Figure 5. Point mutations in Cav1.

Figure 5

Point mutations in Cav1.2 segment IIIS6 reveal correlation between inactivation and PAA-sensitivity. A) α-Helical representation of Cav1.2 segment IIIS6 forming part of the highly PAA sensitive Cav1.1/Cav2.1 chimera AL1.24 IIIS6 amino acid residues contributing to PAA- and DIL-sensitivity5,40 (fig. 1D) are shown in black. Inactivation determinants close to the inner channel mouth (I1163, F1164 and V1165 corresponding to IFV-inactivation motif39) are highlighted in open circles. B) PAA-sensitivity of chimera AL1 and mutants F1164A and IF1163,1164AA (inactivating at a slower rate) were estimated as use-dependent channel inhibition by 100 μM (-)gallopamil (10 100 ms-pulses from -80 mV to 10 mV at 0.1 Hz). The most rapidly inactivating construct AL1 displays the highest apparent PAA-sensitivity. I1163A and to a greater extend double mutation IF1163,1164AA gradually slow the rate of channel inactivation and channel inhibition by (-)gallopamil (see ref. 41 for a similar role of V1165 in DIL-sensitivity). C) A correlation (R=0.92) between the rate of channel inactivation (current decay during 100 ms) and drug-sensitivity (use-dependent channel block) of various AL1 mutants. Data reproduced from reference 39 with permission.

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

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