In this paper, we report on the comprehensive alcohol-/ion-responsive properties of a smart copolymer poly(N-isopropylacrylamide-co-benzo-18-crown-6-acrylamide) (P(NIPAM-co-BCAm)). The orthogonal design method is adopted for experimental design. The experimental results show that alcohol can trigger the shrinking and Ba2+ can induce the swelling of the P(NIPAM-co-BCAm) copolymer. According to the phase transition temperature (LCST) change results of the copolymer, the influence of variables on the LCST changes weakens in the following order: alcohol concentration > alcohol species > metal ion species > BCAm concentration > ion concentration. The larger the alcohol concentration and the larger the molecular size of alcohols, the lower the LCST value; on the contrary, the more the BCAm content in the copolymer or the larger the BCAm/ion complex stability constant (lgK) or the larger the ion concentration is, the higher the LCST value. For a P(NIPAM-co-BCAm) copolymer with a fixed BCAm content, a binary function of ion concentration and lgK of BCAm/ion is developed to precisely predict the LCST values of the copolymer in different metal ion solutions. The results provide valuable information for fabricating artificial biomimetic G-protein-gated inwardly rectifying potassium (GIRK) channels that are activated by alcohol and inhibited by Ba2+. (c) 2014 The Chemical Industry and Engineering Society of China, and Chemical Industry Press. All rights reserved.