Transfer of 1,4-Dihydropyridine Sensitivity from L-Type to Class A (BI) Calcium Channels

AbstractL-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 α1A/α1S construct. This chimera fully exhibits the DHP sensitivity of channels formed by L-type α1 subunits. In addition, it displays the electrophysiological properties of α1A, as well as its sensitivity toward the peptide toxins ω-agatoxin IVA and ω-conotoxin MVIIC