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Molecular basis for pharmacological differences between brain and cardiac sodium channels
S H Heinemann1, H Terlau, K Imoto
1Max-Planck-Institut für biophysikalische Chemie, Abteilung Membranbiophysik, Göttingen, Federal Republic of Germany.
Pflugers Archiv : European Journal of Physiology
|October 1, 1992
Summary
Two amino acid differences in brain sodium channels alter sensitivity to toxins and metal ions. These mutations help understand structural differences between brain and heart sodium channel proteins.
Area of Science:
- Neuroscience
- Molecular Biology
- Biophysics
Background:
- Brain and heart sodium channels exhibit distinct sensitivities to toxins and metal ions.
- Previous studies implicated SS2 regions in determining toxin sensitivity.
- Only two amino acid differences exist between rat brain sodium channel II and rat heart I sodium channel.
Purpose of the Study:
- To investigate the functional roles of specific amino acid differences between brain and heart sodium channels.
- To determine how mutations in key regions affect channel sensitivity to various blockers.
Main Methods:
- Site-directed mutagenesis was used to create specific mutations in rat brain sodium channel II.
- Mutant channels were expressed and their sensitivity to tetrodotoxin, saxitoxin, Zn2+, Cd2+, Ca2+, and Co2+ was assessed.
Main Results:
- Replacing phenylalanine 385 with cysteine (F385C) in the brain channel reduced sensitivity to guanidinium toxins and increased sensitivity to Zn2+ and Cd2+.
- Replacing asparagine 388 with arginine (N388R) primarily reduced sensitivity to Ca2+ and Co2+.
- A double mutant (F385C.N388R) displayed combined altered sensitivities.
Conclusions:
- Specific amino acid residues, particularly at position 385, are critical determinants of differential ion channel block.
- These findings provide structural insights into the distinct properties of brain and heart sodium channels.