Figure 2.
Summary diagram of alterations in the intracellular trafficking of cardiac potassium channels involved in acquired arrhythmias. (A) Regulation of hERG channel trafficking by hypokalemia and hyperglycemia. Decreased extracellular potassium triggers hERG channel ubiquitination, internalization, and degradation. Hyperglycemia interrupts the interaction between hERG and the chaperone HSP90 and prevents its anterograde trafficking to the membrane, activating the UPR and channel degradation. (B) Regulation of KV1.5 trafficking by cholesterol. Cholesterol depletion activates the recycling and exocytosis of the KV1.5 channel from the recycling endosome without affecting either the secretory route or the fast recycling pathway mediated by the early endosome. (C) Regulation of KV1.5 trafficking by mechanical constraint and atrial remodeling. In control condition, both anterograde and retrograde pathways are at equilibrium. Laminar shear stress stimulates the integrin/phospho-FAK signaling, which activates the recycling of KV1.5 channels accumulated in the recycling endosome. In remodeled atria and during AF, this recycling pathway is constitutively activated and the trafficking balance is altered in the direction of a favored anterograde traffic to the detriment of retrograde traffic. Abbreviations: A: anterograde; CCP: clathrin-coated pit (cleaved by dynamin); EB1: end-binding protein 1; EE: early endosome; ER: endoplasmic reticulum; FAK: focal adhesion kinase; HSP90: heat shock protein 90; P: phosphorylation; PM: plasma membrane; RE: recycling endosome; R: retrograde; SV: secretory vesicle; Ub: ubiquitylation; UPR: unfolded protein response.