Molecular localization of ion selectivity sites within the pore of a human L-type cardiac calcium channel

A highly conserved position of negatively charged amino acids is present in the SS2 segments of the S5-S6 linker regions among calcium channels. We report here that replacing Glu residues at this position alters the ion selectivity of the human cardiac calcium channel. Substituting Glu334 in motif I...

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Bibliographic Details
Published in:	The Journal of biological chemistry Vol. 268; no. 18; pp. 13026 - 13029
Main Authors:	SHAOQING TANG, MIKALA, G, BAHINSKI, A, YATANI, A, VARADI, G, SCHWARTZ, A
Format:	Journal Article
Language:	English
Published:	Bethesda, MD American Society for Biochemistry and Molecular Biology 25-06-1993
Subjects:	Amino Acid Sequence Binding Sites Biological and medical sciences Biological Transport Calcium Channels - genetics Calcium Channels - metabolism Cations - metabolism Cell physiology Electrophysiology Fundamental and applied biological sciences. Psychology Glutamates - metabolism Glutamic Acid Humans Membrane and intracellular transports Molecular and cellular biology Molecular Sequence Data Mutation Myocardium - metabolism Sequence Homology, Amino Acid Heart Human Calcium Structure activity relation Substrate specificity Ionic channel Selectivity Glutamate
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Summary:	A highly conserved position of negatively charged amino acids is present in the SS2 segments of the S5-S6 linker regions among calcium channels. We report here that replacing Glu residues at this position alters the ion selectivity of the human cardiac calcium channel. Substituting Glu334 in motif I or Glu1086 in motif III with Lys produced mutant calcium channels that permeated sodium ions 10-fold more effectively than barium ions. More conservative changes such as substitution of Glu1086 with Gln or substitution of Glu1387 with Ala also increased sodium permeation through the mutant calcium channels. Sodium currents through the mutant calcium channels could be modulated by dihydropyridines and blocked by external divalent cations. These results suggest that Glu334, Glu1086, and Glu1387 are part of a ring of glutamate residues formed in the pore-lining SS1-SS2 region and are critical in determining ion selectively and permeability of a human cardiac calcium channel.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9258 1083-351X
DOI:	10.1016/s0021-9258(19)38613-2