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Carboxyl Tail Region of the Kv2.2 Subunit Mediates Novel Developmental Regulation of Channel Density

¹Department of Physiology and Biophysics C-240, ²Medical Scientist Training Program, University of Colorado Health Sciences Center, Denver, Colorado 80262

Submitted 17 May 2004; accepted in final form 4 August 2004

Molecular mechanisms underlying the acquisition of stable electrical phenotypes in developing neurons remain poorly defined. As Xenopus embryonic spinal neurons mature, they initially exhibit dramatic changes in excitability due to a threefold increase in voltage-gated potassium current (I_Kv) density. Later when mature neurons begin synapse formation, I_Kv density remains stable. Elevation of Kv1.1 and Kv2.1 RNA levels indicates that excess transcript levels of these Kv genes can increase current density in both young and mature neurons. In contrast, Kv2.2 overexpression increases I_Kv density in young but not mature neurons despite the presence of protein translated from injected RNA at this stage. Because protein domains can determine biophysical as well as subcellular localization properties of channel subunits, we tested whether a region of the Kv2.2 subunit regulated functional expression in mature neurons. We focused on the large cytoplasmic carboxy tail, a region that differs most between Kv2.2 and the structurally related Kv2.1 subunit. Chimeric Kv2 subunits were generated in which different regions of the large cytoplasmic carboxyl tail were exchanged between Kv2.1 and Kv2.2 subunits. All chimeric Kv2 subunits induced voltage-gated potassium currents when expressed heterologously in oocytes. In vivo chimeric subunits increased I_Kv density in young neurons on overexpression in the developing embryo. In contrast, in mature neurons, only those chimeras lacking a domain in the proximal carboxy terminus, proxC, increased I_Kv density when overexpressed. Thus the proxC domain mediates developmental and subunit-specific regulation of I_Kv and identifies a novel function for protein domains.

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