Influenza virus uses mGluR2 as an endocytic receptor to enter cells. The study identifies that the metabotropic glutamate receptor subtype 2 (mGluR2) and potassium calcium-activated channel subfamily M alpha 1 (KCa1.1) are involved in the initiation and completion of clathrin-mediated endocytosis (CME) of influenza virus. The viral haemagglutinin (HA) protein directly interacts with mGluR2, using it as an endocytic receptor to initiate CME. mGluR2 activates KCa1.1, leading to F-actin polymerization, maturation of clathrin-coated pits, and completion of CME. mGluR2-knockout mice showed increased resistance to different influenza subtypes, suggesting that blocking HA and mGluR2 interaction could be a promising host-directed antiviral strategy. Influenza A viruses are categorized into subtypes based on their HA and neuraminidase (NA) proteins. The study also shows that mGluR2 is involved in the internalization of influenza virus, and that mGluR2 serves as an endocytic receptor for CME. KCa1.1 regulates F-actin polymerization, which is essential for the maturation of clathrin-coated pits and the completion of CME. The study further shows that mGluR2 and KCa1.1 work together to facilitate the internalization of influenza virus. The findings suggest that mGluR2-mediated CME is a common mechanism for influenza virus internalization. The study also shows that mGluR2 knockout significantly reduces influenza virus replication in the nasal turbinates and lungs of mice, and prevents the replication of H5 and H7 viruses in the brain. The study highlights the importance of mGluR2 and KCa1.1 in the CME of influenza virus and suggests that blocking the interaction between influenza virus HA and mGluR2 could be a promising host-directed antiviral strategy.Influenza virus uses mGluR2 as an endocytic receptor to enter cells. The study identifies that the metabotropic glutamate receptor subtype 2 (mGluR2) and potassium calcium-activated channel subfamily M alpha 1 (KCa1.1) are involved in the initiation and completion of clathrin-mediated endocytosis (CME) of influenza virus. The viral haemagglutinin (HA) protein directly interacts with mGluR2, using it as an endocytic receptor to initiate CME. mGluR2 activates KCa1.1, leading to F-actin polymerization, maturation of clathrin-coated pits, and completion of CME. mGluR2-knockout mice showed increased resistance to different influenza subtypes, suggesting that blocking HA and mGluR2 interaction could be a promising host-directed antiviral strategy. Influenza A viruses are categorized into subtypes based on their HA and neuraminidase (NA) proteins. The study also shows that mGluR2 is involved in the internalization of influenza virus, and that mGluR2 serves as an endocytic receptor for CME. KCa1.1 regulates F-actin polymerization, which is essential for the maturation of clathrin-coated pits and the completion of CME. The study further shows that mGluR2 and KCa1.1 work together to facilitate the internalization of influenza virus. The findings suggest that mGluR2-mediated CME is a common mechanism for influenza virus internalization. The study also shows that mGluR2 knockout significantly reduces influenza virus replication in the nasal turbinates and lungs of mice, and prevents the replication of H5 and H7 viruses in the brain. The study highlights the importance of mGluR2 and KCa1.1 in the CME of influenza virus and suggests that blocking the interaction between influenza virus HA and mGluR2 could be a promising host-directed antiviral strategy.