Kvβ Subunit Oxidoreductase Activity and Kv1 Potassium Channel Trafficking*

By C. R. Campomanes, K. Carroll, L. Manganas, M. E. Hershberger, Belvin Gong, Dana E. Antonucci, K. Rhodes, J. Trimmer. Journal of Biological Chemistry, 2002

85 citations recorded by the source corpus.

Voltage-gated Kv1 potassium channels consist of pore-forming α subunits and cytoplasmic Kvβ subunits. The latter play diverse roles in modulating the gating, stability, and trafficking of Kv1 channels. The crystallographic structure of the Kvβ2 subunit revealed surprising structural homology with aldo-keto reductases, including a triosephosphate isomerase barrel structure, conservation of key catalytic residues, and a bound NADP+ cofactor (Gulbis, J. M., Mann, S., and MacKinnon, R. (1999) Cell 90, 943–952). Each Kv1-associated Kvβ subunit (Kvβ1.1, Kvβ1.2, Kvβ2, and Kvβ3) shares striking amino acid conservation in key catalytic and cofactor binding residues. Here, by a combination of structural modeling and biochemical and cell biological analyses of structure-based mutations, we investigate the potential role for putative Kvβ subunit enzymatic activity in the trafficking of Kv1 channels. We found that all Kvβ subunits promote cell surface expression of coexpressed Kv1.2 α subunits in transfected COS-1 cells. Kvβ1.1 and Kvβ2 point mutants lacking a key catalytic tyrosine residue found in the active site of all aldo-keto reductases have wild-type trafficking characteristics. However, mutations in residues within the NADP+ binding pocket eliminated effects on Kv1.2 trafficking. In cultured hippocampal neurons, Kvβ subunit coexpression led to axonal targeting of Kv1.2, recapitulating the Kv1.2 localization observed in many brain neurons. Similar to the trafficking results in COS-1 cells, mutations within the cofactor binding pocket reduced axonal targeting of Kv1.2, whereas those in the catalytic tyrosine did not. Together, these data suggest that NADP+ binding and/or the integrity of the binding pocket structure, but not catalytic activity, of Kvβ subunits is required for intracellular trafficking of Kv1 channel complexes in mammalian cells and for axonal targeting in neurons.

Subfields: Cardiology and Cardiovascular Medicine, Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e3b7b1482ce168306956dc11cc376c4d9f953e57

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In Cellular and Molecular Neuroscience

1. E. Nestler
2. V. Krishnan
3. S. Russo
4. W. Renthal
5. Arvind Kumar
6. O. Berton
7. R. Neve
8. D. Lagace

In Molecular Biology

1. E. Nestler
2. V. Krishnan
3. S. Russo
4. W. Renthal
5. Arvind Kumar
6. D. Lagace
7. G. Koob
8. Colleen A. Mcclung

Citations in the corpus

• Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. (2007, background): “, 2007) HSV-dnK [Kcnab2 double-mutant: S188A & R189L] (Campomanes et al., 2002; Gulbis et al., 1999) Recombinant BDNF (a generous gift from Regeneron Pharmaceuticals, Graham et al.”