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Separable effects of human Kv1.2 N- and C-termini on inactivation and expression of human Kv1.4

E. A. Accili, Y. A. Kuryshev *, B. A. Wible ¹ and A. M. Brown *

1. The Kv subunits of voltage-gated K⁺ channels alter the functional expression and gating of non- or slowly inactivating Kv1 subunits via two separate domains. To determine how Kv subunits modulate a rapidly inactivating Kv1 subunit, we did two-microelectrode voltage clamp experiments on human Kv1.4 voltage-gated K⁺ channels expressed heterologously in Xenopus oocytes. In addition we tested a slowly inactivating mutant of Kv1.4 lacking amino acids 2-146 of the N-terminal -ball domain (Kv1.4N2-146). Kv1.4 or Kv1.4N2-146 were co-expressed with either rat Kv2 or human Kv1.2. To separate domain effects, we also used a mutant of Kv1.2 lacking the unique 79 amino acid N-terminal -ball domain (Kv1-C).

2. For the mutant Kv1.4N2-146 we found that Kv1-C or Kv2 increased current amplitude without altering activation or inactivation. By contrast Kv1.2 produced rapid inactivation and slowed deactivation due to block produced by the -ball. The -ball also increased the rate of C-type inactivation in 5 mM, but not 50 mM, external K⁺ consistent with an effect of blockade on K⁺ efflux.

3. For Kv1.4, Kv1-C produced a voltage-independent increase in the rate of inactivation and shifted the inactivation curve to more hyperpolarized potentials, but had no effect on deactivation. Kv1-C, Kv2 and Kv1.2 slowed recovery from inactivation similarly, thereby excluding involvement of the -ball. Kv1.2 produced an additional more rapid, voltage-dependent component of inactivation, significantly reduced peak outward current and shifted steady-state inactivation towards hyperpolarized potentials.

4. Yeast two-hybrid studies showed that - interaction was restricted to the N-terminus of Kv1.4 and the C-terminus of Kv1.2 or Kv2. Direct interaction with the -ball did not occur. Our interpretation is that Kv1-C and Kv2 enhanced N-type inactivation produced by the Kv1.4 -ball allosterically.

5. We propose that Kv1.2 has three effects on Kv1.4, the first two of which it shares with Kv2. First, Kv1-C and Kv2 have a current-enhancing effect. Second, Kv1-C and Kv2 increase block by the -ball allosterically. Third, the -ball of K1.2 directly blocks both Kv1.4 and Kv1.4N2-146. When both - and -balls are present, competition for their respective binding sites slows the block produced by either ball.

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