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Mol Cell Biochem
1997 Jan 01;1661-2:125-34. doi: 10.1023/a:1006847632410.
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Charged amino acids near the pore entrance influence ion-conduction of a human L-type cardiac calcium channel.
Bahinski A
,
Yatani A
,
Mikala G
,
Tang S
,
Yamamoto S
,
Schwartz A
.
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Voltage-dependent L-type Ca2+ channels form highly selective pores for Ca2+ ions in the membranes of excitable cells. We investigated the functional role of negatively charged residues, within or near the selectivity region, in ion permeation of a human cardiac L-type Ca2+ channel. Glutamates in each of the four repeats, and an aspartate in repeat IV, were substituted with positively charged lysine. Wild-type and mutant Ca2+ channels were expressed in Xenopus oocytes. Block by Ca2+ and Mg2 of inward Li+ currents through the channels was used to assess the effects of amino acid substitutions on high-affinity divalent cation binding. The rank order of IC50's for Ca2+ block of I(Li) was: E677K > E1086K > E334K > E1387K > D1391K > or approximately wild-type. The order of IC50's for Mg2+ block of I(Li) indicated differential involvement of the same residues in Mg2+ binding: E 1387K > E334K > E1086K > E677K > D 1391K = wild-type. Mutants E1387K and D1391K effectively permeated Ba2+, but exhibited a decreased single-channel conductance. The unitary current amplitude carried by Na+, in the absence of external divalent cations, was slightly decreased in the E1387K mutant but not in the D1391K mutant. The results confirm that each of the four glutamates participate unequally in high-affinity Ca2+ binding. Additionally, our results indicate that these glutamate residues participate in Mg2+ binding. The glutamate at position 1387 may be only peripherally involved in the formation of a high-affinity Ca2+ -binding site but is central to a Mg2+ binding site accessible from the external side of the pore. The aspartate at position 1391 is most likely located just external to the selectivity region.
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