Aquaporin-4 (AQP4) is a water cannel playing a role in water transport and homeostasis of the brain. Previously, we observed that deletion of the C-terminal domain causes degradation of AQP4. In this report, we identified three amino-acid sequences that regulate the expression level of AQP4. First, deleting C-terminal 10 amino acids (Asp³¹⁴-Val³²³) greatly reduced the level of AQP4. Substitutions of Ala for Asp³¹⁴and/or Glu³¹⁸mimicked this effect, suggesting that two acidic amino acids in this region is important to prevent AQP4 from degradation. Second, this reduction of AQP4 was rescued when the C-terminal domain was deleted more than 43 amino acids, suggesting that the region between Val²⁸⁰and Lys³¹³contains a signal for the degradation. Substitution of Phe for Tyr²⁷⁷or Arg for Val²⁸⁰increased the level of AQP4 lacking C-terminal 42 amino acids (Δ282-323), suggesting that a tyrosine-based endocytic motif (YXXΦ) is involved in the degradation of AQP4. Finally, deletion between Lys²⁵⁹and Ala²⁷⁰ increased the level of AQP4. In contrast to the disruption of the putative YXXΦmotif, the 12-amino-acid deletion could not rescue AQP4 Δ282-323 from degradation, indicating that the deletion increased the level of AQP4 with a different mechanism from YXXΦmotif mutants.