Figure 3. Single amino acids in segment IVS6 of a diltiazem-sensitive Cav2.

Figure 3

Single amino acids in segment IVS6 of a diltiazem-sensitive Cav2.1 mutant affect drug sensitivity and channel inactivation. A) a-Helical representation of Cav2.1 segment IVS6. Transfer of four Cav1.2 amino acids (Y, A, I, M, highlighted as black circles, a1A numbering, accession number: P27884) enhances DIL- (and PAA- ) sensitivity.25 B) Use-dependent IBa inhibition by 100 μM d-cis-diltiazem (DIL) during a train of 15 pulses applied at 0.1 Hz. Wild type Cav2.1 (upper left traces) is barely drug-sensitive. A triple mutant AL2525 (Y, A, I from Cav1.2) shows a high sensitivity for d-cis-diltiazem and displays a faster inactivation than wild type (upper right traces). Transfer of an additional L-type residue (F1805M) further increases the rate of inactivation and apparent drug-sensitivity of quadruple mutant (Y,M,A,I; bottom left traces). Mutating A1808 back to S (double mutant Y, I; middle left) or I1811 back to M (double mutant Y, A; middle right) impaires inactivation and apparent DIL-sensitivity. Substitution of Y1804 back to I in double mutant A, I (bottom right) reduces use-dependent block without considerably slowing inactivation kinetics (compared to AL25, top right). Reproduced from reference 25 with permission.

From: Calcium Channel Block and Inactivation: Insights from Structure-Activity Studies

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