Abstract
L-type Ca2+ channels are characterized by their unique sensitivity to organic Ca2+ channel modulators like the 1,4-dihydropyridines (DHPs). To identify molecular motifs mediating DHP sensitivity, we transferred this sensitivity from L-type Ca2+ channels to the DHP-insensitive class A brain Ca2+ channel, BI-2. Expression of chimeras revealed minimum sequence stretches conferring DHP sensitivity including segments IIIS5, IIIS6, and the connecting linker, as well as the IVS5-IVS6 linker plus segment IVS6. DHP agonist and antagonist effects are determined by different regions within the repeat IV motif. Sequence regions responsible for DHP sensitivity comprise only 9.4% of the overall primary structure of a DHP-sensitive alpha 1A/alpha 1S construct. This chimera fully exhibits the DHP sensitivity of channels formed by L-type alpha 1 subunits. In addition, it displays the electrophysiological properties of alpha 1A, as well as its sensitivity toward the peptide toxins omega-agatoxin IVA and omega-conotoxin MVIIC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Binding Sites
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Calcium / metabolism*
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Calcium Channel Agonists / pharmacology
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Calcium Channel Blockers / pharmacology
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Calcium Channels / chemistry*
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Calcium Channels / drug effects*
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Calcium Channels / genetics
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Calcium Channels, L-Type
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Carps
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Dihydropyridines / pharmacology*
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Ion Channel Gating / drug effects
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Isradipine / pharmacology
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Molecular Sequence Data
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Peptide Fragments / chemistry
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Peptides / pharmacology
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Protein Structure, Tertiary
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Pyrroles / pharmacology
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Rabbits
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / drug effects*
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Sequence Alignment
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Sequence Homology, Amino Acid
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Spider Venoms / pharmacology
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omega-Agatoxin IVA
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omega-Conotoxins*
Substances
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Calcium Channel Agonists
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Calcium Channel Blockers
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Calcium Channels
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Calcium Channels, L-Type
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Dihydropyridines
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Peptide Fragments
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Peptides
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Pyrroles
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Recombinant Fusion Proteins
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Spider Venoms
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omega-Agatoxin IVA
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omega-Conotoxins
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FPL 64176
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omega-conotoxin-MVIIC
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1,4-dihydropyridine
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Calcium
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Isradipine