Abstract
In the present study we have used two-electrode voltage-clamping of Xenopus oocytes expressing either Kv1.1 or Shaker B (ShB) delta 6-46 K+ channels to examine the effects of 4-aminopyridine (4-AP) on the process of slow inactivation. Neither of these channels exhibits fast inactivation. Channel activation was required for block by 4-AP in both channel types. In the absence of drug, inactivation of Kv1.1 and ShB delta 6-46 channels at 0 mV was biexponential [tau fast = 7.8 +/- 0.3 sec, tau slow = 33.9 +/- 0.9 sec, and Aslow/(Afast + Aslow) = 0.79 +/- 0.02 (n = 10) for Kv1.1 and tau fast = 3.5 +/- 0.4 sec, tau slow = 13.1 +/- 1.8 sec, and Aslow/(Afast + Aslow) = 0.35 +/- 0.06 (n = 3) for ShB delta 6-46]. In the presence of 4-AP, the rates of inactivation of Kv1.1 and ShB delta 6-46 were markedly slowed, resulting in a crossover phenomenon where, in the presence of drug, the outward current was smaller than control at the beginning of the depolarizing pulse but crossed over during the pulse to become larger than the control. The most obvious change induced by 0.2 mM 4-AP was a 2-fold slowing of the slow phase of inactivation [tau fast = 3.9 +/- 1.1 sec, tau slow = 67.1 +/- 3.6 sec, and Aslow/(Afast + Aslow) = 0.85 +/- 0.04 (n = 4) for Kv1.1 and tau fast = 3.5 +/- 0.4 sec, tau slow = 23.7 +/- 2.6 sec, and Aslow/(Afast + Aslow) = 0.75 +/- 0.02 (n = 3) for ShB delta 6-46, in the presence of 0.2 mM 4-AP]. In addition, there was a significant increase in the contribution of the slower phase of inactivation of ShB delta 6-46 channels in the presence of 4-AP. The slowed inactivation in the presence of 4-AP was accompanied by removal of 4-AP block. These results are consistent with the processes of 4-AP block and slow inactivation of Kv1.1 and ShB delta 6-46 channels being mutually exclusive.
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|