Key result
Clathrin blockade increases sarcolemmal KV1.5 expression by ~25%, blunting channel internalization.
Why the study?
Although regulated recycling and molecular determinants of the atria-specific KV1.5 channel have been studied, the dynamic mechanisms regulating channel expression in the plasma membrane remained to be defined.
Answers are grounded in this paper and cite their sources.
The clathrin pathway and microtubule network regulate KV1.5 channel trafficking in atrial myocytes, and their alteration during atrial remodeling in AF may lead to channel accumulation at the plasma membrane.
Ion channel trafficking powerfully influences cardiac electrical activity as it regulates the number of available channels at the plasma membrane. Studies have largely focused on identifying the molecular determinants of the trafficking of the atria-specific KV1.5 channel, the molecular basis of the ultra-rapid delayed rectifier current IKur. Besides, regulated KV1.5 channel recycling upon changes in homeostatic state and mechanical constraints in native cardiomyocytes has been well documented. Here, using cutting-edge imaging in live myocytes, we investigated the dynamics of this channel in the plasma membrane. We demonstrate that the clathrin pathway is a major regulator of the functional expression of KV1.5 channels in atrial myocytes, with the microtubule network as the prominent organizer of KV1.5 transport within the membrane. Both clathrin blockade and microtubule disruption result in channel clusterization with reduced membrane mobility and internalization, whereas disassembly of the actin cytoskeleton does not. Mobile KV1.5 channels are associated with the microtubule plus-end tracking protein EB1 whereas static KV1.5 clusters are associated with stable acetylated microtubules. In human biopsies from patients in atrial fibrillation associated with atrial remodeling, drastic modifications in the trafficking balance occurs together with alteration in microtubule polymerization state resulting in modest reduced endocytosis and increased recycling. Consequently, hallmark of atrial KV1.5 dynamics within the membrane is clathrin- and microtubule- dependent. During atrial remodeling, predominance of anterograde trafficking activity over retrograde trafficking could result in accumulation ok KV1.5 channels in the plasma membrane.
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Melgari et al. (2020) studied Atrial fibrillation (n=10). Clathrin blockade (sucrose or siRNA) and cytoskeleton disruption (colchicine or cytochalasin D) / Permanent atrial fibrillation vs. Control medium / Sinus rhythm controls was evaluated on KV1.5 channel surface expression, membrane dynamics, and total protein expression in atrial fibrillation (p=<0.001).
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