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The mechanisms involved in glucose regulation of insulin secretion by ATP-sensitive (K_ATP) and calcium-activated (K_CA) potassium channels have been extensively studied, but less is known about the role of voltage-gated (K_V) potassium channels in pancreatic β-cells. The incretin hormone, glucose-dependent insulinotropic polypeptide (GIP) stimulates insulin secretion by potentiating events underlying membrane depolarization and exerting direct effects on exocytosis. In the present study, we identified a novel role for GIP in regulating K_V1.4 channel endocytosis. In GIP receptor-expressing HEK293 cells, GIP reduced A-type peak ionic current amplitude of K_V1.4 via activation of protein kinase A (PKA). Using mutant forms of K_V1.4 with Ala-Ser/Thr substitutions in a potential PKA phosphorylation site, C-terminal phosphorylation was shown to be linked to GIP-mediated current amplitude decreases. Proteinase K …