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Institut für Pharmakologie und Toxikologie der Technischen
Universität München, 80802 München, Germany
To elucidate the mechanism underlying the interaction between the
L-type Ca2+ channel and the dihydropyridines (DHPs),
contribution of the repeat III was studied by constructing chimeras
between the DHP-sensitive 
1C and DHP-insensitive 1E subunits. The
chimeras were transiently expressed in human embryonic kidney 293 cells
and the whole-cell Ba2+ current (IBa) was
recorded. Mutating Thr1061 to Tyr in IIIS5 of the 1C sequence
completely abolished the inhibition and stimulation of IBa
by the antagonist (+)-isradipine and agonist (
)-Bay K 8644, whereas
mutating Gln1065 to Met in IIIS5 decreased the affinity for isradipine
100-fold without affecting the stimulating effect of Bay K 8644. The
conserved amino acid residue Tyr1174 in IIIS6 of the 1C subunit was
necessary for the high affinity DHP block. The DHP-dependent block and
stimulation of IBa were transferred to the 1E channel by
the mutation of two amino acid residues in IIIS5 (Y1295T, M1299Q),
three residues in IIIS6 (F1406I, F1409I, V1414M) and three residues in
IVS6 (I1706Y, F1707M, L1714I). The mutated 1E channel was stimulated
2.8-fold by 1 µM Bay K 8644 and blocked by isradipine
with an IC50 value of 60 nM. These results show
that mutation of Thr1061 in the 1C sequence results in a DHP-insensitive L-type channel and that transfer of the high affinity DHP sensitivity requires mutation of eight amino acid residues in the
1E sequence.
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