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Inactivation determinants in segment IIIS6 of Ca_v3.1

R. Marksteiner, P. Schurr, S. Berjukow, E. Margreiter, E. Perez-Reyes * and S. Hering

1. Low threshold, T-type, Ca²⁺ channels of the Ca_v3 family display the fastest inactivation kinetics among all voltage-gated Ca²⁺ channels. The molecular inactivation determinants of this channel family are largely unknown. Here we investigate whether segment IIIS6 plays a role in Ca_v3.1 inactivation as observed previously in high voltage-activated Ca²⁺ channels.
2. Amino acids that are identical in IIIS6 segments of all Ca²⁺ channel subtypes were mutated to alanine (F1505A, F1506A, N1509A, F1511A, V1512A, F1519A, FV1511/1512AA). Additionally M1510 was mutated to isoleucine and alanine.
3. The kinetic properties of the mutants were analysed with the two-microelectrode voltage-clamp technique after expression in Xenopus oocytes. The time constant for the barium current (I_Ba) inactivation, _inact, of wild-type channels at -20 mV was 9.5 ± 0.4 ms; the corresponding time constants of the mutants ranged from 9.2 ± 0.4 ms in V1512A to 45.7 ± 5.2 ms (4.8-fold slowing) in M1510I. Recovery at -80 mV was most significantly slowed by V1512A and accelerated by F1511A.
4. We conclude that amino acids M1510, F1511 and V1512 corresponding to previously identified inactivation determinants in IIIS6 of Ca_v2.1 (Hering et al. 1998) have a significant role in Ca_v3.1 inactivation. These data suggest common elements in the molecular architecture of the inactivation mechanism in high and low threshold Ca²⁺ channels.

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