit 1.
Moncayo-Arlandi, J. & Brugada, R. (2017) Unmasking the molecular link between arrhythmogenic cardiomyopathy and Brugada syndrome
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