Key result
Endocytosis of the voltage-gated potassium channel Kv1.2 from the cell surface is a key mechanism for its suppression by tyrosine kinases.
p-value: p=<0.001
This study identifies endocytosis as the physical mechanism by which tyrosine kinases suppress the voltage-gated potassium channel Kv1.2.
May inform Kv1.2-targeted arrhythmia therapies; leaves open translation from animal models to human disease.
The voltage-gated potassium channel Kv1.2 undergoes tyrosine phosphorylation-dependent suppression of its ionic current. However, little is known about the physical mechanism behind that process. We have found that the Kv1.2 alpha-subunit protein undergoes endocytosis in response to the same stimuli that evoke suppression of Kv1.2 ionic current. The process is tyrosine phosphorylation-dependent because the same tyrosine to phenylalanine mutation in the N-terminus of Kv1.2 that confers resistance to channel suppression (Y132F) also confers resistance to channel endocytosis. Overexpression of a dominant negative form of dynamin blocked stimulus-induced Kv1.2 endocytosis and also blocked suppression of Kv1.2 ionic current. These data indicate that endocytosis of Kv1.2 from the cell surface is a key mechanism for channel suppression by tyrosine kinases.
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Nesti et al. (2004) studied this question. Tyrosine kinase activation (e.g., carbachol, pervanadate) vs. Saline control was evaluated on Kv1.2 surface expression and endocytosis (p=<0.001). Endocytosis of the voltage-gated potassium channel Kv1.2 from the cell surface is a key mechanism for its suppression by tyrosine kinases.
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