The pore has a filter through which chloride and other anions can pass, but lets little else through. These water-filled pores filter anions via three binding sites—Sint, Scen, and Sext—which bind chloride and other anions. The names of these binding sites correspond to their positions within the membrane. Sint is exposed to intracellular fluid, Scen lies inside the membrane or in the center of the filter, and Sext is exposed to extracellular fluid.[4] Each binding site binds different chloride anions simultaneously. In the exchangers, these chloride ions do not interact strongly with one another, due to compensating interactions with the protein. In the channels, the protein does not shield chloride ions at one binding site from the neighboring negatively charged chlorides. Each negative charge exerts a repulsive force on the negative charges next to it. Researchers have suggested that this mutual repulsion contributes to the high rate of conduction through the pore. CLC transporters shuttle H+ across the membrane. The H+ pathway in CLC transporters utilizes two glutamate residues—one on the extracellular side, Gluex, and one on the intracellular side, Gluin. Gluex also serves to regulate chloride exchange between the protein and extracellular solution. This means that the chloride and the proton share a common pathway on the extracellular side, but diverge on the intracellular side. CLC channels also have dependence on H+, but for gating rather than Cl− exchange. Instead of utilizing gradients to exchange two Cl− for one H+, the CLC channels transport one H+ while simultaneously transporting millions of anions. This corresponds with one cycle of the slow gate. Eukaryotic CLC channels also contain cytoplasmic domains. These domains have a pair of CBS motifs, whose function is not fully characterized yet. Though the precise function of these domains is not fully characterized, their importance is illustrated by the pathologies resulting from their mutation. Thomsen's disease, Dent's disease, infantile malignant osteopetrosis, and Bartter's syndrome are all genetic disorders due to such mutations. At least one role of the cytoplasmic CBS domains regards regulation via adenosine nucleotides. Particular CLC transporters and proteins have modulated activity when bound with ATP, ADP, AMP, or adenosine at the CBS domains. The specific effect is unique to each protein, but the implication is that certain CLC transporters and proteins are sensitive to the metabolic state of the cell. Selectivity The Scen acts as the primary selectivity filter for most CLC proteins, allowing the