Claudins are tight junction membrane proteins that regulate paracellular permeability to

Claudins are tight junction membrane proteins that regulate paracellular permeability to ions and solutes in many physiological systems. the Clostridium perfringens enterotoxin (CPE).12 The C-terminal domain name of claudin contains a PDZ (postsynaptic density 95/discs large/zonula occludens-1)-binding motif (YV) that is critical for interaction with the submembrane scaffold protein ZO-1 and intracellular trafficking.13 Claudin mutations have serious consequences, consistent with its primary role in ion homeostasis. Claudin-1 deficient mice die within one day of birth and show a loss of the water barrier of skin.14 Claudin-2 knockout mice drop salt through the kidney, accompanied by hypercalciuria and polyuria.15 Targeted deletion of claudin-5, which is predominantly expressed in vascular endothelia, results in a selective increase in the blood-brain F11R barrier to small molecules.16 Knockout of claudin-11 results in male infertility and severe demyelination in the central nervous system, consistent with its function to maintain proper ion balance in Sertoli tight junctions and at the Nodes of Ranvier.17 Mutations in claudin-14 cause nonsyndromic recessive deafness DFNB29, ostensibly due to a failure in ion balance in the organ of Corti.18 Mutations in claudin-16 have been associated with human FHHNC syndrome (familial hypomagnesemia with hypercalciuria and nephrocalcinosis), a severe renal LP-533401 distributor disease due to uncontrolled loss of serum Mg2+ and Ca2+.19 Electric Properties of Claudin The electric properties of claudin are defined by its ability to alter the ion permeability and selectivity of the tight junction. Measurement of paracellular permeability using cell membrane impermeable tracers indicates that there are 7?8 ? diameter size-selective pores in the tight junction that allow passage of small charged or uncharged solutes.20-22 Most inorganic ions are permeable through the tight junction, including major extracellular ions C Na+, K+, Cl?, Ca2+ and Mg2+. In a non-selective epithelium, the paracellular conductance represents the overall permeability of tight junction to all ions present in the extracellular space. The conductance of tight junction (GTJ) is the reciprocal of its resistance (RTJ) that can be determined using a direct current (DC) circuit according to Ohms legislation (Fig.?1A). A more accurate measurement takes cell membrane capacitance into account by using an alternating current (AC) circuit (Fig.?1B). An alternating current (I) with an angular frequency () generates an oscillating potential (E) across the tight junction with the same frequency but different phase. The impedance (ZTJ), deriving from E/I and its reciprocal (1/ZTJ) reflect tight junction conductance when approaches zero (Fig.?1C). Numerous recordings have led to an important conclusion: the permeability of an ion across the tight junction is usually significantly different from its free-water mobility. The paracellular transport is not a simple diffusion but requires conversation and facilitation from proteins in the tight junction. Claudin is the primary factor underlying the conductance process. The best example is usually claudin-2. Amasheh et al. demonstrated that ectopic manifestation of claudin-2 in high-resistance MDCK I cells improved paracellular conductance by over 20-collapse.23 The limited junction also demonstrates selectivity allowing permeation of only a small amount of ions. The paracellular ion selectivity depends upon claudins. For instance, overexpression of claudin-16 in anion selective LLC-PK1 cells reversed the limited junction selectivity to cation.24 The structural basis for paracellular ion selectivity is encoded in the ECL1 of claudins. Through some chimera research, Colegio et al. demonstrated that claudin-4 used the ion selectivity of claudin-2 when the ECL1 domains of -4 and claudin-2 had been swapped.25 Yu et LP-533401 distributor al. suggested a single-pore model to describe the noticed ion selectivity of claudin-2, where the pore can be LP-533401 distributor a cylinder with conical vestibules and billed side stores from ECL1 placed facing in to the lumen and electrostatically getting together with permeating ions.26 While Yus model well described the cation over anion selectivity of claudin-2, emphasizing a job from the effective charge in its extracellular site, the paracellular conductance appeared not influenced by the extracellular charge solely. Furthermore to ion selectivity and permeability, claudins demonstrate dependence pH, thermodynamics.

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