Microtubule polymerization state and clathrin-dependent internalization regulate dynamics of cardiac potassium channel

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ABSTRACT 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 K V 1.5 channel, the molecular basis of the ultra-rapid delayed rectifier current I Kur . Besides, regulated K V 1.5 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 K V 1.5 channels in atrial myocytes, with the microtubule network as the prominent organizer of K V 1.5 transport within the membrane. Both clathrin blockade and microtubule disruption result in channel clusturization with reduced membrane mobility and internalization, whereas disassembly of the actin cytoskeleton does not. Mobile K V 1.5 channels are associated with the microtubule plus-end tracking protein EB1 whereas static K V 1.5 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 K V 1.5 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 K V 1.5 channels in the plasma membrane.

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