Molecular localization of regions in the L-type calcium channel critical for dihydropyridine action.
Sensitivity to dihydropyridines (DHPs) is a distinct characteristic that differentiates L-type Ca2+ channels from T-, N-, and P-type Ca2+ channels. To identify regions necessary for the functional effects of DHPs, chimeric Ca2+ channels were constructed in which portions of motif III or motif IV of a DHP-insensitive brain Ca2+ channel, BI-2, were introduced into the DHP-sensitive cardiac L-type Ca2+ channel. The resultant chimeric Ca2+ channels were expressed in Xenopus oocytes, and the effects of a DHP agonist and antagonist were studied. The results show that the linker region between S5 and S6 in motif IV of the L-type Ca2+ channel is a major site for DHP action. The DHP agonist and antagonist molecules interact with distinct sites on the alpha 1 subunit of the L-type Ca2+ channel. The data further show that the SS2-S6 region of motif III is not involved in DHP action but may be an important structural component of inactivation.
Tang
S
S
Department of Pharmacology and Cell Biophysics, University of Cincinnati, Ohio 45267-0575.
Yatani
A
A
Bahinski
A
A
Mori
Y
Y
Schwartz
A
A
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D004095:Dihydropyridines / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D017433:Protein Structure, Secondary; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014981:Xenopus
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D046911:Macromolecular Substances; D011993:Recombinant Fusion Proteins