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Modulation of slow inactivation in class A Ca²⁺ channels by -subunits

Stanislav Sokolov, Regina G. Weiß, Evgeni N. Timin * and Steffen Hering

1. -subunit modulation of slow inactivation of class A calcium (Ca²⁺) channels was studied with two-microlectrode voltage clamp after expression of the _1A- (BI-2) together with _1a-, _2a-, ₃- or ₄-subunits in Xenopus oocytes.

2. On- and off-rates of slow inactivation were estimated from the kinetics of recovery from slow inactivation. Ca²⁺ channels with an _1A/-subunit composition inducing the slower rate of fast inactivation displayed the faster rate of slow inactivation. The corresponding order of slow inactivation time constants (_onset) was: _1A/_2a, 33 ± 3 s; _1A/₄, 42 ± 4 s; _1A/_1a, 59 ± 4 s; _1A/₃, 67 ± 5 s (n 7).

3. Recovery of class A Ca²⁺ channels from slow inactivation was voltage dependent and accelerated at hyperpolarized voltages. At a given holding potential recovery kinetics were not significantly modulated by different -subunits.

4. Two mutations in segment IIIS6 (IF1612/1613AA) slowed fast inactivation and accelerated the onset of slow inactivation in the resulting mutant (_1A/IF-AA/₃) in a similar manner as coexpression of the _2a-subunit. Recovery from slow inactivation was slightly slowed in the double mutant.

5. Our data suggest that class A Ca²⁺ channels enter the 'slow inactivated' state more willingly from the open than from the 'fast inactivated' state. The rate of slow inactivation is, therefore, indirectly modulated by different -subunits.

6. Fast and slow inactivation in class A Ca²⁺ channels appears to represent structurally independent conformational changes. Fast inactivation is not a prerequisite for slow inactivation.