Ionic permeability of GABAa receptors

Irrespective of their subunit composition, all GABAa receptors are permeable to the same ions. Based on measurements of the permeation of a series of large, weakly hydrated probe anions, the diameter of the narrowest part of the GABAA receptor channel has been estimated at about 0.55nm (Inomata et al., 1986; Bormann et al., 1987; Akaike et al., 1989; Fatima-Shad and Barry, 1993; Kaila, 1994; Wotring et al., 1999). However, the GABAA channel is not a simple water-filled pore (Takeuchi and Takeuchi, 1971) and its ion selectivity sequence (SCN" >I" >Br" >Cl" >F") differs from the corresponding sequence of relative ion mobilities in free solution, indicating electrostatic interaction between permeant ions and binding sites within the channel (Takeuchi and Takeuchi, 1971; Bormann et al., 1987; Akaike et al., 1989; Fatima-Shad and Barry, 1993). The ionic filter appears to be highly conserved, since both the channel diameter and ionic selectivity sequences are similar in diverse species, ranging from crayfish to frogs to mammals (Kaila, 1994).

Studies of different cl-LGICs have shown that aligned residues within the a-helical M2 region form the lining of the channel pore (Xu and Akabas, 1996; Keramidas et al., 2004), which is at its narrowest towards the intracellular portion of the channel. For homomeric p1 receptors, point mutations introduced towards the cytoplasmic mouth of the channel (within M2 and the proximal region of the M1-M2 linker), which alter effective charges, profoundly affect ion selectivity (Wotring et al., 2001, 2003; Wotring and Weiss, 2002; Carland et al., 2004). In heteromeric apy receptors, comparable mutations indicate that selectivity is determined by the p subunit (Jensen et al., 2002, 2005a, b). Residues within more intracellular sections of the M1-M2 and M3-M4 loops, together with some towards the cytoplasmic end of M1, have also been suggested to contribute to the pathway for ion permeation in various cl-LGICs (Kelley et al., 2003; Filippova et al., 2004; Hales et al., 2006) and these may form parts of intracellular "portals" (i.e., narrow openings potentially capable of allowing ion passage), identified between adjacent subunits (Peters et al., 2005; Unwin, 2005).

Under physiological conditions, Cl" and HCO" are the only anions that act as carriers of current through GABAA channels. Data from measurements of the GABAA reversal potential (EGABA) entered into the Goldman-Hodgkin-Katz (GHK) equation have provided estimates for the relative HCO"/Cl" permeability that range from 0.18 in mouse cultured spinal neurons (Bormann et al., 1987) and 0.3 in crayfish muscle fibre (Kaila and Voipio, 1987; Kaila et al., 1989) to 0.6 in hippo-campal pyramidal neurons (Fatima-Shad and Barry, 1993). While some differences are seen for recombinant receptors (e.g., homomeric p1 vs. apy; Wotring et al., 1999), much of this large variation is likely to have a methodological rather than a biological basis, and novel estimates of PHCO" /Per from native mammalian receptors would be of much interest.

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